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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 ₁-Adrenergic Stimulation

Cardiovascular Division, King's College London, London, United Kingdom (F.C., A.K.S., M.A.); and Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California (M.S.C., J.T.)

Multiple stimuli of physiological and pathophysiological significance, including ₁-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 ₁-adrenergic stimulation, in ventricular myocytes isolated from the adult rat heart. Initial experiments confirmed that pretreatment of myocytes with fmk before exposure to the ₁-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 ₁-adrenergic stimulation in adult myocardium.

Address correspondence to: Dr. Metin Avkiran, Cardiovascular Division, King's College London, The Rayne Institute, St Thomas' Hospital, London, SE1 7EH, United Kingdom. E-mail: metin.avkiran{at}kcl.ac.uk

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