Document Detail

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 alpha1-adrenergic stimulation.
MedLine Citation:
PMID:  17142297     Owner:  NLM     Status:  MEDLINE    
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.
Friederike Cuello; Andrew K Snabaitis; Michael S Cohen; Jack Taunton; Metin Avkiran
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2006-12-01
Journal Detail:
Title:  Molecular pharmacology     Volume:  71     ISSN:  0026-895X     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  2007 Mar 
Date Detail:
Created Date:  2007-02-19     Completed Date:  2007-03-22     Revised Date:  2014-06-18    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  799-806     Citation Subset:  IM    
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MeSH Terms
Cation Transport Proteins / metabolism*
Extracellular Signal-Regulated MAP Kinases / physiology
Myocytes, Cardiac / metabolism*
Protein Kinase Inhibitors / pharmacology*
Receptors, Adrenergic, alpha-1 / physiology*
Ribosomal Protein S6 Kinases / antagonists & inhibitors,  physiology*
Sodium-Hydrogen Antiporter / metabolism*
Grant Support
G0300052//Medical Research Council; R01 GM071434-04/GM/NIGMS NIH HHS
Reg. No./Substance:
0/Cation Transport Proteins; 0/Protein Kinase Inhibitors; 0/Receptors, Adrenergic, alpha-1; 0/SLC9A1 protein, human; 0/Sodium-Hydrogen Antiporter; EC Protein S6 Kinases; EC Signal-Regulated MAP Kinases

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