Review
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World J Biol Chem. Aug 26, 2014; 5(3): 334-345
Published online Aug 26, 2014. doi: 10.4331/wjbc.v5.i3.334
Critical role of bicarbonate and bicarbonate transporters in cardiac function
Hong-Sheng Wang, Yamei Chen, Kanimozhi Vairamani, Gary E Shull
Hong-Sheng Wang, Yamei Chen, Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0524, United States
Kanimozhi Vairamani, Gary E Shull, Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, Cincinnati, OH 45267-0524, United States
Author contributions: Shull GE conceived and wrote the review sections of the manuscript; Wang HS wrote the sections dealing with Figures 2 and 3; Wang HS and Chen Y performed the experiments in Figures 2 and 3; and Vairamani K generated the data in Table 1 and Figure 1.
Supported by National Institutes of Health Grants HL061974 to Shull GE; and ES017263 to Wang HS
Correspondence to: Gary E Shull, PhD, Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0524, United States. shullge@ucmail.uc.edu
Telephone: +1-513-5580056 Fax: +1-513-5591885
Received: January 1, 2014
Revised: March 6, 2014
Accepted: May 16, 2014
Published online: August 26, 2014
Abstract

Bicarbonate is one of the major anions in mammalian tissues and extracellular fluids. Along with accompanying H+, HCO3- is generated from CO2 and H2O, either spontaneously or via the catalytic activity of carbonic anhydrase. It serves as a component of the major buffer system, thereby playing a critical role in pH homeostasis. Bicarbonate can also be utilized by a variety of ion transporters, often working in coupled systems, to transport other ions and organic substrates across cell membranes. The functions of HCO3- and HCO3--transporters in epithelial tissues have been studied extensively, but their functions in heart are less well understood. Here we review studies of the identities and physiological functions of Cl-/HCO3- exchangers and Na+/HCO3- cotransporters of the SLC4A and SLC26A families in heart. We also present RNA Seq analysis of their cardiac mRNA expression levels. These studies indicate that slc4a3 (AE3) is the major Cl-/HCO3- exchanger and plays a protective role in heart failure, and that Slc4a4 (NBCe1) is the major Na+/HCO3- cotransporter and affects action potential duration. In addition, previous studies show that HCO3- has a positive inotropic effect in the perfused heart that is largely independent of effects on intracellular Ca2+. The importance of HCO3- in the regulation of contractility is supported by experiments showing that isolated cardiomyocytes exhibit sharply enhanced contractility, with no change in Ca2+ transients, when switched from Hepes-buffered to HCO3-- buffered solutions. These studies demonstrate that HCO3- and HCO3--handling proteins play important roles in the regulation of cardiac function.

Keywords: SLC4, SLC26, Slc26a6, AE1, AE2, NBCn1

Core tip: Bicarbonate is one of the major anions in mammalian tissues and fluids. It plays a critical role in pH homeostasis and is utilized by various transporters to transport other ions and organic substrates across cell membranes. Here we review studies of the physiological functions of Cl-/HCO3- exchangers and Na+/HCO3- cotransporters in heart, present RNA Seq analysis of their cardiac mRNA expression levels, and show that bicarbonate is required for optimal contractility in isolated cardiac myocytes. These studies demonstrate that HCO3- and HCO3- handling proteins are abundant in heart and play important roles in the regulation of cardiac function.