Regulatory effects of G protein-coupled receptors on cardiac sarcolemmal Na+/H+ exchanger activity: signalling and significance

• Published in: Cardiovascular research Vol. 57; no. 4; pp. 942 - 952
• Main Authors: Avkiran, Metin, Haworth, Robert S
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Science 15.03.2003; Oxford University Press
• Subjects: Biological and medical sciences; Cardiology. Vascular system; Contractile function; Coronary heart disease; G-proteins; GTP-Binding Proteins - metabolism; Heart; Humans; Hypertrophy; Ischemia; Medical sciences; Myocardial Contraction - physiology; Myocardial Reperfusion Injury - metabolism; Myocytes; Myocytes, Cardiac - metabolism; Na/H-exchanger; Receptors; Receptors, Cell Surface - physiology; Sarcolemma - metabolism; Signal transduction; Signal Transduction - physiology; Sodium-Hydrogen Exchangers - metabolism; Rat; Pathogenesis; Receptors: Signal transduction; Contractile function; Rodentia; Contractility; Na/H-exchanger; Cardiovascular disease; Myocytes; Coronary heart disease; Myocardial disease; Vascular disease; Vertebrata; Mammalia; Ischemia; Sarcoplasmic reticulum; Animal; Sodium ion; Myocardium; Ion exchange; Hydrogen ion; G-proteins; G protein; Hypertrophy
• ISSN: 0008-6363; 1755-3245
• DOI: 10.1016/S0008-6363(02)00782-4

In cardiac myocytes, sarcolemmal Na+/H+ exchanger (NHE) activity is subject to regulation by a variety of G protein-coupled receptor (GPCR) systems. This regulation usually manifests as an increase in NHE activity (e.g. in response to the stimulation of α1-adrenergic, angiotensin AT1, endothelin and thrombin receptors), although some GPCR systems have been shown to inhibit sarcolemmal NHE activity (e.g. β1-adrenergic receptors) or to attenuate its stimulation by other ligands (e.g. adenosine A1 and angiotensin AT2 receptors). The pertinent molecular signalling mechanisms are only now beginning to be unravelled, with the extracellular signal regulated kinase/ribosomal S6 kinase pathway and the protein kinase C pathway both appearing to play critical roles in the stimulation of sarcolemmal NHE activity. GPCR-mediated regulation of sarcolemmal NHE activity is likely to play significant roles in modulating myocardial function in both physiological and pathophysiological conditions. These roles include the regulation of (1) myocardial pHi and contractility, (2) myocardial susceptibility to injury and dysfunction during ischaemia and reperfusion, and (3) myocardial hypertrophy in response to neurohormonal and mechanical stimuli. Greater understanding of the pertinent molecular signalling mechanisms distal to GPCR stimulation may reveal novel targets for therapeutic manipulation.