Revising NHE‐1: From Cardiac Homeostasis to Heart Failure and Future Drug Development

Figures

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  Figure 1. (A) Topology model of NHE1 and 3‐dimensional structure of accessory proteins in complex with NHE1‐derived peptides. NHE1 is separated into 2 large domains, the N‐terminal transmembrane domain (~ 500 residues) containing membrane‐spanning helices and the C‐terminal cytoplasmic domain (~ 300 residues) interacting with various cytosolic factors. Binding sites of calcineurin B homologous protein (CHP), calmodulin (CaM), and calcineurin A (CaN‐A) in the NHE1 cytoplasmic domain have been indicated. Structural models for the CHP2–NHE1 peptide (B) and CaM–NHE1 peptide (C) were created from protein data (pdb ID: 2BEC[65] and 2YGG[79], respectively). The green spheres indicate Ca2 + ions. (D) The structure of the CaN–NHE1‐peptide complex was modeled using PD‐FAMS Ligand & Complex [141] by replacing PHPVIVITGPHEE with the NHE1‐derived sequence DLPVITIDPASPQ based on the reference structure (pdb ID: 2P6B) [137]. Only part of the overall structure (2CaN‐A/2CaN‐B/NHE1‐peptide complex) is represented in this figure. NHE1‐derived peptide forming β‐strand (ball‐stick representation) is sandwiched by β‐sheets of 2 CaN‐A molecules. LID, lipid‐interacting domain; PIP2, phosphatidylinositol…

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  Figure 2. Mapping of physiological mechanisms, molecular targets, and therapeutic agents related to arrhythmia. (A) Pro‐arrhythmic processes taking place over successively longer timescales running from ns/μs, ∼10–6 s timescale, molecular events, through ms/s events within each cardiac cycle or multiple cardiac cycles, to hours/days or even week/month, ∼106 s, timescales resulting from (B) an interleaving hierarchy of physiological processes involving interactions (a) at the molecular/membrane level, interactions between surface membrane ion channels underlying automaticity and AP excitation, propagation and recovery. (b) At the cellular level, excitation contraction coupling processes mediate Ca2+signaling. (c) At the systems level, autonomic inputs and their related G‐protein signaling, modulated by central nervous system circadian rhythms. (d) Longer‐term electrophysiological and structural remodeling effects related to metabolic feedback and other upstream modulators. These map onto (C) recently reclassified (a) anti‐arrhythmic drugs that, in turn, act upon (b–e) the molecular targets mediating these physiological processes. These include (b) surface membrane ion channels contributing…

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  Figure 3. Schematic of the mechanism by which the Na + /H+ exchanger (NHE1) and the Na + /Ca2+ exchanger (NCX) interact to generate cardiac injury and dysfunction during ischemia/reperfusion challenge. (1). In the presence of reduced coronary blood flow and absence or reduced oxygen, ischemia causes a reduction in intracellular ATP levels and an accumulation of intracellular H+. The decreased levels of ATP stores impair Na + /K+ ATPase activity reducing Na+ export (2). The elevated intracellular H+ activates NHE1 to remove the H+ in exchange for extracellular Na+ (3). The increasing intracellular Na+ via NHE1, slows the removal of intracellular calcium by NCX or drives NCX in the reverse direction thereby increasing intracellular calcium concentrations in the cell (4). The excess entry of Ca2+ in the cell results in contractile dysfunction and structural damage to the myocardial cell. Republish from Karmazyn M, Pierce GN, Fliegel L. The Remaining Conundrum of the Role of the Na + /H+ Exchanger Isoform 1 (NHE1) in Cardiac Physiology and Pathology: Can It Be Rectified? Rev Cardiovasc Med. 2022 Aug 15;23(8):284. doi: 10.31083/j. rcm2308284. PMID: 39076631; PMCID: PMC11266974. This is an open…