• Albers-Post scheme
• Empirical equations
• Hill equation
• Ion-transporting ATPases
• Michaelis–Menten

• Consejo Nacional de Investigaciones Científicas y Técnicas
• Secretaría de Ciencia y Técnica, Universidad de Buenos Aires
• Agencia Nacional de Promoción de la Investigación, el Desarrollo Tecnológico y la Innovación

• Na+/K+-ATPase
• inward-rectifier potassium channels
• potassium
• resistance arterioles
• vasodilation

• Animals
• Potassium Channels, Inwardly Rectifying/metabolism
• Swine
• Sodium-Potassium-Exchanging ATPase/metabolism
• Arterioles/metabolism
• Arterioles/drug effects
• Arterioles/physiology
• Coronary Vessels/metabolism
• Coronary Vessels/drug effects
• Coronary Vessels/physiology
• Vasodilation/drug effects
• Potassium/metabolism
• Muscle, Smooth, Vascular/metabolism
• Muscle, Smooth, Vascular/drug effects

• American Heart Association 0235258N to T.W.H, and National Institutes of Health (EY018420 to T.W.H. and HL71761 to L.K.) American Heart Association and National Institutes of Health

• Cell biology
• Cellular physiology
• Physiology

• Current threshold
• Infra-red laser
• Membrane excitability
• Optic nerve

• Animals
• Rats
• Optic Nerve/metabolism
• Lasers
• Sodium/metabolism
• Axons/metabolism
• Axons/physiology
• Axons/radiation effects
• Membrane Potentials/physiology
• Male
• Bumetanide/pharmacology
• Rats, Sprague-Dawley

• Cell biology
• Cellular neuroscience
• Cellular physiology

• Na+,K+-ATPase
• Stoichiometric ratio
• Thermodynamic constraints

Cytosolic Na + concentrations regulate cardiac excitation-contraction coupling and contractility. Inhibition of the Na⁺/K⁺-ATPase (NKA) activity increases cardiac contractility by increasing cytosolic Ca²⁺ levels, as increased cytosolic Na⁺ levels are coupled to less Ca²⁺ extrusion and/or increased Ca²⁺ influx from the Na⁺/Ca²⁺-exchanger. NKA consists of one α subunit and one β subunit, with α1 and α2 being the main α isoforms in cardiomyocytes. Substantial evidence suggests that NKAα2 is the primary regulator of cardiac contractility despite being outnumbered by NKAα1 in cardiomyocytes. This review will mainly focus on differential regulation and subcellular localization of the NKAα1 and NKAα2 isoforms, and their relation to the proposed concept of subcellular gradients of Na⁺ in cardiomyocytes. We will also discuss the potential roles of NKAα2 in mediating cardiac hypertrophy and ventricular arrhythmias.

Food choice is one of the most fundamental and most frequent value-based decisions for all animals including humans. However, the neural circuitry involved in food-based decisions is only recently being addressed. Given the relatively fast dynamics of decision formation, electroencephalography (EEG)-informed fMRI analysis is highly beneficial for localizing this circuitry in humans. Here, by using the EEG correlates of evidence accumulation in a simultaneously recorded EEG-fMRI dataset, we found a significant role for the right temporal-parietal operculum (PO) and medial insula including gustatory cortex (GC) in binary choice between food items. These activations were uncovered by using the “EEG energy” (power 2 of EEG) as the BOLD regressor and were missed if conventional analysis with the EEG signal itself were to be used, in agreement with theoretical predictions for EEG and BOLD relations. No significant positive correlations were found with higher powers of EEG (powers 3 or 4) pointing to specificity and sufficiency of EEG energy as the main correlate of the BOLD response. This finding extends the role of cortical areas traditionally involved in palatability processing to value-based decision-making and offers the “EEG energy” as a key regressor of BOLD response in simultaneous EEG-fMRI designs.

• EEG energy
• EEG-informed fMRI analysis
• food choice
• gustatory cortex
• value-based decision-making

Ion pumps (or P-type ATPases) are membrane proteins, which transport ions through biological membranes against a concentration gradient, a function essential for many biological processes, such as muscle contraction, neurotransmission, and metabolism. Molecular mechanisms underlying active ion transport by ion pumps have been investigated by biochemical experiments and high-resolution structure analyses. Here, the transition of sarcoplasmic reticulum Ca²⁺-ATPase upon dissociation of Ca²⁺ is investigated using atomistic molecular dynamics simulations. We find intermediate structures along the pathway are stabilized by transient interactions between A- and P-domains as well as lipid molecules in the transmembrane helices.

Sarcoplasmic reticulum (SR) Ca²⁺-ATPase transports two Ca²⁺ ions from the cytoplasm to the SR lumen against a large concentration gradient. X-ray crystallography has revealed the atomic structures of the protein before and after the dissociation of Ca²⁺, while biochemical studies have suggested the existence of intermediate states in the transition between E1P⋅ADP⋅2Ca²⁺ and E2P. Here, we explore the pathway and free energy profile of the transition using atomistic molecular dynamics simulations with the mean-force string method and umbrella sampling. The simulations suggest that a series of structural changes accompany the ordered dissociation of ADP, the A-domain rotation, and the rearrangement of the transmembrane (TM) helices. The luminal gate then opens to release Ca²⁺ ions toward the SR lumen. Intermediate structures on the pathway are stabilized by transient sidechain interactions between the A- and P-domains. Lipid molecules between TM helices play a key role in the stabilization. Free energy profiles of the transition assuming different protonation states suggest rapid exchanges between Ca²⁺ ions and protons when the Ca²⁺ ions are released toward the SR lumen.

• calcium ion pump
• conformational change
• free energy analysis
• molecular dynamics
• protein–lipid interactions

• action potential repolarization
• atrial fibrillation (AF)
• hypokalemia
• inwardly rectifying K+ current
• mathematical modeling
• plasma potassium levels
• renal dialysis
• sodium potassium (Na+/K+-ATPase) pump

• evolution
• free-energy landscape
• kinetic optimization
• molecular machines
• nonequilibrium steady state

• NKA
• Na channels
• Na homeostasis
• fuzzy space
• subsarcolemmal space

• Biochemistry
• Biomedical engineering
• Bond graph
• Chemical reaction network
• Systems biology

• AMPA-Kainate receptor
• Transmembrane transport
• active transport
• bidirectional assymetric flow
• excitable cell
• ion channels
• passive transport
• rectification

The identification of voltage-sensing elements in membrane proteins is challenging due to the diversity of voltage-sensing mechanisms. Kasimova et al. present a computational approach to predict the elements involved in voltage sensing, which they validate using voltage-gated ion channels.

Voltage-sensitive membrane proteins are united by their ability to transform changes in membrane potential into mechanical work. They are responsible for a spectrum of physiological processes in living organisms, including electrical signaling and cell-cycle progression. Although the mechanism of voltage-sensing has been well characterized for some membrane proteins, including voltage-gated ion channels, even the location of the voltage-sensing elements remains unknown for others. Moreover, the detection of these elements by using experimental techniques is challenging because of the diversity of membrane proteins. Here, we provide a computational approach to predict voltage-sensing elements in any membrane protein, independent of its structure or function. It relies on an estimation of the propensity of a protein to respond to changes in membrane potential. We first show that this property correlates well with voltage sensitivity by applying our approach to a set of voltage-sensitive and voltage-insensitive membrane proteins. We further show that it correctly identifies authentic voltage-sensitive residues in the voltage-sensor domain of voltage-gated ion channels. Finally, we investigate six membrane proteins for which the voltage-sensing elements have not yet been characterized and identify residues and ions that might be involved in the response to voltage. The suggested approach is fast and simple and enables a characterization of voltage sensitivity that goes beyond mere identification of charges. We anticipate that its application before mutagenesis experiments will significantly reduce the number of potential voltage-sensitive elements to be tested.

• Age-related hearing loss
• K-ATPase
• Na
• Ouabain
• Stria vascularis

• Arrhythmias
• Drug safety evaluations, (CiPA)
• Early after-depolarizations (EADs)
• Inward rectification
• K(+) currents
• Mathematical simulations
• Plasma K(+), [K(+)](o)
• Repolarization

The aim of this study was to observe the effects of strophanthin induced inhibition of the Na-/K-ATPase in liver cells using a magnetic resonance (MR) compatible bioreactor. A microcavity array with a high density three-dimensional cell culture served as a functional magnetic resonance imaging (MRI) phantom for sodium multi quantum (MQ) spectroscopy. Direct contrast enhanced (DCE) MRI revealed the homogenous distribution of biochemical substances inside the bioreactor. NMR experiments using advanced bioreactors have advantages with respect to having full control over a variety of physiological parameters such as temperature, gas composition and fluid flow. Simultaneous detection of single quantum (SQ) and triple quantum (TQ) MR signals improves accuracy and was achieved by application of a pulse sequence with a time proportional phase increment (TQTPPI). The time course of the Na-/K-ATPase inhibition in the cell culture was demonstrated by the corresponding alterations of sodium TQ/SQ MR signals.

The Na/K pump exports cytoplasmic Na ions while importing K ions, and its activity is thought to be affected by restricted intracellular Na diffusion in cardiac myocytes. Lu and Hilgemann find instead that the pump can enter an inactivated state and that inactivation can be relieved by cytoplasmic Na.

Decades ago, it was proposed that Na transport in cardiac myocytes is modulated by large changes in cytoplasmic Na concentration within restricted subsarcolemmal spaces. Here, we probe this hypothesis for Na/K pumps by generating constitutive transsarcolemmal Na flux with the Na channel opener veratridine in whole-cell patch-clamp recordings. Using 25 mM Na in the patch pipette, pump currents decay strongly during continuous activation by extracellular K (τ, ∼2 s). In contradiction to depletion hypotheses, the decay becomes stronger when pump currents are decreased by hyperpolarization. Na channel currents are nearly unchanged by pump activity in these conditions, and conversely, continuous Na currents up to 0.5 nA in magnitude have negligible effects on pump currents. These outcomes are even more pronounced using 50 mM Li as a cytoplasmic Na congener. Thus, the Na/K pump current decay reflects mostly an inactivation mechanism that immobilizes Na/K pump charge movements, not cytoplasmic Na depletion. When channel currents are increased beyond 1 nA, models with unrestricted subsarcolemmal diffusion accurately predict current decay (τ ∼15 s) and reversal potential shifts observed for Na, Li, and K currents through Na channels opened by veratridine, as well as for Na, K, Cs, Li, and Cl currents recorded in nystatin-permeabilized myocytes. Ion concentrations in the pipette tip (i.e., access conductance) track without appreciable delay the current changes caused by sarcolemmal ion flux. Importantly, cytoplasmic mixing volumes, calculated from current decay kinetics, increase and decrease as expected with osmolarity changes (τ >30 s). Na/K pump current run-down over 20 min reflects a failure of pumps to recover from inactivation. Simulations reveal that pump inactivation coupled with Na-activated recovery enhances the rapidity and effectivity of Na homeostasis in cardiac myocytes. In conclusion, an autoregulatory mechanism enhances cardiac Na/K pump activity when cytoplasmic Na rises and suppresses pump activity when cytoplasmic Na declines.

• Affinity
• Ion concentration
• Model
• Na-K-ATPase
• Transporter

• Na+/K+-ATPase
• familial hemiplegic migraine
• human ATP1A2
• neuronal hyperexcitability
• protein expression
• protein stability
• protein targeting
• structure-function studies

The K⁺ affinity of the Na,K-ATPase α2 isoform matches its activity to the range of extracellular K⁺ concentrations in the T-tubules at rest and during contraction, maintaining the excitability of active muscle.

The Na,K-ATPase α2 isoform is the predominant Na,K-ATPase in adult skeletal muscle and the sole Na,K-ATPase in the transverse tubules (T-tubules). In quiescent muscles, the α2 isozyme operates substantially below its maximal transport capacity. Unlike the α1 isoform, the α2 isoform is not required for maintaining resting ion gradients or the resting membrane potential, canonical roles of the Na,K-ATPase in most other cells. However, α2 activity is stimulated immediately upon the start of contraction and, in working muscles, its contribution is crucial to maintaining excitation and resisting fatigue. Here, we show that α2 activity is determined in part by the K⁺ concentration in the T-tubules, through its K⁺ substrate affinity. Apparent K⁺ affinity was determined from measurements of the K_1/2 for K⁺ activation of pump current in intact, voltage-clamped mouse flexor digitorum brevis muscle fibers. Pump current generated by the α2 Na,K-ATPase, Ip, was identified as the outward current activated by K⁺ and inhibited by micromolar ouabain. Ip was outward at all potentials studied (−90 to −30 mV) and increased with depolarization in the subthreshold range, −90 to −50 mV. The Q₁₀ was 2.1 over the range of 22–37°C. The K_1/2,K of Ip was 4.3 ± 0.3 mM at −90 mV and was relatively voltage independent. This K⁺ affinity is lower than that reported for other cell types but closely matches the dynamic range of extracellular K⁺ concentrations in the T-tubules. During muscle contraction, T-tubule luminal K⁺ increases in proportion to the frequency and duration of action potential firing. This K_1/2,K predicts a low fractional occupancy of K⁺ substrate sites at the resting extracellular K⁺ concentration, with occupancy increasing in proportion to the frequency of membrane excitation. The stimulation of preexisting pumps by greater K⁺ site occupancy thus provides a rapid mechanism for increasing α2 activity in working muscles.

The Na⁺/K⁺-ATPase restores sodium (Na⁺) and potassium (K⁺) electrochemical gradients dissipated by action potentials and ion-coupled transport processes. As ions are transported, they become transiently trapped between intracellular and extracellular gates. Once the external gate opens, three Na⁺ ions are released, followed by the binding and occlusion of two K⁺ ions. While the mechanisms of Na⁺ release have been well characterized by the study of transient Na⁺ currents, smaller and faster transient currents mediated by external K⁺ have been more difficult to study. Here we show that external K⁺ ions travelling to their binding sites sense only a small fraction of the electric field as they rapidly and simultaneously become occluded. Consistent with these results, molecular dynamics simulations of a pump model show a wide water-filled access channel connecting the binding site to the external solution. These results suggest a mechanism of K⁺ gating different from that of Na⁺ occlusion.

During transport by the Na⁺/K⁺-ATPase, Na⁺ and K⁺ ions become occluded between intra- and extracellular gates. Here Castillo et al. measure transient electrical signals arising from K⁺ occlusion and use molecular simulations to describe a K⁺ gating mechanism fundamentally different to that of Na⁺.

• Cardiomyocyte
• Contraction
• Estrogen-Related Receptor
• Hypoxia
• Peroxisome Proliferator-Activated Receptor γ Coactivator-1

• Age Factors
• Animals
• Cats
• Electric Stimulation
• Hypoxia
• Myocardial Contraction
• Myocytes, Cardiac/metabolism
• Myocytes, Cardiac/physiology
• Protein Isoforms
• Receptors, Estrogen/physiology
• Transcription Factors/biosynthesis
• ERRalpha Estrogen-Related Receptor

The Na⁺/K⁺ pump is a hybrid transporter that can also import protons at physiological K⁺ and Na⁺ concentrations.

A single Na⁺/K⁺-ATPase pumps three Na⁺ outwards and two K⁺ inwards by alternately exposing ion-binding sites to opposite sides of the membrane in a conformational sequence coupled to pump autophosphorylation from ATP and auto-dephosphorylation. The larger flow of Na⁺ than K⁺ generates outward current across the cell membrane. Less well understood is the ability of Na⁺/K⁺ pumps to generate an inward current of protons. Originally noted in pumps deprived of external K⁺ and Na⁺ ions, as inward current at negative membrane potentials that becomes amplified when external pH is lowered, this proton current is generally viewed as an artifact of those unnatural conditions. We demonstrate here that this inward current also flows at physiological K⁺ and Na⁺ concentrations. We show that protons exploit ready reversibility of conformational changes associated with extracellular Na⁺ release from phosphorylated Na⁺/K⁺ pumps. Reversal of a subset of these transitions allows an extracellular proton to bind an acidic side chain and to be subsequently released to the cytoplasm. This back-step of phosphorylated Na⁺/K⁺ pumps that enables proton import is not required for completion of the 3 Na⁺/2 K⁺ transport cycle. However, the back-step occurs readily during Na⁺/K⁺ transport when external K⁺ ion binding and occlusion are delayed, and it occurs more frequently when lowered extracellular pH raises the probability of protonation of the externally accessible carboxylate side chain. The proton route passes through the Na⁺-selective binding site III and is distinct from the principal pathway traversed by the majority of transported Na⁺ and K⁺ ions that passes through binding site II. The inferred occurrence of Na⁺/K⁺ exchange and H⁺ import during the same conformational cycle of a single molecule identifies the Na⁺/K⁺ pump as a hybrid transporter. Whether Na⁺/K⁺ pump–mediated proton inflow may have any physiological or pathophysiological significance remains to be clarified.

• Animals
• Gene Expression Regulation
• Humans
• Ion Channels/chemistry
• Ion Channels/genetics
• Ion Channels/metabolism
• Ion Pumps/chemistry
• Ion Pumps/genetics
• Ion Pumps/metabolism
• RNA Editing
• Receptors, Glutamate/chemistry
• Receptors, Glutamate/genetics
• Receptors, Glutamate/metabolism
• Synaptic Transmission

• Z01 NS003019-01 Intramural NIH HHS

• basal ganglia
• cerebellum

• enterocytes
• epithelial transport
• homeostasis
• ionic regulation
• mathematical modeling

AIM: Functional characterization of ATP1A2 mutations that are related to familial or sporadic hemiplegic migraine (FHM2, SHM).

METHODS: cRNA of human Na⁺/K⁺-ATPase α₂- and β₁-subunits were injected in Xenopus laevis oocytes. FHM2 or SHM mutations of residues located in putative α/β interaction sites or in the α₂-subunit’s C-terminal region were investigated. Mutants were analyzed by the two-electrode voltage-clamp (TEVC) technique on Xenopus oocytes. Stationary K⁺-induced Na⁺/K⁺ pump currents were measured, and the voltage dependence of apparent K⁺ affinity was investigated. Transient currents were recorded as ouabain-sensitive currents in Na⁺ buffers to analyze kinetics and voltage-dependent pre-steady state charge translocations. The expression of constructs was verified by preparation of plasma membrane and total membrane fractions of cRNA-injected oocytes.

RESULTS: Compared to the wild-type enzyme, the mutants G900R and E902K showed no significant differences in the voltage dependence of K⁺-induced currents, and analysis of the transient currents indicated that the extracellular Na⁺ affinity was not affected. Mutant G855R showed no pump activity detectable by TEVC. Also for L994del and Y1009X, pump currents could not be recorded. Analysis of the plasma and total membrane fractions showed that the expressed proteins were not or only minimally targeted to the plasma membrane. Whereas the mutation K1003E had no impact on K⁺ interaction, D999H affected the voltage dependence of K⁺-induced currents. Furthermore, kinetics of the transient currents was altered compared to the wild-type enzyme, and the apparent affinity for extracellular Na⁺ was reduced.

CONCLUSION: The investigated FHM2/SHM mutations influence protein function differently depending on the structural impact of the mutated residue.

• Na⁺/K⁺-ATPase
• Electrophysiology
• Voltage dependence
• Familial hemiplegic migraine
• C-terminus
• β-subunit

A common assumption of excitotoxic mechanisms in the nervous system is that the ionic imbalance resulting from overstimulation of glutamate receptors and increased Na⁺ and Ca⁺⁺ influx overwhelms cellular energy metabolic systems leading to cell death. The goal of this study was to examine how a chronic Na⁺ channel leak current in developing Purkinje cells in the heterozygous Lurcher mutant (+/Lc) affects the expression and distribution of the α3 subunit of the Na⁺/K⁺ ATPase pump, a key component of the homeostasis system that maintains ionic equilibrium in neurons. The expression pattern of the catalytic α3 Na⁺/K⁺ ATPase subunit was analyzed by immunohistochemistry, histochemistry, and Western Blots in wild type (WT) and +/Lc cerebella at postnatal days P10, P15, and P25 to determine if there are changes in the distribution of active Na⁺/K⁺ ATPase subunits in degenerating Purkinje cells. The results suggest that the expression of the catalytic α3 subunit is altered in chronically depolarized +/Lc Purkinje cells, although the density of active Na⁺/K⁺ ATPase pumps is not significantly altered compared with WT in the cerebellar cortex at P15, and then declines from P15 to P25 in the +/Lc cerebellum as the +/Lc Purkinje cells degenerate.

• ACE
• AR
• Ang II
• GSH
• Grx1
• Heart failure
• I(p)
• NADPH oxidase
• NO
• Na(+)–K(+) pump
• ONOO(−)
• PKA
• PKC
• PKG
• PP2A
• Redox regulation
• [Na(+)](i)
• adrenergic receptor
• angiotensin II
• angiotensin converting enzyme
• cAMP
• cyclic adenosine monophosphate, πGST, π isoform of glutathione S-transferase
• electrogenic Na(+)–K(+) pump current
• glutaredoxin 1
• glutathione
• intracellular Na(+) concentration
• nicotinamide adenine dinucleotide phosphate-oxidase
• nitric oxide
• peroxynitrite
• protein kinase A
• protein kinase C
• protein kinase G
• protein phosphatase 2A
• sGC
• soluble guanylyl cyclase

• Action Potentials/drug effects
• Action Potentials/physiology
• Animals
• Calcium/metabolism
• Cardiac Glycosides/pharmacology
• Computer Simulation
• Heart/physiology
• Humans
• Ion Transport
• Myocardium/metabolism
• Potassium/metabolism
• Sodium/metabolism
• Sodium-Potassium-Exchanging ATPase/physiology
• Systems Biology

• 100246 Wellcome Trust
• G0700278 Medical Research Council

• Animals
• Cell Movement/drug effects
• Digoxin/pharmacology
• Dogs
• Electric Stimulation/methods
• Enzyme Inhibitors/pharmacology
• Ion Transport/drug effects
• Madin Darby Canine Kidney Cells
• Membrane Potentials/drug effects
• Membrane Potentials/physiology
• Models, Biological
• Ouabain/pharmacology
• Protein Transport/drug effects
• Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors
• Sodium-Potassium-Exchanging ATPase/metabolism
• Wound Healing/physiology
• Wounds and Injuries/pathology
• Wounds and Injuries/therapy

• R01 EY019101 NEI NIH HHS
• 1R01EY019101 NEI NIH HHS

• Amino Acid Sequence
• Animals
• Cyclic AMP-Dependent Protein Kinases/metabolism
• Humans
• Membrane Proteins/chemistry
• Membrane Proteins/metabolism
• Models, Molecular
• Molecular Sequence Data
• Myocardium/metabolism
• Nitric Oxide/metabolism
• Phosphoproteins/chemistry
• Phosphoproteins/metabolism
• Phosphorylation
• Protein Kinase C/metabolism
• Protein Processing, Post-Translational
• Sequence Alignment
• Sodium-Potassium-Exchanging ATPase/chemistry
• Sodium-Potassium-Exchanging ATPase/metabolism

• PG/10/93/28650 British Heart Foundation
• RG/12/4/29426 British Heart Foundation
• RG/07/001/22628 British Heart Foundation
• PG/12/6/29366 British Heart Foundation
• RG/07/001 British Heart Foundation
• G0700903 Medical Research Council
• G070090 Medical Research Council

• Animals
• Arterioles/enzymology
• Arterioles/metabolism
• Arterioles/physiology
• Cell Polarity/physiology
• Electric Stimulation/methods
• Ion Transport/physiology
• Male
• Membrane Potentials/physiology
• Myocytes, Smooth Muscle/enzymology
• Myocytes, Smooth Muscle/metabolism
• Myocytes, Smooth Muscle/physiology
• Rats
• Rats, Sprague-Dawley
• Sodium-Potassium-Exchanging ATPase/metabolism

• antarctica
• ion channels
• ion transporters
• na⁺/k⁺-atpase
• octopus
• temperature adaptation

• Acclimatization/genetics
• Adaptation, Physiological/genetics
• Amino Acid Sequence
• Animals
• Antarctic Regions
• Binding Sites
• Cell Membrane/metabolism
• Electrophysiology/methods
• Ions
• Lipid Bilayers/chemistry
• Molecular Conformation
• Molecular Sequence Data
• Protein Isoforms
• Protein Structure, Tertiary
• Sodium-Potassium-Exchanging ATPase/chemistry
• Sodium-Potassium-Exchanging ATPase/metabolism
• Temperature
• Xenopus

• ZIA NS002993 Intramural NIH HHS
• S06GM08102 NIGMS NIH HHS
• R01 NS064259 NINDS NIH HHS
• G12 RR 03051 NCRR NIH HHS
• 2 U54 NS039405-06 NINDS NIH HHS
• P20 RR16470 NCRR NIH HHS
• P20 RR016470 NCRR NIH HHS
• G12 RR003051 NCRR NIH HHS
• 1R01NS64259 NINDS NIH HHS
• U54 NS039405 NINDS NIH HHS
• S06 GM008102 NIGMS NIH HHS
• G12 MD007600 NIMHD NIH HHS

• Action Potentials/physiology
• Arrhythmias, Cardiac
• Calcium Channels, L-Type/physiology
• Calmodulin/metabolism
• Computational Biology
• Heart Ventricles/cytology
• Humans
• Models, Cardiovascular
• Myocytes, Cardiac/physiology
• Patch-Clamp Techniques
• Reproducibility of Results
• Sodium Channels/physiology
• Ventricular Function/physiology

• R01 HL049054 NHLBI NIH HHS
• R56 HL049054 NHLBI NIH HHS
• R01-HL049054-18 NHLBI NIH HHS
• R01-HLR01033343-26 PHS HHS

• Action Potentials
• Biophysics/methods
• Calcium/chemistry
• Calcium Channels/physiology
• Computational Biology/methods
• Female
• Humans
• Membrane Potentials/physiology
• Models, Theoretical
• Myometrium/pathology
• Myometrium/physiology
• Potassium/chemistry
• Pregnancy
• Sodium/chemistry
• Uterine Contraction/physiology

• BBSRC/B/1678X Biotechnology and Biological Sciences Research Council
• G0900525 Medical Research Council
• G0902091 Medical Research Council