Evidence for Direct Regulation of Myocardial Na+/H+Exchanger Isoform 1 Phosphorylation and Activity by 90-kDa Ribosomal S6 Kinase (RSK): Effects of the Novel and Specific RSK Inhibitor fmk on Responses to α1-Adrenergic Stimulation
- 1 December 2006
- journal article
- Published by American Society for Pharmacology & Experimental Therapeutics (ASPET) in Molecular Pharmacology
- Vol. 71 (3), 799-806
- https://doi.org/10.1124/mol.106.029900
Abstract
Multiple stimuli of physiological and pathophysiological significance, including alpha1-adrenoceptor agonists, stimulate the cardiac sarcolemmal Na+/H+ exchanger isoform 1 (NHE1) through activation of the mitogen-activated or extracellular signal-regulated kinase (ERK) kinase (MEK) ERK-90-kDa ribosomal S6 kinase (RSK) signaling cascade. However, the individual contributions of ERK and RSK, which can each phosphorylate the NHE1 regulatory domain, to such stimulation are unknown. In the present study, we have used the novel RSK inhibitor fmk to determine the role of RSK as a direct regulator of NHE1 phosphorylation and activity in response to alpha1-adrenergic stimulation, in ventricular myocytes isolated from the adult rat heart. Initial experiments confirmed that pretreatment of myocytes with fmk before exposure to the alpha1-adrenoceptor agonist phenylephrine inhibited RSK C-terminal kinase activity and thereby RSK N-terminal kinase activation, without affecting MEK or ERK activation. Pretreatment of myocytes with fmk also inhibited phenylephrine-induced increases in NHE1 phosphorylation and the rate of NHE1-mediated H+ efflux under conditions of intracellular acidosis. These findings reveal, for the first time to our knowledge, that RSK is the principal regulator of NHE1 phosphorylation and activity after alpha1-adrenergic stimulation in adult myocardium.This publication has 37 references indexed in Scilit:
- A Novel Role for Protein Phosphatase 2A in Receptor-mediated Regulation of the Cardiac Sarcolemmal Na+/H+ Exchanger NHE1Published by Elsevier BV ,2006
- Inhibiting p90 Ribosomal S6 Kinase Prevents Na + -H + Exchanger–Mediated Cardiac Ischemia-Reperfusion InjuryCirculation, 2006
- Regulation of the extracellular signal-regulated kinase pathway in adult myocardium: differential roles of Gq/11, Gi and G12/13 proteins in signalling by α1-adrenergic, endothelin-1 and thrombin-sensitive protease-activated receptorsCellular Signalling, 2005
- Inhibition of the Na+/H+ exchanger attenuates the deterioration of ventricular function during pacing-induced heart failure in rabbitsCardiovascular Research, 2004
- Regression of Isoproterenol-Induced Cardiac Hypertrophy by Na + /H + Exchanger InhibitionHypertension, 2003
- Inhibition of Na + -H + Exchange Prevents Hypertrophy, Fibrosis, and Heart Failure in β 1 -Adrenergic Receptor Transgenic MiceCirculation Research, 2002
- Activation of Na+/H+ Exchanger-directed Protein Kinases in the Ischemic and Ischemic-reperfused Rat MyocardiumPublished by Elsevier BV ,2001
- Adenosine A1 receptor stimulation inhibits α1‐adrenergic activation of the cardiac sarcolemmal Na+/H+ exchangerBritish Journal of Pharmacology, 2000
- 90-kDa Ribosomal S6 Kinase Is Phosphorylated and Activated by 3-Phosphoinositide-dependent Protein Kinase-1Published by Elsevier BV ,1999
- Angiotensin II stimulates sodium-hydrogen exchange in adult rabbit ventricular myocytesCardiovascular Research, 1995