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Johnston JG, Welch AK, Cain BD, Sayeski PP, Gumz ML, Wingo CS. Aldosterone: Renal Action and Physiological Effects. Compr Physiol 2023; 13:4409-4491. [PMID: 36994769 PMCID: PMC11472823 DOI: 10.1002/cphy.c190043] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/31/2023]
Abstract
Aldosterone exerts profound effects on renal and cardiovascular physiology. In the kidney, aldosterone acts to preserve electrolyte and acid-base balance in response to changes in dietary sodium (Na+ ) or potassium (K+ ) intake. These physiological actions, principally through activation of mineralocorticoid receptors (MRs), have important effects particularly in patients with renal and cardiovascular disease as demonstrated by multiple clinical trials. Multiple factors, be they genetic, humoral, dietary, or otherwise, can play a role in influencing the rate of aldosterone synthesis and secretion from the adrenal cortex. Normally, aldosterone secretion and action respond to dietary Na+ intake. In the kidney, the distal nephron and collecting duct are the main targets of aldosterone and MR action, which stimulates Na+ absorption in part via the epithelial Na+ channel (ENaC), the principal channel responsible for the fine-tuning of Na+ balance. Our understanding of the regulatory factors that allow aldosterone, via multiple signaling pathways, to function properly clearly implicates this hormone as central to many pathophysiological effects that become dysfunctional in disease states. Numerous pathologies that affect blood pressure (BP), electrolyte balance, and overall cardiovascular health are due to abnormal secretion of aldosterone, mutations in MR, ENaC, or effectors and modulators of their action. Study of the mechanisms of these pathologies has allowed researchers and clinicians to create novel dietary and pharmacological targets to improve human health. This article covers the regulation of aldosterone synthesis and secretion, receptors, effector molecules, and signaling pathways that modulate its action in the kidney. We also consider the role of aldosterone in disease and the benefit of mineralocorticoid antagonists. © 2023 American Physiological Society. Compr Physiol 13:4409-4491, 2023.
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Affiliation(s)
- Jermaine G Johnston
- Division of Nephrology, Hypertension and Renal Transplantation, Department of Medicine, University of Florida, Gainesville, Florida, USA
- Department of Physiology and Functional Genomics, University of Florida, Gainesville, Florida, USA
- Nephrology Section, Veteran Administration Medical Center, North Florida/South Georgia Malcom Randall Department of Veterans Affairs Medical Center, Gainesville, Florida, USA
| | - Amanda K Welch
- Division of Nephrology, Hypertension and Renal Transplantation, Department of Medicine, University of Florida, Gainesville, Florida, USA
- Nephrology Section, Veteran Administration Medical Center, North Florida/South Georgia Malcom Randall Department of Veterans Affairs Medical Center, Gainesville, Florida, USA
| | - Brian D Cain
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA
| | - Peter P Sayeski
- Department of Physiology and Functional Genomics, University of Florida, Gainesville, Florida, USA
| | - Michelle L Gumz
- Division of Nephrology, Hypertension and Renal Transplantation, Department of Medicine, University of Florida, Gainesville, Florida, USA
- Department of Physiology and Functional Genomics, University of Florida, Gainesville, Florida, USA
- Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, Florida, USA
- Nephrology Section, Veteran Administration Medical Center, North Florida/South Georgia Malcom Randall Department of Veterans Affairs Medical Center, Gainesville, Florida, USA
| | - Charles S Wingo
- Division of Nephrology, Hypertension and Renal Transplantation, Department of Medicine, University of Florida, Gainesville, Florida, USA
- Department of Physiology and Functional Genomics, University of Florida, Gainesville, Florida, USA
- Nephrology Section, Veteran Administration Medical Center, North Florida/South Georgia Malcom Randall Department of Veterans Affairs Medical Center, Gainesville, Florida, USA
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Johnstone EKM, Abhayawardana RS, See HB, Seeber RM, O'Brien SL, Thomas WG, Pfleger KDG. Complex interactions between the angiotensin II type 1 receptor, the epidermal growth factor receptor and TRIO-dependent signaling partners. Biochem Pharmacol 2021; 188:114521. [PMID: 33741329 DOI: 10.1016/j.bcp.2021.114521] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 03/04/2021] [Accepted: 03/10/2021] [Indexed: 12/13/2022]
Abstract
Transactivation of the epidermal growth factor receptor (EGFR) by the angiotensin II (AngII) type 1 (AT1) receptor is involved in AT1 receptor-dependent growth effects and cardiovascular pathologies, however the mechanisms underpinning this transactivation are yet to be fully elucidated. Recently, a potential intermediate of this process was identified following the discovery that a kinase called TRIO was involved in AngII/AT1 receptor-mediated transactivation of EGFR. To investigate the mechanisms by which TRIO acts as an intermediate in AngII/AT1 receptor-mediated EGFR transactivation we used bioluminescence resonance energy transfer (BRET) assays to investigate proximity between the AT1 receptor, EGFR, TRIO and other proteins of interest. We found that AngII/AT1 receptor activation caused a Gαq-dependent increase in proximity of TRIO with Gγ2 and the AT1-EGFR heteromer, as well as trafficking of TRIO towards the Kras plasma membrane marker and into early, late and recycling endosomes. In contrast, we found that AngII/AT1 receptor activation caused a Gαq-independent increase in proximity of TRIO with Grb2, GRK2 and PKCζ, as well as trafficking of TRIO up to the plasma membrane from the Golgi. Furthermore, we confirmed the proximity between the AT1 receptor and the EGFR using the Receptor-Heteromer Investigation Technology, which showed AngII-induced recruitment of Grb2, GRK2, PKCζ, Gγ2 and TRIO to the EGFR upon AT1 coexpression. In summary, our results provide further evidence for the existence of the AT1-EGFR heteromer and reveal potential mechanisms by which TRIO contributes to the transactivation process.
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Affiliation(s)
- Elizabeth K M Johnstone
- Molecular Endocrinology and Pharmacology, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia 6009, Australia; Centre for Medical Research, The University of Western Australia, Crawley, Western Australia 6009, Australia; Australian Research Council Centre for Personalised Therapeutics Technologies, Australia.
| | - Rekhati S Abhayawardana
- Molecular Endocrinology and Pharmacology, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia 6009, Australia; Centre for Medical Research, The University of Western Australia, Crawley, Western Australia 6009, Australia; Australian Research Council Centre for Personalised Therapeutics Technologies, Australia
| | - Heng B See
- Molecular Endocrinology and Pharmacology, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia 6009, Australia; Centre for Medical Research, The University of Western Australia, Crawley, Western Australia 6009, Australia; Australian Research Council Centre for Personalised Therapeutics Technologies, Australia
| | - Ruth M Seeber
- Molecular Endocrinology and Pharmacology, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia 6009, Australia; Centre for Medical Research, The University of Western Australia, Crawley, Western Australia 6009, Australia; Australian Research Council Centre for Personalised Therapeutics Technologies, Australia
| | - Shannon L O'Brien
- Receptor Biology Group, The School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia 4072, Queensland, Australia; Institute of Metabolism and Systems Research (IMSR) and Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham, Birmingham B15 2TT, United Kingdom
| | - Walter G Thomas
- Receptor Biology Group, The School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia 4072, Queensland, Australia
| | - Kevin D G Pfleger
- Molecular Endocrinology and Pharmacology, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia 6009, Australia; Centre for Medical Research, The University of Western Australia, Crawley, Western Australia 6009, Australia; Australian Research Council Centre for Personalised Therapeutics Technologies, Australia; Dimerix Limited, Nedlands, Western Australia 6009, Australia.
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Abstract
PURPOSE OF REVIEW The renin-angiotensin-aldosterone system (RAAS) plays important roles in regulating blood pressure and body fluid, which contributes to the pathophysiology of hypertension and cardiovascular/renal diseases. However, accumulating evidence has further revealed the complexity of this signal transduction system, including direct interactions with other receptors and proteins. This review focuses on recent research advances in RAAS with an emphasis on its receptors. RECENT FINDINGS Both systemically and locally produced angiotensin II (Ang II) bind to Ang II type 1 receptor (AT1R) and elicit strong biological functions. Recent studies have shown that Ang II-induced activation of Ang II type 2 receptor (AT2R) elicits the opposite functions to those of AT1R. However, accumulating evidence has now expanded the components of RAAS, including (pro)renin receptor, angiotensin-converting enzyme 2, angiotensin 1-7, and Mas receptor. In addition, the signal transductions of AT1R and AT2R are regulated by not only Ang II but also its receptor-associated proteins such as AT1R-associated protein and AT2R-interacting protein. Recent studies have indicated that inappropriate activation of local mineralocorticoid receptor contributes to cardiovascular and renal tissue injuries through aldosterone-dependent and -independent mechanisms. Since the mechanisms of RAAS signal transduction still remain to be elucidated, further investigations are necessary to explore novel molecular mechanisms of the RAAS, which will provide alternative therapeutic agents other than existing RAAS blockers.
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Lu Y, Li X, Zhou H, Shao S, He S, Hong M, Liu J, Xu Y, Wu Y, Zhu D, Wang J, Gao P. Transactivation domain of Krüppel‐like factor 15 negatively regulates angiotensin II–induced adventitial inflammation and fibrosis. FASEB J 2019; 33:6254-6268. [DOI: 10.1096/fj.201801809r] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- Yuan‐Yuan Lu
- Department of HypertensionState Key Laboratory of Medical GenomicsShanghai Key Laboratory of HypertensionRuijin HospitalShanghai Jiao Tong University School of Medicine Shanghai China
| | - Xiao‐Dong Li
- Department of HypertensionState Key Laboratory of Medical GenomicsShanghai Key Laboratory of HypertensionRuijin HospitalShanghai Jiao Tong University School of Medicine Shanghai China
- Shanghai Institute of Hypertension Shanghai China
| | - Han‐Dan Zhou
- Department of HypertensionState Key Laboratory of Medical GenomicsShanghai Key Laboratory of HypertensionRuijin HospitalShanghai Jiao Tong University School of Medicine Shanghai China
| | - Shuai Shao
- Department of HypertensionState Key Laboratory of Medical GenomicsShanghai Key Laboratory of HypertensionRuijin HospitalShanghai Jiao Tong University School of Medicine Shanghai China
| | - Shun He
- Department of HypertensionState Key Laboratory of Medical GenomicsShanghai Key Laboratory of HypertensionRuijin HospitalShanghai Jiao Tong University School of Medicine Shanghai China
| | - Mo‐Na Hong
- Department of HypertensionState Key Laboratory of Medical GenomicsShanghai Key Laboratory of HypertensionRuijin HospitalShanghai Jiao Tong University School of Medicine Shanghai China
| | - Jia‐Chen Liu
- Department of HypertensionState Key Laboratory of Medical GenomicsShanghai Key Laboratory of HypertensionRuijin HospitalShanghai Jiao Tong University School of Medicine Shanghai China
| | - Ying‐Le Xu
- Department of HypertensionState Key Laboratory of Medical GenomicsShanghai Key Laboratory of HypertensionRuijin HospitalShanghai Jiao Tong University School of Medicine Shanghai China
- Shanghai Institute of Hypertension Shanghai China
| | - Yong‐Jie Wu
- Department of HypertensionState Key Laboratory of Medical GenomicsShanghai Key Laboratory of HypertensionRuijin HospitalShanghai Jiao Tong University School of Medicine Shanghai China
- Shanghai Institute of Hypertension Shanghai China
| | - Ding‐Liang Zhu
- Department of HypertensionState Key Laboratory of Medical GenomicsShanghai Key Laboratory of HypertensionRuijin HospitalShanghai Jiao Tong University School of Medicine Shanghai China
- Shanghai Institute of Hypertension Shanghai China
| | - Ji‐Guang Wang
- Department of HypertensionState Key Laboratory of Medical GenomicsShanghai Key Laboratory of HypertensionRuijin HospitalShanghai Jiao Tong University School of Medicine Shanghai China
- Shanghai Institute of Hypertension Shanghai China
| | - Ping‐Jin Gao
- Department of HypertensionState Key Laboratory of Medical GenomicsShanghai Key Laboratory of HypertensionRuijin HospitalShanghai Jiao Tong University School of Medicine Shanghai China
- Shanghai Institute of Hypertension Shanghai China
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Turu G, Balla A, Hunyady L. The Role of β-Arrestin Proteins in Organization of Signaling and Regulation of the AT1 Angiotensin Receptor. Front Endocrinol (Lausanne) 2019; 10:519. [PMID: 31447777 PMCID: PMC6691095 DOI: 10.3389/fendo.2019.00519] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2019] [Accepted: 07/15/2019] [Indexed: 12/30/2022] Open
Abstract
AT1 angiotensin receptor plays important physiological and pathophysiological roles in the cardiovascular system. Renin-angiotensin system represents a target system for drugs acting at different levels. The main effects of ATR1 stimulation involve activation of Gq proteins and subsequent IP3, DAG, and calcium signaling. It has become evident in recent years that besides the well-known G protein pathways, AT1R also activates a parallel signaling pathway through β-arrestins. β-arrestins were originally described as proteins that desensitize G protein-coupled receptors, but they can also mediate receptor internalization and G protein-independent signaling. AT1R is one of the most studied receptors, which was used to unravel the newly recognized β-arrestin-mediated pathways. β-arrestin-mediated signaling has become one of the most studied topics in recent years in molecular pharmacology and the modulation of these pathways of the AT1R might offer new therapeutic opportunities in the near future. In this paper, we review the recent advances in the field of β-arrestin signaling of the AT1R, emphasizing its role in cardiovascular regulation and heart failure.
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Affiliation(s)
- Gábor Turu
- Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
- MTA-SE Laboratory of Molecular Physiology, Semmelweis University, Hungarian Academy of Sciences, Budapest, Hungary
| | - András Balla
- Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
- MTA-SE Laboratory of Molecular Physiology, Semmelweis University, Hungarian Academy of Sciences, Budapest, Hungary
| | - László Hunyady
- Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
- MTA-SE Laboratory of Molecular Physiology, Semmelweis University, Hungarian Academy of Sciences, Budapest, Hungary
- *Correspondence: László Hunyady
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Forrester SJ, Booz GW, Sigmund CD, Coffman TM, Kawai T, Rizzo V, Scalia R, Eguchi S. Angiotensin II Signal Transduction: An Update on Mechanisms of Physiology and Pathophysiology. Physiol Rev 2018; 98:1627-1738. [PMID: 29873596 DOI: 10.1152/physrev.00038.2017] [Citation(s) in RCA: 720] [Impact Index Per Article: 102.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The renin-angiotensin-aldosterone system plays crucial roles in cardiovascular physiology and pathophysiology. However, many of the signaling mechanisms have been unclear. The angiotensin II (ANG II) type 1 receptor (AT1R) is believed to mediate most functions of ANG II in the system. AT1R utilizes various signal transduction cascades causing hypertension, cardiovascular remodeling, and end organ damage. Moreover, functional cross-talk between AT1R signaling pathways and other signaling pathways have been recognized. Accumulating evidence reveals the complexity of ANG II signal transduction in pathophysiology of the vasculature, heart, kidney, and brain, as well as several pathophysiological features, including inflammation, metabolic dysfunction, and aging. In this review, we provide a comprehensive update of the ANG II receptor signaling events and their functional significances for potential translation into therapeutic strategies. AT1R remains central to the system in mediating physiological and pathophysiological functions of ANG II, and participation of specific signaling pathways becomes much clearer. There are still certain limitations and many controversies, and several noteworthy new concepts require further support. However, it is expected that rigorous translational research of the ANG II signaling pathways including those in large animals and humans will contribute to establishing effective new therapies against various diseases.
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Affiliation(s)
- Steven J Forrester
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University , Philadelphia, Pennsylvania ; Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center , Jackson, Mississippi ; Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa , Iowa City, Iowa ; and Duke-NUS, Singapore and Department of Medicine, Duke University Medical Center , Durham, North Carolina
| | - George W Booz
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University , Philadelphia, Pennsylvania ; Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center , Jackson, Mississippi ; Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa , Iowa City, Iowa ; and Duke-NUS, Singapore and Department of Medicine, Duke University Medical Center , Durham, North Carolina
| | - Curt D Sigmund
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University , Philadelphia, Pennsylvania ; Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center , Jackson, Mississippi ; Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa , Iowa City, Iowa ; and Duke-NUS, Singapore and Department of Medicine, Duke University Medical Center , Durham, North Carolina
| | - Thomas M Coffman
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University , Philadelphia, Pennsylvania ; Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center , Jackson, Mississippi ; Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa , Iowa City, Iowa ; and Duke-NUS, Singapore and Department of Medicine, Duke University Medical Center , Durham, North Carolina
| | - Tatsuo Kawai
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University , Philadelphia, Pennsylvania ; Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center , Jackson, Mississippi ; Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa , Iowa City, Iowa ; and Duke-NUS, Singapore and Department of Medicine, Duke University Medical Center , Durham, North Carolina
| | - Victor Rizzo
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University , Philadelphia, Pennsylvania ; Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center , Jackson, Mississippi ; Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa , Iowa City, Iowa ; and Duke-NUS, Singapore and Department of Medicine, Duke University Medical Center , Durham, North Carolina
| | - Rosario Scalia
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University , Philadelphia, Pennsylvania ; Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center , Jackson, Mississippi ; Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa , Iowa City, Iowa ; and Duke-NUS, Singapore and Department of Medicine, Duke University Medical Center , Durham, North Carolina
| | - Satoru Eguchi
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University , Philadelphia, Pennsylvania ; Department of Pharmacology and Toxicology, School of Medicine, University of Mississippi Medical Center , Jackson, Mississippi ; Department of Pharmacology, Center for Hypertension Research, Roy J. and Lucille A. Carver College of Medicine, University of Iowa , Iowa City, Iowa ; and Duke-NUS, Singapore and Department of Medicine, Duke University Medical Center , Durham, North Carolina
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Zhang M, Wu G. Mechanisms of the anterograde trafficking of GPCRs: Regulation of AT1R transport by interacting proteins and motifs. Traffic 2018; 20:110-120. [PMID: 30426616 DOI: 10.1111/tra.12624] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 10/29/2018] [Accepted: 11/08/2018] [Indexed: 12/11/2022]
Abstract
Anterograde cell surface transport of nascent G protein-coupled receptors (GPCRs) en route from the endoplasmic reticulum (ER) through the Golgi apparatus represents a crucial checkpoint to control the amount of the receptors at the functional destination and the strength of receptor activation-elicited cellular responses. However, as compared with extensively studied internalization and recycling processes, the molecular mechanisms of cell surface trafficking of GPCRs are relatively less defined. Here, we will review the current advances in understanding the ER-Golgi-cell surface transport of GPCRs and use angiotensin II type 1 receptor as a representative GPCR to discuss emerging roles of receptor-interacting proteins and specific motifs embedded within the receptors in controlling the forward traffic of GPCRs along the biosynthetic pathway.
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Affiliation(s)
- Maoxiang Zhang
- Guangzhou University of Chinese Medicine, Guangzhou, China.,Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia
| | - Guangyu Wu
- Department of Pharmacology and Toxicology, Medical College of Georgia, Augusta University, Augusta, Georgia
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Abstract
Phospholipases are lipolytic enzymes that hydrolyze phospholipid substrates at specific ester bonds. Phospholipases are widespread in nature and play very diverse roles from aggression in snake venom to signal transduction, lipid mediator production, and metabolite digestion in humans. Phospholipases vary considerably in structure, function, regulation, and mode of action. Tremendous advances in understanding the structure and function of phospholipases have occurred in the last decades. This introductory chapter is aimed at providing a general framework of the current understanding of phospholipases and a discussion of their mechanisms of action and emerging biological functions.
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Jiang D, Zhuang J, Peng W, Lu Y, Liu H, Zhao Q, Chi C, Li X, Zhu G, Xu X, Yan C, Xu Y, Ge J, Pang J. Phospholipase Cγ1 Mediates Intima Formation Through Akt-Notch1 Signaling Independent of the Phospholipase Activity. J Am Heart Assoc 2017; 6:JAHA.117.005537. [PMID: 28698260 PMCID: PMC5586285 DOI: 10.1161/jaha.117.005537] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Background Vascular smooth muscle cell proliferation, migration, and dedifferentiation are critical for vascular diseases. Recently, it was demonstrated that Notch receptors have opposing effects on intima formation after vessel injury. Therefore, it is important to investigate the specific regulatory pathways that activate the different Notch receptors. Methods and Results There was a time‐ and dose‐dependent activation of Notch1 by angiotensin II and platelet‐derived growth factor in vascular smooth muscle cells. When phospholipase Cγ1 (PLCγ1) expression was reduced by small interfering RNA, Notch1 activation and Hey2 expression (Notch target gene) induced by angiotensin II or platelet‐derived growth factor were remarkably inhibited, while Notch2 degradation was not affected. Mechanistically, we observed an association of PLCγ1 and Akt, which increased after angiotensin II or platelet‐derived growth factor stimulation. PLCγ1 knockdown significantly inhibited Akt activation. Importantly, PLCγ1 phospholipase site mutation (no phospholipase activity) did not affect Akt activation. Furthermore, PLCγ1 depletion inhibited platelet‐derived growth factor–induced vascular smooth muscle cell proliferation, migration, and dedifferentiation, while it increased apoptosis. In vivo, PLCγ1 and control small interfering RNA were delivered periadventitially in pluronic gel and complete carotid artery ligation was performed. Morphometric analysis 21 days after ligation demonstrated that PLCγ1 small interfering RNA robustly attenuated intima area and intima/media ratio compared with the control group. Conclusions PLCγ1‐Akt–mediated Notch1 signaling is crucial for intima formation. This effect is attributable to PLCγ1‐Akt interaction but not PLCγ1 phospholipase activity. Specific inhibition of the PLCγ1 and Akt interaction will be a promising therapeutic strategy for preventing vascular remodeling.
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Affiliation(s)
- Dongyang Jiang
- Department of Cardiology, Pan-Vascular Research Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jianhui Zhuang
- Department of Cardiology, Pan-Vascular Research Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Wenhui Peng
- Department of Cardiology, Pan-Vascular Research Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Yuyan Lu
- Department of Cardiology, Pan-Vascular Research Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Hao Liu
- Department of Cardiology, Pan-Vascular Research Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Qian Zhao
- Department of Cardiology, Pan-Vascular Research Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Chen Chi
- Department of Cardiology, Pan-Vascular Research Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiankai Li
- Department of Cardiology, Pan-Vascular Research Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Guofu Zhu
- Department of Cardiology, Pan-Vascular Research Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Xiangbin Xu
- Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY
| | - Chen Yan
- Department of Cardiology, Pan-Vascular Research Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.,Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY
| | - Yawei Xu
- Department of Cardiology, Pan-Vascular Research Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Junbo Ge
- Department of Cardiology, Pan-Vascular Research Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China
| | - Jinjiang Pang
- Department of Cardiology, Pan-Vascular Research Institute, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China .,Aab Cardiovascular Research Institute and Department of Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY
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10
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AT1 receptor signaling pathways in the cardiovascular system. Pharmacol Res 2017; 125:4-13. [PMID: 28527699 DOI: 10.1016/j.phrs.2017.05.008] [Citation(s) in RCA: 160] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Revised: 05/10/2017] [Accepted: 05/11/2017] [Indexed: 01/14/2023]
Abstract
The importance of the renin angiotensin aldosterone system in cardiovascular physiology and pathophysiology has been well described whereas the detailed molecular mechanisms remain elusive. The angiotensin II type 1 receptor (AT1 receptor) is one of the key players in the renin angiotensin aldosterone system. The AT1 receptor promotes various intracellular signaling pathways resulting in hypertension, endothelial dysfunction, vascular remodeling and end organ damage. Accumulating evidence shows the complex picture of AT1 receptor-mediated signaling; AT1 receptor-mediated heterotrimeric G protein-dependent signaling, transactivation of growth factor receptors, NADPH oxidase and ROS signaling, G protein-independent signaling, including the β-arrestin signals and interaction with several AT1 receptor interacting proteins. In addition, there is functional cross-talk between the AT1 receptor signaling pathway and other signaling pathways. In this review, we will summarize an up to date overview of essential AT1 receptor signaling events and their functional significances in the cardiovascular system.
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11
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Hunyady L, Gáborik Z, Vauquelin G, Catt KJ. Review: Structural requirements for signalling and regulation of AT1-receptors. J Renin Angiotensin Aldosterone Syst 2016; 2:S16-S23. [DOI: 10.1177/14703203010020010301] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Affiliation(s)
- László Hunyady
- Department of Physiology, Semmelweis University Medical
School, Budapest, Hungary,
| | - Zsuzsanna Gáborik
- Department of Physiology, Semmelweis University Medical
School, Budapest, Hungary
| | - Georges Vauquelin
- Department of Molecular and Biochemical Pharmacology,
Institute of Molecular Biology and Biotechnology, Free University of Brussels
(VUB), Sint-Genesius Rode, Belgium
| | - Kevin J Catt
- Endocrinology and Reproduction Research Branch, National
Institute of Child Health and Human Development, National Institutes of Health,
Bethesda, USA
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12
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Wang S, Li Y, Miao W, Zhao H, Zhang F, Liu N, Su G, Cai X. Angiopoietin-like protein 2 expression is suppressed by angiotensin II via the angiotensin II type 1 receptor in rat cardiomyocytes. Mol Med Rep 2016; 14:2607-13. [PMID: 27483989 PMCID: PMC4991724 DOI: 10.3892/mmr.2016.5544] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 07/11/2016] [Indexed: 11/05/2022] Open
Abstract
The present study aimed to determine the inhibitory effects of angiotensin II (AngII) on angiopoietin‑like protein 2 (Angptl2) in rat primary cardiomyocytes, and to investigate the potential association between angiotensin II type 1 receptor (AT1R) and these effects. Cardiomyocytes were isolated from 3-day-old Wistar rats, and were cultured and identified. Subsequently, the expression levels of Angptl2 were detected following incubation with various concentrations of AngII for various durations using western blotting, reverse transcription‑quantitative polymerase chain reaction, enzyme-linked immunosorbent assay and immunofluorescence. Finally, under the most appropriate conditions (100 nmol/l AngII, 24 h), the cardiomyocytes were divided into six groups: Normal, AngII, AngII + losartan, normal + losartan, AngII + PD123319 and normal + PD123319 groups, in order to investigate the possible function of AT1R in Angptl2 suppression. Losartan and PD123319 are antagonists of AT1R and angiotensin II type 2 receptor, respectively. The statistical significance of the results was analyzed using Student's t‑test or one‑way analysis of variance. The results demonstrated that Angptl2 expression was evidently suppressed (P<0.05) following incubation with 100 nmol/l AngII for 24 h. Conversely, the expression levels of Angptl2 were significantly increased in the AngII + losartan group compared with the AngII group (P<0.01). However, no significant difference was detected between the AngII + PD123319, normal + losartan or normal + PD123319 groups and the normal group. The present in vitro study indicated that AngII was able to suppress Angptl2 expression, whereas losartan was able to significantly reverse this decrease by inhibiting AT1R.
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Affiliation(s)
- Shuya Wang
- Department of Cardiovascular Medicine, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China
| | - Ying Li
- Department of Cardiovascular Medicine, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China
| | - Wei Miao
- Department of Cardiovascular Medicine, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China
| | - Hong Zhao
- Department of Cardiovascular Medicine, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China
| | - Feng Zhang
- Department of Cardiovascular Medicine, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China
| | - Nan Liu
- Department of Cardiovascular Medicine, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China
| | - Guohai Su
- Department of Cardiovascular Medicine, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China
| | - Xiaojun Cai
- Department of Cardiovascular Medicine, Jinan Central Hospital Affiliated to Shandong University, Jinan, Shandong 250013, P.R. China
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Karnik SS, Unal H, Kemp JR, Tirupula KC, Eguchi S, Vanderheyden PML, Thomas WG. International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli [corrected]. Pharmacol Rev 2015; 67:754-819. [PMID: 26315714 PMCID: PMC4630565 DOI: 10.1124/pr.114.010454] [Citation(s) in RCA: 225] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The renin angiotensin system (RAS) produced hormone peptides regulate many vital body functions. Dysfunctional signaling by receptors for RAS peptides leads to pathologic states. Nearly half of humanity today would likely benefit from modern drugs targeting these receptors. The receptors for RAS peptides consist of three G-protein-coupled receptors—the angiotensin II type 1 receptor (AT1 receptor), the angiotensin II type 2 receptor (AT2 receptor), the MAS receptor—and a type II trans-membrane zinc protein—the candidate angiotensin IV receptor (AngIV binding site). The prorenin receptor is a relatively new contender for consideration, but is not included here because the role of prorenin receptor as an independent endocrine mediator is presently unclear. The full spectrum of biologic characteristics of these receptors is still evolving, but there is evidence establishing unique roles of each receptor in cardiovascular, hemodynamic, neurologic, renal, and endothelial functions, as well as in cell proliferation, survival, matrix-cell interaction, and inflammation. Therapeutic agents targeted to these receptors are either in active use in clinical intervention of major common diseases or under evaluation for repurposing in many other disorders. Broad-spectrum influence these receptors produce in complex pathophysiological context in our body highlights their role as precise interpreters of distinctive angiotensinergic peptide cues. This review article summarizes findings published in the last 15 years on the structure, pharmacology, signaling, physiology, and disease states related to angiotensin receptors. We also discuss the challenges the pharmacologist presently faces in formally accepting newer members as established angiotensin receptors and emphasize necessary future developments.
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Affiliation(s)
- Sadashiva S Karnik
- Department of Molecular Cardiology, Lerner Research Institute of Cleveland Clinic, Cleveland, Ohio (S.S.K., H.U., J.R.K., K.C.T.); Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania (S.E.); Faculty of Sciences and Bioengineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium (P.M.L.V.); and Department of General Physiology, School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia (W.G.T.)
| | - Hamiyet Unal
- Department of Molecular Cardiology, Lerner Research Institute of Cleveland Clinic, Cleveland, Ohio (S.S.K., H.U., J.R.K., K.C.T.); Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania (S.E.); Faculty of Sciences and Bioengineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium (P.M.L.V.); and Department of General Physiology, School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia (W.G.T.)
| | - Jacqueline R Kemp
- Department of Molecular Cardiology, Lerner Research Institute of Cleveland Clinic, Cleveland, Ohio (S.S.K., H.U., J.R.K., K.C.T.); Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania (S.E.); Faculty of Sciences and Bioengineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium (P.M.L.V.); and Department of General Physiology, School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia (W.G.T.)
| | - Kalyan C Tirupula
- Department of Molecular Cardiology, Lerner Research Institute of Cleveland Clinic, Cleveland, Ohio (S.S.K., H.U., J.R.K., K.C.T.); Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania (S.E.); Faculty of Sciences and Bioengineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium (P.M.L.V.); and Department of General Physiology, School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia (W.G.T.)
| | - Satoru Eguchi
- Department of Molecular Cardiology, Lerner Research Institute of Cleveland Clinic, Cleveland, Ohio (S.S.K., H.U., J.R.K., K.C.T.); Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania (S.E.); Faculty of Sciences and Bioengineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium (P.M.L.V.); and Department of General Physiology, School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia (W.G.T.)
| | - Patrick M L Vanderheyden
- Department of Molecular Cardiology, Lerner Research Institute of Cleveland Clinic, Cleveland, Ohio (S.S.K., H.U., J.R.K., K.C.T.); Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania (S.E.); Faculty of Sciences and Bioengineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium (P.M.L.V.); and Department of General Physiology, School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia (W.G.T.)
| | - Walter G Thomas
- Department of Molecular Cardiology, Lerner Research Institute of Cleveland Clinic, Cleveland, Ohio (S.S.K., H.U., J.R.K., K.C.T.); Cardiovascular Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania (S.E.); Faculty of Sciences and Bioengineering Sciences, Vrije Universiteit Brussel, Brussels, Belgium (P.M.L.V.); and Department of General Physiology, School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland, Australia (W.G.T.)
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Balakumar P, Jagadeesh G. Structural determinants for binding, activation, and functional selectivity of the angiotensin AT1 receptor. J Mol Endocrinol 2014; 53:R71-92. [PMID: 25013233 DOI: 10.1530/jme-14-0125] [Citation(s) in RCA: 54] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
The renin-angiotensin system (RAS) plays an important role in the pathophysiology of cardiovascular disorders. Pharmacologic interventions targeting the RAS cascade have led to the discovery of renin inhibitors, angiotensin-converting enzyme inhibitors, and AT(1) receptor blockers (ARBs) to treat hypertension and some cardiovascular and renal disorders. Mutagenesis and modeling studies have revealed that differential functional outcomes are the results of multiple active states conformed by the AT(1) receptor upon interaction with angiotensin II (Ang II). The binding of agonist is dependent on both extracellular and intramembrane regions of the receptor molecule, and as a consequence occupies more extensive area of the receptor than a non-peptide antagonist. Both agonist and antagonist bind to the same intramembrane regions to interfere with each other's binding to exhibit competitive, surmountable interaction. The nature of interactions with the amino acids in the receptor is different for each of the ARBs given the small differences in the molecular structure between drugs. AT(1) receptors attain different conformation states after binding various Ang II analogues, resulting in variable responses through activation of multiple signaling pathways. These include both classical and non-classical pathways mediated through growth factor receptor transactivations, and provide cross-communication between downstream signaling molecules. The structural requirements for AT(1) receptors to activate extracellular signal-regulated kinases 1 and 2 through G proteins, or G protein-independently through β-arrestin, are different. We review the structural and functional characteristics of Ang II and its analogs and antagonists, and their interaction with amino acid residues in the AT(1) receptor.
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Affiliation(s)
- Pitchai Balakumar
- Pharmacology UnitFaculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Kedah Darul Aman, MalaysiaDivision of Cardiovascular and Renal ProductsCenter for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland 20993, USA
| | - Gowraganahalli Jagadeesh
- Pharmacology UnitFaculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Kedah Darul Aman, MalaysiaDivision of Cardiovascular and Renal ProductsCenter for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, Maryland 20993, USA
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Balakumar P, Jagadeesh G. A century old renin-angiotensin system still grows with endless possibilities: AT1 receptor signaling cascades in cardiovascular physiopathology. Cell Signal 2014; 26:2147-60. [PMID: 25007996 DOI: 10.1016/j.cellsig.2014.06.011] [Citation(s) in RCA: 131] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Accepted: 06/27/2014] [Indexed: 12/25/2022]
Abstract
Ang II, the primary effector pleiotropic hormone of the renin-angiotensin system (RAS) cascade, mediates physiological control of blood pressure and electrolyte balance through its action on vascular tone, aldosterone secretion, renal sodium absorption, water intake, sympathetic activity and vasopressin release. It affects the function of most of the organs far beyond blood pressure control including heart, blood vessels, kidney and brain, thus, causing both beneficial and deleterious effects. However, the protective axis of the RAS composed of ACE2, Ang (1-7), alamandine, and Mas and MargD receptors might oppose some harmful effects of Ang II and might promote beneficial cardiovascular effects. Newly identified RAS family peptides, Ang A and angioprotectin, further extend the complexities in understanding the cardiovascular physiopathology of RAS. Most of the diverse actions of Ang II are mediated by AT1 receptors, which couple to classical Gq/11 protein and activate multiple downstream signals, including PKC, ERK1/2, Raf, tyrosine kinases, receptor tyrosine kinases (EGFR, PDGF, insulin receptor), nuclear factor κB and reactive oxygen species (ROS). Receptor activation via G12/13 stimulates Rho-kinase, which causes vascular contraction and hypertrophy. The AT1 receptor activation also stimulates G protein-independent signaling pathways such as β-arrestin-mediated MAPK activation and Src-JAK/STAT. AT1 receptor-mediated activation of NADPH oxidase releases ROS, resulting in the activation of pro-inflammatory transcription factors and stimulation of small G proteins such as Ras, Rac and RhoA. The components of the RAS and the major Ang II-induced signaling cascades of AT1 receptors are reviewed.
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Affiliation(s)
- Pitchai Balakumar
- Pharmacology Unit, Faculty of Pharmacy, AIMST University, Semeling, 08100 Bedong, Kedah Darul Aman, Malaysia.
| | - Gowraganahalli Jagadeesh
- Division of Cardiovascular and Renal Products, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 20993, USA.
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16
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Tovo-Rodrigues L, Roux A, Hutz MH, Rohde LA, Woods AS. Functional characterization of G-protein-coupled receptors: a bioinformatics approach. Neuroscience 2014; 277:764-79. [PMID: 24997265 DOI: 10.1016/j.neuroscience.2014.06.049] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2014] [Revised: 05/22/2014] [Accepted: 06/18/2014] [Indexed: 12/18/2022]
Abstract
Complex molecular and cellular mechanisms regulate G protein-coupled receptors (GPCRs). It is suggested that proteins intrinsically disordered regions (IDRs) are to play a role in GPCR's intra and extracellular regions plasticity, due to their potential for post-translational modification and interaction with other proteins. These regions are defined as lacking a stable three-dimensional (3D) structure. They are rich in hydrophilic and charged, amino acids and are capable to assume different conformations which allow them to interact with multiple partners. In this study we analyzed 75 GPCR involved in synaptic transmission using computational tools for sequence-based prediction of IDRs within a protein. We also evaluated putative ligand-binding motifs using receptor sequences. The disorder analysis indicated that neurotransmitter GPCRs have a significant amount of disorder in their N-terminus, third intracellular loop (3IL) and C-terminus. About 31%, 39% and 53% of human GPCR involved in synaptic transmission are disordered in these regions. Thirty-three percent of receptors show at least one predicted PEST motif, this being statistically greater than the estimate for the rest of human GPCRs. About 90% of the receptors had at least one putative site for dimerization in their 3IL or C-terminus. ELM instances sampled in these domains were 14-3-3, SH3, SH2 and PDZ motifs. In conclusion, the increased flexibility observed in GPCRs, added to the enrichment of linear motifs, PEST and heteromerization sites, may be critical for the nervous system's functional plasticity.
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Affiliation(s)
- L Tovo-Rodrigues
- Department of Genetics, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil; Structural Biology Unit, Integrative Neuroscience Branch, NIDA IRP, NIH, MD, United States
| | - A Roux
- Structural Biology Unit, Integrative Neuroscience Branch, NIDA IRP, NIH, MD, United States
| | - M H Hutz
- Department of Genetics, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - L A Rohde
- Child and Adolescent Psychiatric Division, Department of Psychiatry, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil
| | - A S Woods
- Structural Biology Unit, Integrative Neuroscience Branch, NIDA IRP, NIH, MD, United States.
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17
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Abstract
A series of studies conducted 20 years ago, documenting the cardiac hypertrophy phenotype and its underlying signaling mechanism induced by angiotensin II (Ang II) and mechanical stress, showed a remarkable similarity between the effect of the Gαq agonist and that of mechanical forces on cardiac hypertrophy. Subsequent studies confirmed the involvement of autocrine/paracrine mechanisms, including stretch-induced release of Ang II in load-induced cardiac hypertrophy. Recent studies showed that the Ang II type 1 (AT1) receptor is also directly activated by mechanical forces, suggesting that AT1 receptors play an important role in mediating load-induced cardiac hypertrophy through both ligand- and mechanical stress-dependent mechanisms.
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Affiliation(s)
- Daniela Zablocki
- From the Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, New Jersey Medical School, Rutgers Biomedical and Health Sciences, Newark
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18
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Two distinct calmodulin binding sites in the third intracellular loop and carboxyl tail of angiotensin II (AT(1A)) receptor. PLoS One 2013; 8:e65266. [PMID: 23755207 PMCID: PMC3673938 DOI: 10.1371/journal.pone.0065266] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2013] [Accepted: 04/24/2013] [Indexed: 11/25/2022] Open
Abstract
In this study, we present data that support the presence of two distinct calmodulin binding sites within the angiotensin II receptor (AT1A), at juxtamembrane regions of the N-terminus of the third intracellular loop (i3, amino acids 214–231) and carboxyl tail of the receptor (ct, 302–317). We used bioluminescence resonance energy transfer assays to document interactions of calmodulin with the AT1A holo-receptor and GST-fusion protein pull-downs to demonstrate that i3 and ct interact with calmodulin in a Ca2+-dependent fashion. The former is a 1–12 motif and the latter belongs to 1-5-10 calmodulin binding motif. The apparent Kd of calmodulin for i3 is 177.0±9.1 nM, and for ct is 79.4±7.9 nM as assessed by dansyl-calmodulin fluorescence. Replacement of the tryptophan (W219) for alanine in i3, and phenylalanine (F309 or F313) for alanine in ct reduced their binding affinities for calmodulin, as predicted by computer docking simulations. Exogenously applied calmodulin attenuated interactions between G protein βγ subunits and i3 and ct, somewhat more so for ct than i3. Mutations W219A, F309A, and F313A did not alter Gβγ binding, but reduced the ability of calmodulin to compete with Gβγ, suggesting that calmodulin and Gβγ have overlapping, but not identical, binding requirements for i3 and ct. Calmodulin interference with the Gβγ binding to i3 and ct regions of the AT1A receptor strongly suggests that calmodulin plays critical roles in regulating Gβγ-dependent signaling of the receptor.
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Abstract
STUDY DESIGN Immunohistochemical and biochemical analyses of the rat intervertebral disc (IVD) tissue renin-angiotensin system (tRAS). OBJECTIVE To examine the expression and function of tRAS in the rat IVD. SUMMARY OF BACKGROUND DATA Angiotensin II (Ang II), the major effector of tRAS, is a hormone that contributes to inflammation and fibrosis in many organs. The expression of tRAS in the rat IVD has not been determined. METHODS tRAS expression in rat and bovine IVDs was examined using real-time polymerase chain reaction (rat) and immunohistochemistry (rat and bovine). Rat annulus fibrosus cells in monolayer culture were used to examine the biological role of tRAS in vitro. The effect of Ang II peptide on extracellular matrix metabolism was assessed by real-time polymerase chain reaction. RESULTS mRNA of tRAS components, including angiotensin converting enzyme, Ang II, Ang II receptor type 1, Ang II receptor type 2, and Cathepsin D (a renin-like enzyme), was clearly confirmed by real-time polymerase chain reaction analysis. In rat and bovine annulus fibrosus and nucleus pulposus cells in monolayer culture, immunohistochemical analysis showed that each tRAS component was clearly expressed. In rat IVD tissues, immunoreactivity to each antibody for tRAS components was also observed. Proliferation of rat annulus fibrosus cells was mildly stimulated by Ang II peptide. Ang II peptide also had minor stimulatory effect on the expression of the extracellular matrix components, growth factors, and catabolic proteins. CONCLUSION Our results demonstrate for the first time that the tRAS components necessary to activate tRAS have been found in the normal rat IVD at both mRNA and protein levels. To elucidate the association between tRAS and the process of IVD degeneration, the expression and function of tRAS in the human degenerated IVD should be examined in a future study.
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20
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Wen H, Gwathmey JK, Xie LH. Oxidative stress-mediated effects of angiotensin II in the cardiovascular system. World J Hypertens 2012; 2:34-44. [PMID: 24587981 PMCID: PMC3936474 DOI: 10.5494/wjh.v2.i4.34] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Angiotensin II (Ang II), an endogenous peptide hormone, plays critical roles in the pathophysiological modulation of cardiovascular functions. Ang II is the principle effector of the renin-angiotensin system for maintaining homeostasis in the cardiovascular system, as well as a potent stimulator of NAD(P)H oxidase, which is the major source and primary trigger for reactive oxygen species (ROS) generation in various tissues. Recent accumulating evidence has demonstrated the importance of oxidative stress in Ang II-induced heart diseases. Here, we review the recent progress in the study on oxidative stress-mediated effects of Ang II in the cardiovascular system. In particular, the involvement of Ang II-induced ROS generation in arrhythmias, cell death/heart failure, ischemia/reperfusion injury, cardiac hypertrophy and hypertension are discussed. Ca2+/calmodulin-dependent protein kinase II is an important molecule linking Ang II, ROS and cardiovascular pathological conditions.
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22
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Evans AN, Henning T, Gelsleichter J, Nunez BS. Molecular classification of an elasmobranch angiotensin receptor: quantification of angiotensin receptor and natriuretic peptide receptor mRNAs in saltwater and freshwater populations of the Atlantic stingray. Comp Biochem Physiol B Biochem Mol Biol 2010; 157:423-31. [PMID: 20869458 DOI: 10.1016/j.cbpb.2010.09.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2010] [Revised: 09/14/2010] [Accepted: 09/16/2010] [Indexed: 10/19/2022]
Abstract
Among the most conserved osmoregulatory hormone systems in vertebrates are the renin-angiotensin system (RAS) and the natriuretic peptides (NPs). We examined the RAS and NP system in the euryhaline Atlantic stingray, Dasyatis sabina (Lesueur). To determine the relative sensitivity of target organs to these hormonal systems, we isolated cDNA sequences encoding the D. sabina angiotensin receptor (AT) and natriuretic peptide type-B receptor (NPR-B). We then determined the tissue-specific expression of their mRNAs in saltwater D. sabina from local Texas waters and an isolated freshwater population in Lake Monroe, Florida. AT mRNA was most abundant in interrenal tissue from both populations. NPR-B mRNA was most abundant in rectal gland tissue from both populations, and also highly abundant in the kidney of saltwater D. sabina. This study is the first to report the sequence of an elasmobranch angiotensin receptor, and phylogenetic analysis indicates that the D. sabina receptor is more similar to AT(1) vs. AT(2) proteins. This classification is further supported by molecular analysis of AT(1) and AT(2) proteins demonstrating conservation of AT(1)-specific amino acid residues and motifs in D. sabina AT. Molecular classification of the elasmobranch angiotensin receptor as an AT(1)-like protein provides fundamental insight into the evolution of the vertebrate RAS.
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Affiliation(s)
- Andrew N Evans
- The University of Texas Marine Science Institute, Port Aransas, Texas 78373, USA.
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23
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Huynh J, Thomas WG, Aguilar MI, Pattenden LK. Role of helix 8 in G protein-coupled receptors based on structure-function studies on the type 1 angiotensin receptor. Mol Cell Endocrinol 2009; 302:118-27. [PMID: 19418628 DOI: 10.1016/j.mce.2009.01.002] [Citation(s) in RCA: 46] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
G protein-coupled receptors (GPCRs) are transmembrane receptors that convert extracellular stimuli to intracellular signals. The type 1 angiotensin II receptor is a widely studied GPCR with roles in blood pressure regulation,water and salt balance and cell growth. The complex molecular and structural changes that underpin receptor activation and signaling are the focus of intense research. Increasingly, there is an appreciation that the plasma membrane participates in receptor function via direct, physical interactions that reciprocally modulate both lipid and receptor and provide microdomains for specialized activities. Reversible protein:lipid interactions are commonly mediated by amphipathic -helices in proteins and one such motif - a short helix, referred to as helix VIII/8 (H8), located at the start of the carboxyl (C)-terminus of GPCRs - is gaining recognition for its importance to GPCR function. Here, we review the identification of H8 in GPCRs and examine its capacity to sense and interact with diverse proteins and lipid environment, most notably with acidic lipids that include phosphatidylinositol phosphates.
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MESH Headings
- Binding Sites
- Humans
- Lipids/chemistry
- Protein Binding
- Protein Structure, Secondary
- Receptor, Angiotensin, Type 1/chemistry
- Receptor, Angiotensin, Type 1/metabolism
- Receptor, Angiotensin, Type 1/physiology
- Receptors, G-Protein-Coupled/chemistry
- Receptors, G-Protein-Coupled/metabolism
- Receptors, G-Protein-Coupled/physiology
- Signal Transduction
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Affiliation(s)
- John Huynh
- School of Biomedical Sciences, The University of Queensland, Brisbane, St Lucia, Queensland, Australia
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25
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Ito M. Functional roles of neuropeptides in cerebellar circuits. Neuroscience 2009; 162:666-72. [PMID: 19361475 DOI: 10.1016/j.neuroscience.2009.01.019] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2008] [Accepted: 01/09/2009] [Indexed: 11/16/2022]
Abstract
Whereas the cerebellum contains 22 different types of neuropeptides as presently known, their expression is generally weak and diffusely dispersed in cerebellar tissues, which often makes their functional significance doubtful. Nevertheless, our knowledge about certain neuropeptides has advanced to the extent that we can figure out their unique functional roles in cerebellar circuits. Throughout the cerebellum, CRF is contained in climbing fibers and its spontaneous release is required for the induction of cerebellar long-term depression (LTD), a cellular mechanism of motor learning. Corticotropin-releasing factor (CRF) is also expressed in the paraventricular nucleus-pituitary system and amygdala-lower brainstem system, both of which are involved in coping responses to stress. In view that motor learning requires stressful efforts for correcting errors in repeated trials, CRF in climbing fibers may imply that the olivocerebellar system is part of a large CRF-operated functional system that acts to cope with various stressors. Orexin, on the other hand, is contained in beaded fibers, which, originating from the hypothalamus, project to various brainstem nuclei and also to the cerebellum, exclusively the flocculus. Currently available evidence suggests that, in fight-or-flight situations, orexinergic neurons switch the state of cardiovascular control systems including the flocculus to secure blood supply to working muscles. Considerable knowledge has also been accumulated about angiotensin II, galanin, and cerebellin, but there is still a gap in defining their unique functional roles in cerebellar circuits.
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Affiliation(s)
- M Ito
- RIKEN, Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan.
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26
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Lu R, Alioua A, Kumar Y, Kundu P, Eghbali M, Weisstaub NV, Gingrich JA, Stefani E, Toro L. c-Src tyrosine kinase, a critical component for 5-HT2A receptor-mediated contraction in rat aorta. J Physiol 2008; 586:3855-69. [PMID: 18599541 DOI: 10.1113/jphysiol.2008.153593] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Serotonin (5-hydroxytryptamine, 5-HT) receptors (5-HTRs) play critical roles in brain and cardiovascular functions. In the vasculature, 5-HT induces potent vasoconstrictions, which in aorta are mainly mediated by activation of the 5-HT(2A)R subtype. We previously proposed that one signalling mechanism of 5-HT-induced vasoconstriction could be c-Src, a member of the Src tyrosine kinase family. We now provide evidence for a central role of c-Src in 5-HT(2A)R-mediated contraction. Inhibition of Src kinase activity with 10 mum 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) prior to contraction resulted in approximately 90-99% inhibition of contractions induced by 5-HT or by alpha-methyl-5-HT (5-HT(2)R agonist). In contrast, PP2 pretreatment only partly inhibited contractions induced by angiotensin II and the thromboxane A(2) mimetic, U46619, and had no significant action on phenylephrine-induced contractions. 5-Hydroxytryptamine increased Src kinase activity and PP2-sensitive tyrosine-phosphorylated proteins. As expected for c-Src identity, PP2 pretreatment inhibited 5-HT-induced contraction with an IC(50) of approximately 1 mum. Ketanserin (10 nm), a 5-HT(2A) antagonist, but not antagonists of 5-HT(2B)R (100 nm SB204741) or 5-HT(2C)R (20 nm RS102221), prevented 5-HT-induced contractions, mimicking PP2 and implicating 5-HT(2A)R as the major receptor subtype coupled to c-Src. In HEK 293T cells, c-Src and 5-HT(2A)R were reciprocally co-immunoprecipitated and co-localized at the cell periphery. Finally, 5-HT-induced Src activity was unaffected by inhibition of Rho kinase, supporting a role of c-Src upstream of Rho kinase. Together, the results highlight c-Src activation as one of the early and pivotal mechanisms in 5-HT(2A)R contractile signalling in aorta.
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Affiliation(s)
- Rong Lu
- Department of Anaesthesiology, Division of Molecular Medicine, University of California, Los Angeles, Los Angeles, CA 90095-7115, USA
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27
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Speth RC, Karamyan VT. Brain angiotensin receptors and binding proteins. Naunyn Schmiedebergs Arch Pharmacol 2008; 377:283-93. [PMID: 18172611 DOI: 10.1007/s00210-007-0238-7] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2007] [Accepted: 11/26/2007] [Indexed: 12/29/2022]
Abstract
This review addresses classical and novel aspects of the brain angiotensin system. The brain contains both the AT1 and AT2 angiotensin II (Ang II) receptor subtypes which are well-characterized guanine nucleotide binding protein (G protein)-coupled receptors (GPCRs). Like other GPCRs, novel signal transduction pathways and protein interactions are being described for Ang II receptors. For brain AT1 receptors, there is a controversy regarding the identity of the active angiotensin peptide in the brain which is addressed in this review. This review also summarizes a recent discovery of a novel, membrane-bound, non-AT1, non-AT2 binding site for angiotensin peptides that appears to be brain-specific. This binding site is unmasked by a limited concentration range of the organometallic sulfhydryl-reactive agent p-chloromercuribenzoic acid (PCMB) suggesting that functional expression of this binding site may depend on the redox state of the milieu of the brain. While this binding site has similarities to a previously described soluble angiotensin-binding protein found in liver that is unmasked by PCMB, it has many different characteristics. The possible functional significance of this novel non-AT1, non-AT2 binding site for angiotensin peptides as a mediator of non-traditional actions of Ang II in the brain, e.g., stimulation of dopamine release from the striatum, as a peptidase, or as a clearance receptor, and the importance of the state of the internal environment of the brain to its function is reviewed.
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Affiliation(s)
- Robert C Speth
- Department of Pharmacology, Research Institute of Pharmaceutical Sciences, University of Mississippi, University, Oxford, MS 38677, USA.
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28
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Mogi M, Iwai M, Horiuchi M. Emerging Concepts of Regulation of Angiotensin II Receptors. Arterioscler Thromb Vasc Biol 2007; 27:2532-9. [PMID: 17717300 DOI: 10.1161/atvbaha.107.144154] [Citation(s) in RCA: 66] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Angiotensin (Ang) II exerts its important physiological functions through 2 distinct receptor subtypes, type 1 (AT
1
) and type 2 (AT
2
) receptors. Recently, new evidence has accumulated showing the existence of several novel receptor interacting proteins and various angiotensin II receptor activation mechanisms beyond the classical actions of receptors for Ang II. These associated proteins could contribute not only to Ang II receptors’ functions, but also to influencing pathophysiological states. Receptor dimerization of Ang II receptors such as homodimer, heterodimer, and complex formation with other G protein-coupled receptors has also been focused on as a new mechanism of their activation or inactivation. Moreover, ligand-independent receptor activation systems such as mechanical stretch for the AT
1
receptor have also been revealed. These emerging concepts of regulation of Ang II receptors and a new insight into future drug discovery are discussed in this review.
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MESH Headings
- Adaptor Proteins, Signal Transducing/metabolism
- Angiotensin II/metabolism
- Angiotensin II Type 1 Receptor Blockers/pharmacology
- Angiotensin II Type 1 Receptor Blockers/therapeutic use
- Animals
- Antihypertensive Agents/pharmacology
- Antihypertensive Agents/therapeutic use
- Autoantibodies/metabolism
- Dimerization
- Drug Inverse Agonism
- GTP-Binding Proteins/metabolism
- Humans
- Hypertension/drug therapy
- Hypertension/metabolism
- Kruppel-Like Transcription Factors/metabolism
- Ligands
- Membrane Transport Proteins/metabolism
- Multiprotein Complexes/metabolism
- Protein Conformation
- Protein Tyrosine Phosphatase, Non-Receptor Type 6/metabolism
- Receptor, Angiotensin, Type 1/chemistry
- Receptor, Angiotensin, Type 1/drug effects
- Receptor, Angiotensin, Type 1/immunology
- Receptor, Angiotensin, Type 1/metabolism
- Receptor, Angiotensin, Type 2/agonists
- Receptor, Angiotensin, Type 2/chemistry
- Receptor, Angiotensin, Type 2/metabolism
- Signal Transduction/drug effects
- Tumor Suppressor Proteins/metabolism
- Ubiquitin-Conjugating Enzymes/metabolism
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Affiliation(s)
- Masaki Mogi
- FAHA, Professor and Chairman, Department of Molecular Cardiovascular Biology and Pharmacology, Ehime University, Graduate School of Medicine, Shitsukawa, Tohon, Ehime 791-0295, Japan
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29
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Choi H, Leto TL, Hunyady L, Catt KJ, Bae YS, Rhee SG. Mechanism of angiotensin II-induced superoxide production in cells reconstituted with angiotensin type 1 receptor and the components of NADPH oxidase. J Biol Chem 2007; 283:255-267. [PMID: 17981802 DOI: 10.1074/jbc.m708000200] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The mechanism of angiotensin II (Ang II)-induced superoxide production was investigated with HEK293 or Chinese hamster ovary cells reconstituted with the angiotensin type 1 receptor (AT(1)R) and NADPH oxidase (either Nox1 or Nox2) along with a pair of adaptor subunits (either NOXO1 with NOXA1 or p47(phox) with p67(phox)). Ang II enhanced the activity of both Nox1 and Nox2 supported by either adaptor pair, with more effective activation of Nox1 in the presence of NOXO1 and NOXA1 and of Nox2 in the presence of p47(phox) and p67(phox). Expression of several AT(1)R mutants showed that interaction of the receptor with G proteins but not that with beta-arrestin or with other proteins (Jak2, phospholipase C-gamma1, SH2 domain-containing phosphatase 2) that bind to the COOH-terminal region of AT(1)R, was necessary for Ang II-induced superoxide production. The effects of constitutively active alpha subunits of G proteins and of various pharmacological agents implicated signaling by a pathway comprising AT(1)R, Galpha(q/11), phospholipase C-beta, and protein kinase C as largely, but not exclusively, responsible for Ang II-induced activation of Nox1 and Nox2 in the reconstituted cells. A contribution of Galpha(12/13), phospholipase D, and phosphatidyl-inositol 3-kinase to Ang II-induced superoxide generation was also suggested, whereas Src and the epidermal growth factor receptor did not appear to participate in this effect of Ang II. In reconstituted cells stimulated with Ang II, Nox2 exhibited a more sensitive response than Nox1 to the perturbation of protein kinase C, phosphatidylinositol 3-kinase, or the small GTPase Rac1.
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Affiliation(s)
- Hyun Choi
- Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea
| | - Thomas L Leto
- Laboratory of Host Defenses, NIAID, National Institutes of Health, Bethesda, Maryland 20892
| | - László Hunyady
- Department of Physiology, Semmelweis University, H-1088 Budapest, Hungary
| | - Kevin J Catt
- Endocrinology and Reproduction Research Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892
| | - Yun Soo Bae
- Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea.
| | - Sue Goo Rhee
- Division of Life and Pharmaceutical Sciences, Ewha Womans University, Seoul 120-750, Korea.
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30
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Higuchi S, Ohtsu H, Suzuki H, Shirai H, Frank GD, Eguchi S. Angiotensin II signal transduction through the AT1 receptor: novel insights into mechanisms and pathophysiology. Clin Sci (Lond) 2007; 112:417-28. [PMID: 17346243 DOI: 10.1042/cs20060342] [Citation(s) in RCA: 320] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
The intracellular signal transduction of AngII (angiotensin II) has been implicated in cardiovascular diseases, such as hypertension, atherosclerosis and restenosis after injury. AT(1) receptor (AngII type-1 receptor), a G-protein-coupled receptor, mediates most of the physiological and pathophysiological actions of AngII, and this receptor is predominantly expressed in cardiovascular cells, such as VSMCs (vascular smooth muscle cells). AngII activates various signalling molecules, including G-protein-derived second messengers, protein kinases and small G-proteins (Ras, Rho, Rac etc), through the AT(1) receptor leading to vascular remodelling. Growth factor receptors, such as EGFR (epidermal growth factor receptor), have been demonstrated to be 'trans'-activated by the AT(1) receptor in VSMCs to mediate growth and migration. Rho and its effector Rho-kinase/ROCK are also implicated in the pathological cellular actions of AngII in VSMCs. Less is known about the endothelial AngII signalling; however, recent studies suggest the endothelial AngII signalling positively, as well as negatively, regulates the NO (nitric oxide) signalling pathway and, thereby, modulates endothelial dysfunction. Moreover, selective AT(1)-receptor-interacting proteins have recently been identified that potentially regulate AngII signal transduction and their pathogenic functions in the target organs. In this review, we focus our discussion on the recent findings and concepts that suggest the existence of the above-mentioned novel signalling mechanisms whereby AngII mediates the formation of cardiovascular diseases.
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Affiliation(s)
- Sadaharu Higuchi
- Cardiovascular Research Center, Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19140, USA
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31
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Rakotoarisoa L, Carricaburu V, Leblanc C, Mironneau C, Mironneau J, Macrez N. Angiotensin II-induced delayed stimulation of phospholipase C gamma1 requires activation of both phosphatidylinositol 3-kinase gamma and tyrosine kinase in vascular myocytes. J Cell Mol Med 2007; 10:734-48. [PMID: 16989733 PMCID: PMC3933155 DOI: 10.1111/j.1582-4934.2006.tb00433.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/02/2022] Open
Abstract
In vascular smooth muscles, angiotensin II (AII) has been reported to activate phospholipase C (PLC) and phosphatidylinositol 3-kinase (PI3K). We investigated the time-dependent effects of AII on both phosphatidylinositol 3,4,5-trisphosphate (PtdInsP3) and inositol phosphates (InsPs) accumulation in permeabilized microsomes from rat portal vein smooth muscle in comparison with those of noradrenaline (NA). AII stimulated an early production of PtdInsP3 (within 30 s) followed by a delayed production of InsPs (within 3-5 min), in contrast to NA which activated only a fast production of InsPs. The use of pharmacological inhibitors and antibodies raised against the PI3K and PLC isoforms expressed in portal vein smooth muscle showed that AII specifically activated PI3Kδ and that this isoform was involved in the AII-induced stimulation of InsPs accumulation. NA-induced InsPs accumulation depended on PLCβ1 activation whereas AII-induced InsPs accumulation depended on PLCγ1 activation. AII-induced PLCδ1 activation required both tyrosine kinase and PI3Kδ since genistein and tyrphostin B48 (inhibitors of tyrosine kinase), LY294002 and wortmannin (inhibitors of PI3K) and anti-PI3Kδ antibody abolished AII-induced stimulation of InsPs accumulation. Increased tyrosine phosphorylation of PLCβ1 was only detected for long-lasting applications of AII and was suppressed by genistein. These data indicate that activation of both PI3Kβ and tyrosine kinase is a prerequisite for AII-induced stimulation of PLCβ1 in vascular smooth muscle and suggest that the sequential activation of the three enzymes may be responsible for the slow and long-lasting contraction induced by AII.
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Affiliation(s)
- Lala Rakotoarisoa
- Laboratoire de Signalisation et Interactions Cellulaires, Université de Bordeaux, Bordeaux, France
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32
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Oshita A, Iwai M, Chen R, Ide A, Okumura M, Fukunaga S, Yoshii T, Mogi M, Higaki J, Horiuchi M. Attenuation of Inflammatory Vascular Remodeling by Angiotensin II Type 1 Receptor–Associated Protein. Hypertension 2006; 48:671-6. [PMID: 16923992 DOI: 10.1161/01.hyp.0000238141.99816.47] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
To explore the role of angiotensin II Type 1 receptor–associated protein (ATRAP) in vascular remodeling, we developed transgenic mice for mouse ATRAP cDNA and examined remodeling after inflammatory vascular injury induced by polyethylene cuff placement. In ATRAP transgenic (ATRAP-Tg) mice, ATRAP mRNA was increased 3- to 4-fold in the heart, aorta, and femoral artery. ATRAP-Tg mice showed no significant change in body weight, systolic blood pressure, heart rate, and heart/body weight ratio. However, cell proliferation and neointimal formation in the injured artery were attenuated in ATRAP-Tg mice. The increase in NADPH oxidase activity and the expression of p22
phox
, a reduced nicotinamide-adenine dinucleotide/reduced nicotinamide-adenine dinucleotide phosphate oxidase subunit, after cuff placement was also attenuated in ATRAP-Tg mice. Moreover, activation of extracellular signal–regulated kinase, signal transducer and activator of transcription 1, and signal transducer and activator of transcription 3 after cuff placement was significantly reduced in ATRAP-Tg mice. Pressor response and cardiac hypertrophy induced by angiotensin II infusion and pressure overload were also attenuated in ATRAP-Tg mice. These results suggest that ATRAP plays an important role in vascular remodeling as a negative regulator.
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Affiliation(s)
- Akira Oshita
- Department of Molecular and Cellular Biology, Ehime University School of Medicine, Tohon, Ehime, Japan
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33
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Zhai P, Galeotti J, Liu J, Holle E, Yu X, Wagner T, Sadoshima J. An Angiotensin II Type 1 Receptor Mutant Lacking Epidermal Growth Factor Receptor Transactivation Does Not Induce Angiotensin II–Mediated Cardiac Hypertrophy. Circ Res 2006; 99:528-36. [PMID: 16902180 DOI: 10.1161/01.res.0000240147.49390.61] [Citation(s) in RCA: 83] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
We have shown previously that tyrosine 319 in a conserved YIPP motif in the C terminus of angiotensin II (Ang II) type 1 receptors (AT
1
Rs) is essential for transactivation of epidermal growth factor receptor (EGFR) in vitro. We hypothesized that the signaling mechanism mediated through the specific amino acid sequence in the G protein–coupled receptor plays an important role in mediating cardiac hypertrophy in vivo. Transgenic mice with cardiac-specific overexpression of wild-type AT
1
R (Tg-WT) and an AT
1
R with a mutation in the YIPP motif (Tg-Y319F) were studied. Tg-Y319F mice developed no significant cardiac hypertrophy, in contrast to the significant development of hypertrophy in Tg-WT mice. Expression of fetal-type genes, such as atrial natriuretic factor, was also significantly lower in Tg-Y319F than in Tg-WT mice. Infusion of Ang II caused an enhancement of hypertrophy in Tg-WT mice but failed to induce hypertrophy in Tg-Y319F mice. Left ventricular myocardium in Tg-Y319F mice developed significantly less apoptosis and fibrosis than that in Tg-WT mice. EGFR phosphorylation was significantly inhibited in Tg-Y319F mice, confirming that EGFR was not activated in Tg-Y319F mouse hearts. In contrast, activation/phosphorylation of protein kinase C, STAT3, extracellular signal-regulated kinase, and Akt and translocation of Gαq/11 to the cytosolic fraction were maintained in Tg-Y319F hearts. Furthermore, a genetic cross between Tg-WT and transgenic mice with cardiac-specific overexpression of dominant negative EGFR mimicked the phenotype of Tg-Y319F mice. In conclusion, overexpression of AT
1
-Y319F in cardiac myocytes diminished EGFR transactivation and inhibited a pathological form of cardiac hypertrophy. The YIPP motif in the AT
1
R plays an important role in mediating cardiac hypertrophy in vivo.
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Affiliation(s)
- Peiyong Zhai
- Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine & Dentistry of New Jersey, New Jersey Medical School, Newark 07103, USA
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34
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Zhai P, Yamamoto M, Galeotti J, Liu J, Masurekar M, Thaisz J, Irie K, Holle E, Yu X, Kupershmidt S, Roden DM, Wagner T, Yatani A, Vatner DE, Vatner SF, Sadoshima J. Cardiac-specific overexpression of AT1 receptor mutant lacking G alpha q/G alpha i coupling causes hypertrophy and bradycardia in transgenic mice. J Clin Invest 2006; 115:3045-56. [PMID: 16276415 PMCID: PMC1265872 DOI: 10.1172/jci25330] [Citation(s) in RCA: 135] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2005] [Accepted: 08/30/2005] [Indexed: 12/25/2022] Open
Abstract
Ang II type 1 (AT1) receptors activate both conventional heterotrimeric G protein-dependent and unconventional G protein-independent mechanisms. We investigated how these different mechanisms activated by AT1 receptors affect growth and death of cardiac myocytes in vivo. Transgenic mice with cardiac-specific overexpression of WT AT1 receptor (AT1-WT; Tg-WT mice) or an AT1 receptor second intracellular loop mutant (AT1-i2m; Tg-i2m mice) selectively activating G(alpha)q/G(alpha)i-independent mechanisms were studied. Tg-i2m mice developed more severe cardiac hypertrophy and bradycardia coupled with lower cardiac function than Tg-WT mice. In contrast, Tg-WT mice exhibited more severe fibrosis and apoptosis than Tg-i2m mice. Chronic Ang II infusion induced greater cardiac hypertrophy in Tg-i2m compared with Tg-WT mice whereas acute Ang II administration caused an increase in heart rate in Tg-WT but not in Tg-i2m mice. Membrane translocation of PKCepsilon, cytoplasmic translocation of G(alpha)q, and nuclear localization of phospho-ERKs were observed only in Tg-WT mice while activation of Src and cytoplasmic accumulation of phospho-ERKs were greater in Tg-i2m mice, consistent with the notion that G(alpha)q/G(alpha)i-independent mechanisms are activated in Tg-i2m mice. Cultured myocytes expressing AT1-i2m exhibited a left and upward shift of the Ang II dose-response curve of hypertrophy compared with those expressing AT1-WT. Thus, the AT1 receptor mediates downstream signaling mechanisms through G(alpha)q/G(alpha)i-dependent and -independent mechanisms, which induce hypertrophy with a distinct phenotype.
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MESH Headings
- Animals
- Apoptosis/genetics
- Bradycardia/genetics
- Bradycardia/metabolism
- Bradycardia/pathology
- Cells, Cultured
- Electrocardiography
- Extracellular Signal-Regulated MAP Kinases/metabolism
- Fibrosis/genetics
- Fibrosis/metabolism
- GTP-Binding Protein alpha Subunits, Gi-Go/deficiency
- GTP-Binding Protein alpha Subunits, Gi-Go/genetics
- GTP-Binding Protein alpha Subunits, Gi-Go/metabolism
- GTP-Binding Protein alpha Subunits, Gq-G11/deficiency
- GTP-Binding Protein alpha Subunits, Gq-G11/genetics
- GTP-Binding Protein alpha Subunits, Gq-G11/metabolism
- Hypertrophy, Left Ventricular/genetics
- Hypertrophy, Left Ventricular/metabolism
- Hypertrophy, Left Ventricular/pathology
- Mice
- Mice, Transgenic
- Mutation
- Myocytes, Cardiac/metabolism
- Myocytes, Cardiac/pathology
- Phenotype
- Protein Kinase C-epsilon/metabolism
- Rats
- Rats, Wistar
- Receptor, Angiotensin, Type 1/deficiency
- Receptor, Angiotensin, Type 1/genetics
- Receptor, Angiotensin, Type 1/metabolism
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Affiliation(s)
- Peiyong Zhai
- Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103, USA
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35
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Marrero MB. Introduction to JAK/STAT signaling and the vasculature. Vascul Pharmacol 2005; 43:307-9. [PMID: 16263337 DOI: 10.1016/j.vph.2005.09.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2005] [Accepted: 09/05/2005] [Indexed: 01/31/2023]
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36
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Hunyady L, Catt KJ. Pleiotropic AT1 receptor signaling pathways mediating physiological and pathogenic actions of angiotensin II. Mol Endocrinol 2005; 20:953-70. [PMID: 16141358 DOI: 10.1210/me.2004-0536] [Citation(s) in RCA: 402] [Impact Index Per Article: 20.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Angiotensin II (Ang II) activates a wide spectrum of signaling responses via the AT1 receptor (AT1R) that mediate its physiological control of blood pressure, thirst, and sodium balance and its diverse pathological actions in cardiovascular, renal, and other cell types. Ang II-induced AT1R activation via Gq/11 stimulates phospholipases A2, C, and D, and activates inositol trisphosphate/Ca2+ signaling, protein kinase C isoforms, and MAPKs, as well as several tyrosine kinases (Pyk2, Src, Tyk2, FAK), scaffold proteins (G protein-coupled receptor kinase-interacting protein 1, p130Cas, paxillin, vinculin), receptor tyrosine kinases, and the nuclear factor-kappaB pathway. The AT1R also signals via Gi/o and G11/12 and stimulates G protein-independent signaling pathways, such as beta-arrestin-mediated MAPK activation and the Jak/STAT. Alterations in homo- or heterodimerization of the AT1R may also contribute to its pathophysiological roles. Many of the deleterious actions of AT1R activation are initiated by locally generated, rather than circulating, Ang II and are concomitant with the harmful effects of aldosterone in the cardiovascular system. AT1R-mediated overproduction of reactive oxygen species has potent growth-promoting, proinflammatory, and profibrotic actions by exerting positive feedback effects that amplify its signaling in cardiovascular cells, leukocytes, and monocytes. In addition to its roles in cardiovascular and renal disease, agonist-induced activation of the AT1R also participates in the development of metabolic diseases and promotes tumor progression and metastasis through its growth-promoting and proangiogenic activities. The recognition of Ang II's pathogenic actions is leading to novel clinical applications of angiotensin-converting enzyme inhibitors and AT1R antagonists, in addition to their established therapeutic actions in essential hypertension.
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Affiliation(s)
- László Hunyady
- Department of Physiology, Faculty of Medicine, Semmelweis University, Budapest, Hungary
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37
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Pulakat L, Rahman S, Gray A, Knowle D, Gavini N. Roles of the intracellular regions of angiotensin II receptor AT2 in mediating reduction of intracellular cGMP levels. Cell Signal 2005; 17:395-404. [PMID: 15567070 DOI: 10.1016/j.cellsig.2004.08.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2004] [Revised: 08/21/2004] [Accepted: 08/23/2004] [Indexed: 02/04/2023]
Abstract
We have shown previously that the angiotensin II (Ang II) receptor AT2 reduces the intracellular levels of cGMP in Xenopus oocytes when activated by ligand binding, and the C-terminal cytoplasmic tail of the AT2 acts as a negative regulator of this function. Here we report the effects of mutations in the 2nd and 3rd intracellular loops of AT2 on AT2-mediated cGMP reduction. Mutating the highly conserved DRY motif (D141G-R142G-Y143A) of the 2nd ICL implicated in activating G(alpha) subunit of trimeric G-proteins did not affect AT2-mediated cGMP reduction. Moreover, anti-Gialpha antibody or phosphodiesterase inhibitor IBMX did not inhibit AT2-mediated cGMP reduction, suggesting that Gialpha activation and subsequent phosphodiesterase activation are not involved in this function. In contrast, mutations T250R-R251N and L255F-K256R located in the C-terminus of the 3rd ICL of AT2 retained ligand-binding properties of the wild-type AT2, and its ability to interact with the ErbB3 in yeast two-hybrid assay, but abolished AT2-mediated cGMP reduction. Similarities in the roles of ICLs of AT2 in AT2-mediated cGMP reduction in oocytes, and AT2-mediated SHP1 activation in COS-7 cells, (need of 3rd ICL for both functions and lack of involvement of DRY motif), suggest that the cascade of events in these two signaling mechanisms could be similar, and that an oocyte-specific SHP1-like protein may be involved in AT2-mediated cGMP reduction in these cells.
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Affiliation(s)
- Lakshmi Pulakat
- Department of Biological Sciences, Bowling Green State University, Bowling Green, OH 43403, USA
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38
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Enyeart JJ, Danthi SJ, Liu H, Enyeart JA. Angiotensin II inhibits bTREK-1 K+ channels in adrenocortical cells by separate Ca2+- and ATP hydrolysis-dependent mechanisms. J Biol Chem 2005; 280:30814-28. [PMID: 15994319 DOI: 10.1074/jbc.m504283200] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
Bovine adrenocortical cells express bTREK-1 K+ channels that set the resting membrane potential (V(m)) and couple angiotensin II (AngII) and adrenocorticotropic hormone (ACTH) receptors to membrane depolarization and corticosteroid secretion. In this study, it was discovered that AngII inhibits bTREK-1 by separate Ca2+- and ATP hydrolysis-dependent signaling pathways. When whole cell patch clamp recordings were made with pipette solutions that support activation of both Ca2+- and ATP-dependent pathways, AngII was significantly more potent and effective at inhibiting bTREK-1 and depolarizing adrenal zona fasciculata cells, than when either pathway is activated separately. External ATP also inhibited bTREK-1 through these two pathways, but ACTH displayed no Ca2+-dependent inhibition. AngII-mediated inhibition of bTREK-1 through the novel Ca2+-dependent pathway was blocked by the AT1 receptor antagonist losartan, or by including guanosine-5'-O-(2-thiodiphosphate) in the pipette solution. The Ca2+-dependent inhibition of bTREK-1 by AngII was blunted in the absence of external Ca2+ or by including the phospholipase C antagonist U73122, the inositol 1,4,5-trisphosphate receptor antagonist 2-amino-ethoxydiphenyl borate, or a calmodulin inhibitory peptide in the pipette solution. The activity of unitary bTREK-1 channels in inside-out patches from adrenal zona fasciculata cells was inhibited by application of Ca2+ (5 or 10 microM) to the cytoplasmic membrane surface. The Ca2+ ionophore ionomycin also inhibited bTREK-1 currents through channels expressed in CHO-K1 cells. These results demonstrate that AngII and selected paracrine factors that act through phospholipase C inhibit bTREK-1 in adrenocortical cells through simultaneous activation of separate Ca2+- and ATP hydrolysis-dependent signaling pathways, providing for efficient membrane depolarization. The novel Ca2+-dependent pathway is distinctive in its lack of ATP dependence, and is clearly different from the calmodulin kinase-dependent mechanism by which AngII modulates T-type Ca2+ channels in these cells.
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Affiliation(s)
- John J Enyeart
- Department of Neuroscience, The Ohio State University College of Medicine and Public Health, Columbus, Ohio 43210-1239, USA.
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39
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Pulakat L, Cooper S, Knowle D, Mandavia C, Bruhl S, Hetrick M, Gavini N. Ligand-dependent complex formation between the Angiotensin II receptor subtype AT2 and Na+/H+ exchanger NHE6 in mammalian cells. Peptides 2005; 26:863-73. [PMID: 15808917 DOI: 10.1016/j.peptides.2004.12.015] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2004] [Revised: 12/14/2004] [Accepted: 12/14/2004] [Indexed: 11/22/2022]
Abstract
Involvement of Angiotensin II (Ang II) in the regulation of sodium levels by modulating the Na+/H+ exchangers is demonstrated in many tissues. Screening of a mouse 17-day fetus cDNA library with the Angiotensin II receptor AT2 as the bait in yeast two-hybrid assay led us to identify an AT2-interacting mouse fetus peptide that shared 98% amino acid identity with the corresponding region of the human NHE6. NCBI Blast search showed that the clone 6430520C02 (GenBank Accession # AK032326) of the mouse genome project carried the complete sequence of this new mouse NHE6 isoform. The human and mouse NHE6 peptides share 97% overall homology. Further analysis showed that the region spanning the third intracellular loop and C-terminal cytoplasmic tail of the AT2 directly interacted with a 182 amino acid region that spans the predicted 5th intracellular loop and the initial part of the C-terminus of the mouse NHE6 in yeast two-hybrid assay. This 182-amino acid region that interacted with the AT2 also shares 98% homology with the corresponding region of rat NHE6 and therefore is highly conserved across species. We detected widespread expression of this NHE6 isoform in several rat tissues including 10-day fetus, 17-day fetus, and 30-day post-natal tissues of heart, brain, kidney and muscle. Moreover, the AT2 co-immunoiprecipitated with a hemagglutinin tagged NHE6 when expressed in human cell line MCF-7, and activated by AngII. This ligand-dependent complex formation between the AT2 and NHE6 suggests that the hormone Ang II may act as a regulator of NHE6, and Ang II-mediated direct protein-protein interaction between AT2 and NHE6 could be a mechanism for modulating the functions of the ubiquitously expressed NHE6 in different tissues.
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Affiliation(s)
- Lakshmi Pulakat
- Department of Biological Sciences, Bowling Green State University, Bowling Green, OH 43403, USA.
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40
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Abstract
G protein-coupled receptors (GPCR) interact not only with heterotrimeric G proteins but also with accessory proteins called GPCR interacting proteins (GIP). These proteins have important functions. They are implicated in GPCR targeting to specific cellular compartments, in their assembling into large functional complexes called "receptosomes," in their trafficking to and from the plasma membrane, and in the fine-tuning of their signaling properties. There are several types of GIPs. Some are transmembrane proteins such as another GPCR (homodimerization and heterodimerization), ionic channels, ionotropic receptors, and single transmembrane proteins. The latter is implicated in the fine-tuning of receptor pharmacology or signaling. Other GIPs are soluble proteins interacting mainly with the "magic" C-terminal tail. Among them, PDZ domain-containing proteins are the most abundant. They generally, but not always, interact with the extreme C-terminal domain of GPCRs. Some GIPs interact with specific sequences of the C-terminal such as the Homer binding sequence (-PPxxFR-), the dopamine receptor interacting protein (DRIP) binding sequence (-FxxxFxxxF-), etc. Finally, only few GIPs have been found thus far to interact with the third intracellular loop of GPCRs. The future will tell us if this situation is only due to technical reasons.
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Affiliation(s)
- Joël Bockaert
- UPR CNRS 2580, CCIPE, 141 Rue de la Cardonille, 34094 Montpellier Cedex 5, France.
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41
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Shivakumar BR, Wang Z, Hammond TG, Harris RC. EP24.15 interacts with the angiotensin II type I receptor and bradykinin B2 receptor. Cell Biochem Funct 2005; 23:195-204. [PMID: 15376229 DOI: 10.1002/cbf.1176] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
The carboxyl-terminal cytoplasmic domain of the angiotensin II type 1 receptor (AT1) is known to interact with several classes of intracellular proteins that may modulate receptor function. Employing yeast two-hybrid screening of a human embryonic kidney cDNA library with the carboxyl-terminal cytoplasmic domain of the AT1 receptor as a bait, we have isolated EP24.15 (EC 3.4.24.15, thimet oligopeptidase) as a potentially interacting protein. EP24.15 is widely distributed and is known to degrade bioactive peptides such as angiotensin I and II and bradykinin. In addition, EP24.15 was previously identified as a putative soluble angiotensin II binding protein. Two-hybrid screening also determined that EP24.15 can interact with the B2 bradykinin receptor. Transient expression of EP24.15 in a porcine kidney epithelial cell line stably expressing full length AT1 and full length B2 followed by affinity chromatography and co-immunoprecipitation confirmed EP24.15 association with both AT1 and B2 receptors. EP24.15 was also co-immunoprecipitated with AT1 and B2 in rat kidney brush border membranes (BBM) and basolateral membranes (BLM). Both AT1 and B2 undergo ligand-induced endocytosis. Analysis of endosomal fractions following immunoprecipitation with AT1 or B2 antibodies detected strong association of EP24.15 with the receptors in both light and heavy endosomal populations. Therefore, the present study indicates that EP24.15 associates with AT1 and B2 receptors both at the plasma membrane and after receptor internalization and suggests a possible mechanism for endosomal disposition of ligand that may facilitate receptor recycling.
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MESH Headings
- Animals
- Cell Membrane/enzymology
- Cytoplasm/enzymology
- Endosomes/enzymology
- Gene Library
- Glutathione Transferase/genetics
- Humans
- Kidney Cortex/cytology
- Kidney Cortex/enzymology
- LLC-PK1 Cells
- Metalloendopeptidases/metabolism
- Mice
- Protein Structure, Tertiary
- Rats
- Receptor, Angiotensin, Type 1/chemistry
- Receptor, Angiotensin, Type 1/genetics
- Receptor, Angiotensin, Type 1/metabolism
- Receptor, Bradykinin B2/chemistry
- Receptor, Bradykinin B2/genetics
- Receptor, Bradykinin B2/metabolism
- Recombinant Fusion Proteins/genetics
- Swine
- Two-Hybrid System Techniques
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Affiliation(s)
- Bangalore R Shivakumar
- Department of Medicine, Vanderbilt University and Veterans Affairs Medical Center Nashville, TN 37232, USA
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Duchene J, Chauhan SD, Lopez F, Pecher C, Estève JP, Girolami JP, Bascands JL, Schanstra JP. Direct protein–protein interaction between PLCγ1 and the bradykinin B2 receptor—Importance of growth conditions. Biochem Biophys Res Commun 2005; 326:894-900. [PMID: 15607753 DOI: 10.1016/j.bbrc.2004.11.126] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2004] [Indexed: 11/28/2022]
Abstract
Recently, we have described a novel protein-protein interaction between the G-protein coupled bradykinin B2 receptor and tyrosine phosphatase SHP-2 via an immunoreceptor tyrosine-based inhibition motif (ITIM) sequence located in the C-terminal part of the B2 receptor and the Src homology (SH2) domains of SHP-2. Here we show that phospholipase C (PLC)gamma1, another SH2 domain containing protein, can also interact with this ITIM sequence. Using surface plasmon resonance analysis, we observed that PLCgamma1 interacted with a peptide containing the phosphorylated form of the bradykinin B2 receptor ITIM sequence. In CHO cells expressing the wild-type B2 receptor, bradykinin-induced transient recruitment and activation of PLCgamma1. Interestingly, this interaction was only observed in quiescent and not in proliferating cells. Mutation of the key ITIM residue abolished this interaction with and activation of PLCgamma1. Finally we also identified bradykinin-induced PLCgamma1 recruitment and activation in primary culture renal mesangial cells.
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Affiliation(s)
- Johan Duchene
- Inserm U388, IFR 31, Hopital Rangueil, TSA 50032, 31059 Toulouse Cedex 9, France
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43
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Pulakat L, Mandavia CH, Gavini N. Role of Phe308 in the seventh transmembrane domain of the AT2 receptor in ligand binding and signaling. Biochem Biophys Res Commun 2004; 319:1138-43. [PMID: 15194486 DOI: 10.1016/j.bbrc.2004.05.092] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2004] [Indexed: 11/28/2022]
Abstract
Studies on Angiotensin II (Ang II) receptor type AT1 have suggested that interaction between the two highly conserved residues, Tyr292 in the 7th transmembrane domain (TMD) and the Asp74 in the 2nd TMD, is critical for linking the Ang II binding and AT1 receptor-Gq protein coupling. In the Ang II receptor type AT2, the Asp is conserved (Asp90 in 2nd TMD), however, there is no Tyr residue in the 7th TMD and Phe308 occupies the analogous position to Tyr292 of the AT1. Replacing this Phe308 with Ala reduced receptor affinity to peptidic ligands (125)I-Ang II (K(d) = 0.37 nM) and (125)I-CGP42112A (K(d) = 0.56 nM), but retained the ability of the AT2 to reduce cGMP levels in Xenopus oocytes. Thus, the Phe308 of the AT2 does not mimic the role of Tyr292 of the AT1 in the receptor activation upon Ang II binding. We have also shown that the M8 mutant of the AT2 with the 7th TMD similar to that of wild type AT2 can couple to PLC like the AT1 and bind the AT2-specific ligands with high affinity. Since the Ang II is shown to bind to both the AT1 and the AT2 in an identical manner, we propose that the absence of Tyr in the 7th TMD of the AT2 does not prevent the receptor from coupling to Gq-protein, rather may contribute to the freedom of the AT2 to couple to trimeric G-proteins in both G- betagamma dependent and independent manners upon Ang II binding.
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Affiliation(s)
- Lakshmi Pulakat
- Department of Biological Sciences, Bowling Green State University, Bowling Green, OH 43403, USA.
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44
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Arnould M, Tassa A, Ferrand A, Archer E, Estève JP, Pénalba V, Portolan G, Escherich A, Moroder L, Fourmy D, Seva C, Dufresne M. The G-protein-coupled CCK2 receptor associates with phospholipase Cgamma1. FEBS Lett 2004; 568:89-93. [PMID: 15196926 DOI: 10.1016/j.febslet.2004.05.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2004] [Accepted: 05/05/2004] [Indexed: 12/14/2022]
Abstract
In ElasCCK2 transgenic mice expressing cholecystokinin (CCK2) receptor in acinar cells, pancreatic phenotypic alterations and preneoplastic lesions are observed. We determined whether activation of phospholipase C gamma1 (PLCgamma1), known to contribute to the tumorigenesis pathophysiology, could take place as a new signaling pathway induced by the CCK2 receptor. Overexpression and activation of the PLCgamma1 in response to gastrin was observed in acinar cells. The possibility that the C-terminal tyrosine 438 of the CCK2 receptor associates with the SH2 domains of PLCgamma1 was examined. A specific interaction was demonstrated using surface plasmon resonance, confirmed in a cellular system and by molecular modeling.
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Affiliation(s)
- Marika Arnould
- INSERM U531, Institut Louis Bugnard, IFR31, CHU Rangueil, Bât L3, Toulouse, France
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45
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Hunyady L, Gáborik Z, Shah BH, Jagadeesh G, Clark AJL, Catt KJ. Structural determinants of agonist-induced signaling and regulation of the angiotensin AT1 receptor. Mol Cell Endocrinol 2004; 217:89-100. [PMID: 15134806 DOI: 10.1016/j.mce.2003.10.014] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Angiotensin II (Ang II) regulates aldosterone secretion by stimulating inositol phosphate production and Ca(2+) signaling in adrenal glomerulosa cells via the G(q)-coupled AT(1) receptor, which is rapidly internalized upon agonist binding. Ang II also binds to the heptahelical AT(2) receptor, which neither activates inositol phosphate signaling nor undergoes receptor internalization. The differential behaviors of the AT(1) and AT(2) receptors were analyzed in chimeric angiotensin receptors created by swapping the second (IL2), the third (IL3) intracellular loops and/or the cytoplasmic tail (CT) between these receptors. When transiently expressed in COS-7 cells, the chimeric receptors showed only minor alterations in their ligand binding properties. Measurements of the internalization kinetics and inositol phosphate responses of chimeric AT(1A) receptors indicated that the CT is required for normal receptor internalization, and IL2 is a determinant of G protein activation. In addition, the amino-terminal portion of IL3 is required for both receptor functions. However, only substitution of IL2 impaired Ang II-induced ERK activation, suggesting that alternative mechanisms are responsible for ERK activation in signaling-deficient mutant AT(1) receptors. Substitution of IL2, IL3, or CT of the AT(1A) receptor into the AT(2) receptor sequence did not endow the latter with the ability to internalize or to mediate inositol phosphate signaling responses. These data suggest that the lack of receptor internalization and inositol phosphate signal generation by the AT(2) receptor is a consequence of its different activation mechanism, rather than the inability of its cytoplasmic domains to couple to intracellular effectors.
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MESH Headings
- Amino Acid Sequence
- Animals
- COS Cells
- Calcium Signaling/genetics
- Cricetinae
- GTP-Binding Proteins/genetics
- GTP-Binding Proteins/metabolism
- Inositol Phosphates/metabolism
- Mitogen-Activated Protein Kinase 3/metabolism
- Mutagenesis, Site-Directed
- Phosphorylation
- Protein Binding/genetics
- Protein Structure, Tertiary/genetics
- Rats
- Receptor, Angiotensin, Type 1/genetics
- Receptor, Angiotensin, Type 1/metabolism
- Receptor, Angiotensin, Type 2/genetics
- Receptor, Angiotensin, Type 2/metabolism
- Receptors, Interleukin-2/genetics
- Receptors, Interleukin-2/metabolism
- Receptors, Interleukin-3/genetics
- Receptors, Interleukin-3/metabolism
- Recombinant Fusion Proteins/genetics
- Recombinant Fusion Proteins/metabolism
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Affiliation(s)
- László Hunyady
- Department of Physiology, Semmelweis University, Faculty of Medicine, H-1088 Budapest, Hungary.
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Guo DF, Chenier I, Tardif V, Orlov SN, Inagami T. Type 1 angiotensin II receptor-associated protein ARAP1 binds and recycles the receptor to the plasma membrane. Biochem Biophys Res Commun 2003; 310:1254-65. [PMID: 14559250 DOI: 10.1016/j.bbrc.2003.09.154] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
The carboxyl terminus of the type 1 angiotensin II receptor (AT(1)) plays an important role in receptor phosphorylation, desensitization, and internalization. The yeast two-hybrid system was employed to isolate proteins associated with the carboxyl terminal region of the AT(1A) receptor. In the present study, we report the isolation of a novel protein, ARAP1, which promotes recycling of AT(1A) to the plasma membrane in HEK-293 cells. ARAP1 cDNA encodes a 493-amino-acid protein and its mRNA is ubiquitously expressed in rat tissues. A complex of ARAP1 and AT(1A) was observed by immunoprecipitation and Western blotting in HEK-293 cells. In the presence of ARAP1, recycled AT(1A) showed a significant Ca(2+) release response to a second stimulation by Ang II 30 min after the first treatment. Immunocytochemical analysis revealed co-localization of recycled AT(1A) and ARAP1 in the plasma membrane 45 min after the initial exposure to Ang II. Taken together, these results indicate a role for ARAP1 in the recycling of the AT(1) receptor to the plasma membrane with presumable concomitant recovery of receptor signal functions.
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Affiliation(s)
- Deng-Fu Guo
- Research Centre, Hôtel-Dieu du CHUM, Department of Medicine, Université de Montréal, Montréal, Québec, Canada H2W 1T8.
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47
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Bockaert J, Marin P, Dumuis A, Fagni L. The 'magic tail' of G protein-coupled receptors: an anchorage for functional protein networks. FEBS Lett 2003; 546:65-72. [PMID: 12829238 DOI: 10.1016/s0014-5793(03)00453-8] [Citation(s) in RCA: 174] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
All cell types express a great variety of G protein-coupled receptors (GPCRs) that are coupled to only a limited set of G proteins. This disposition favors cross-talk between transduction pathways. However, GPCRs are organized into functional units. They promote specificity and thus avoid unsuitable cross-talk. New methodologies (mostly yeast two-hybrid screens and proteomics) have been used to discover more than 50 GPCR-associated proteins that are involved in building these units. In addition, these protein networks participate in the trafficking, targeting, signaling, fine-tuning and allosteric regulation of GPCRs. To date, proteins that interact with the GPCR C-terminus are the most abundant and are the focus of this review.
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Affiliation(s)
- Joël Bockaert
- Laboratoire de Génomique Fonctionnelle, UPR CNRS 2580, 141 rue de la Cardonille, 34094 Montpellier Cedex 5, France.
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48
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Inada Y, Nakane T, Chiba S. Relationship between ligand binding and YIPP motif in the C-terminal region of human AT1 receptor. BIOCHIMICA ET BIOPHYSICA ACTA 2003; 1640:33-41. [PMID: 12676352 DOI: 10.1016/s0167-4889(02)00400-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
The YIPP (tyrosine-isoleucine-proline-proline, amino acids 319-322) motif within the C-terminal part of the human AT(1) receptor is associated with angiotensin II (AII)-induced activation of the Jak-STAT pathway and phospholipase Cgamma1 phosphorylation. We report here that mutations of the YIPP motif strongly affect ligand-binding to the receptor. We analysed AT(1) receptors of the wild type (WT) and 11 mutants with a FLAG-epitope-tag within their C-terminal portion. Mutations of the "P-P" amino acid sequence of this motif decreased both AII binding and the AII-induced intracellular Ca(2+) transients. Mutant and WT receptors were expressed equally in the cell membrane and were localized within the plasma membrane. These results suggest that the "P-P" amino acid sequence within the YIPP motif is important for AII binding to the AT(1) receptor.
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Affiliation(s)
- Yoichi Inada
- Department of Pharmacology, Shinshu University School of Medicine, 3-1-1 Asahi, 390-8621, Matsumoto, Japan
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49
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Seta K, Sadoshima J. Phosphorylation of tyrosine 319 of the angiotensin II type 1 receptor mediates angiotensin II-induced trans-activation of the epidermal growth factor receptor. J Biol Chem 2003; 278:9019-26. [PMID: 12522132 DOI: 10.1074/jbc.m208017200] [Citation(s) in RCA: 53] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
Although tyrosine kinases are critically involved in the angiotensin II (Ang II) type 1 (AT1) receptor signaling, how AT1 receptors activate tyrosine kinases is not fully understood. We examined the structural requirements of the AT1 receptor for transactivation of the epidermal growth factor (EGF) receptor (EGFR). Studies using carboxyl terminal-truncated AT1 receptors indicated that the amino acid sequence between 312 and 337 is required for activation of EGFR. The role of the conserved YIPP motif in this sequence in transactivation of EGFR was investigated by mutating tyrosine 319. Ang II failed to activate EGFR in cells expressing AT1-Y319F, whereas EGFR was activated even without Ang II in cells expressing AT1-Y319E, which mimics the AT1 receptor phosphorylated at Tyr-319. Immunoblot analyses using anti-phospho Tyr-319-specific antibody showed that Ang II increased phosphorylation of Tyr-319. EGFR interacted with the AT1 receptor but not with AT1-Y319F in response to Ang II stimulation, whereas the EGFR-AT1 receptor interaction was inhibited in the presence of dominant negative SHP-2. The requirement of Tyr-319 seems specific for EGFR because Ang II-induced activation of other tyrosine kinases, including Src and JAK2, was preserved in cells expressing AT1-Y319F. Extracellular signal-regulated kinase activation was also maintained in AT1-Y319F through activation of Src. Overexpression of wild type AT1 receptor in cardiac fibroblasts enhanced Ang II-induced proliferation. By contrast, overexpression of AT1-Y319F failed to enhance cell proliferation. In summary, Tyr-319 of the AT1 receptor is phosphorylated in response to Ang II and plays a key role in mediating Ang II-induced transactivation of EGFR and cell proliferation, possibly through its interaction with SHP-2 and EGFR.
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MESH Headings
- Amino Acid Motifs
- Amino Acid Sequence
- Animals
- COS Cells
- Calcium/metabolism
- Cell Division
- Cells, Cultured
- Conserved Sequence
- DNA, Complementary/metabolism
- ErbB Receptors/metabolism
- Fibroblasts/metabolism
- Genes, Dominant
- Humans
- Immunoblotting
- Intracellular Signaling Peptides and Proteins
- Molecular Sequence Data
- Mutagenesis, Site-Directed
- Mutation
- Myocardium/cytology
- Phosphorylation
- Plasmids/metabolism
- Precipitin Tests
- Protein Binding
- Protein Structure, Tertiary
- Protein Tyrosine Phosphatase, Non-Receptor Type 1
- Protein Tyrosine Phosphatase, Non-Receptor Type 11
- Protein Tyrosine Phosphatases/metabolism
- Protein-Tyrosine Kinases/metabolism
- Rats
- Rats, Wistar
- Receptor, Angiotensin, Type 1
- Receptors, Angiotensin/chemistry
- Receptors, Angiotensin/metabolism
- Sequence Homology, Amino Acid
- Time Factors
- Transcriptional Activation
- Transfection
- Tyrosine/chemistry
- Tyrosine/metabolism
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Affiliation(s)
- Koichi Seta
- Cardiovascular Research Institute, Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey 07103, USA
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50
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Vázquez J, Sun C, Du J, Fuentes L, Sumners C, Raizada MK. Transduction of a functional domain of the AT1 receptor in neurons by HIV-Tat PTD. Hypertension 2003; 41:751-6. [PMID: 12623991 DOI: 10.1161/01.hyp.0000047878.13793.41] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Despite advances in transgenic and gene transfer technologies, in vivo structure-function studies of the angiotensin II type I receptor (AT1R) have revealed limited information on the diverse actions of angiotensin II. Our objective in the present study was to determine if protein transduction technology with the use of the HIV-Tat protein transduction domain could fill this gap. Recombinant HIV-Tat protein transduction domain fused to EGFP and to the third intracellular loop of the AT1R was expressed. Incubation of hypothalamus and brainstem neurons with this peptide indicated an efficient transport of the protein to most of the cells. This transduction was accompanied by an increase in neuronal firing rate, an effect similar to that observed with angiotensin II stimulation of the neuronal AT1R. The characteristics of the chronotropic effects of recombinant third intracellular loop and its synthetic counterpart were similar and comparable to the effects of angiotensin II on these neurons. In addition, in the presence of the protein kinase C inhibitor calphostin C, the peptide failed to increase firing rate. These observations demonstrated that transduction of neurons with the third intracellular loop of the AT1R produces chronotropic effects similar to those induced by angiotensin II. The data suggests that protein transduction technology could be useful for in vivo AT1R domain transduction.
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MESH Headings
- Action Potentials
- Animals
- Coculture Techniques
- Gene Products, tat/chemistry
- Gene Products, tat/genetics
- Green Fluorescent Proteins
- HIV/chemistry
- Luminescent Proteins/genetics
- Neurons/metabolism
- Neurons/physiology
- Protein Engineering/methods
- Protein Kinase C/metabolism
- Protein Structure, Tertiary
- Protein Transport
- Rats
- Rats, Inbred WKY
- Receptor, Angiotensin, Type 1
- Receptors, Angiotensin/chemistry
- Receptors, Angiotensin/genetics
- Receptors, Angiotensin/metabolism
- Recombinant Fusion Proteins/metabolism
- tat Gene Products, Human Immunodeficiency Virus
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Affiliation(s)
- Jorge Vázquez
- Department of Physiology and Functional Genomics and the University of Florida, McKnight Brain Institute, Gainesville 32610, USA
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