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Intracellular ß1-Adrenergic Receptors and Organic Cation Transporter 3 Mediate Phospholamban Phosphorylation to Enhance Cardiac Contractility.
Wang, Ying; Shi, Qian; Li, Minghui; Zhao, Meimi; Reddy Gopireddy, Raghavender; Teoh, Jian-Peng; Xu, Bing; Zhu, Chaoqun; Ireton, Kyle E; Srinivasan, Sanghavi; Chen, Shaoliang; Gasser, Paul J; Bossuyt, Julie; Hell, Johannes W; Bers, Donald M; Xiang, Yang K.
Afiliação
  • Wang Y; Department of Pharmacology, University of California at Davis (Y.W., Q.S., M.L., M.Z., R.R.G., J.-P.T., B.X., C.Z., K.E.I., S.S., J.B., J.W.H., D.M.B., Y.K.X.).
  • Shi Q; Department of Pharmacology, University of California at Davis (Y.W., Q.S., M.L., M.Z., R.R.G., J.-P.T., B.X., C.Z., K.E.I., S.S., J.B., J.W.H., D.M.B., Y.K.X.).
  • Li M; Department of Pharmacology, University of California at Davis (Y.W., Q.S., M.L., M.Z., R.R.G., J.-P.T., B.X., C.Z., K.E.I., S.S., J.B., J.W.H., D.M.B., Y.K.X.).
  • Zhao M; Nanjing First Hospital, Nanjing Medical University, China (M.L., S.C.).
  • Reddy Gopireddy R; Department of Pharmacology, University of California at Davis (Y.W., Q.S., M.L., M.Z., R.R.G., J.-P.T., B.X., C.Z., K.E.I., S.S., J.B., J.W.H., D.M.B., Y.K.X.).
  • Teoh JP; Department of Pharmaceutical Toxicology, China Medical University (M.Z.).
  • Xu B; Department of Pharmacology, University of California at Davis (Y.W., Q.S., M.L., M.Z., R.R.G., J.-P.T., B.X., C.Z., K.E.I., S.S., J.B., J.W.H., D.M.B., Y.K.X.).
  • Zhu C; Department of Pharmacology, University of California at Davis (Y.W., Q.S., M.L., M.Z., R.R.G., J.-P.T., B.X., C.Z., K.E.I., S.S., J.B., J.W.H., D.M.B., Y.K.X.).
  • Ireton KE; Department of Pharmacology, University of California at Davis (Y.W., Q.S., M.L., M.Z., R.R.G., J.-P.T., B.X., C.Z., K.E.I., S.S., J.B., J.W.H., D.M.B., Y.K.X.).
  • Srinivasan S; VA Northern California Health Care System, Mather, CA (B.X., Y.K.X.).
  • Chen S; Department of Pharmacology, University of California at Davis (Y.W., Q.S., M.L., M.Z., R.R.G., J.-P.T., B.X., C.Z., K.E.I., S.S., J.B., J.W.H., D.M.B., Y.K.X.).
  • Gasser PJ; Department of Pharmacology, University of California at Davis (Y.W., Q.S., M.L., M.Z., R.R.G., J.-P.T., B.X., C.Z., K.E.I., S.S., J.B., J.W.H., D.M.B., Y.K.X.).
  • Bossuyt J; Department of Pharmacology, University of California at Davis (Y.W., Q.S., M.L., M.Z., R.R.G., J.-P.T., B.X., C.Z., K.E.I., S.S., J.B., J.W.H., D.M.B., Y.K.X.).
  • Hell JW; Nanjing First Hospital, Nanjing Medical University, China (M.L., S.C.).
  • Bers DM; Department of Biomedical Sciences, Marquette University, Milwaukee, WI (P.J.G.).
  • Xiang YK; Department of Pharmacology, University of California at Davis (Y.W., Q.S., M.L., M.Z., R.R.G., J.-P.T., B.X., C.Z., K.E.I., S.S., J.B., J.W.H., D.M.B., Y.K.X.).
Circ Res ; 128(2): 246-261, 2021 01 22.
Article em En | MEDLINE | ID: mdl-33183171
ABSTRACT
RATIONALE ß1ARs (ß1-adrenoceptors) exist at intracellular membranes and OCT3 (organic cation transporter 3) mediates norepinephrine entry into cardiomyocytes. However, the functional role of intracellular ß1AR in cardiac contractility remains to be elucidated.

OBJECTIVE:

Test localization and function of intracellular ß1AR on cardiac contractility. METHODS AND

RESULTS:

Membrane fractionation, super-resolution imaging, proximity ligation, coimmunoprecipitation, and single-molecule pull-down demonstrated a pool of ß1ARs in mouse hearts that were associated with sarco/endoplasmic reticulum Ca2+-ATPase at the sarcoplasmic reticulum (SR). Local PKA (protein kinase A) activation was measured using a PKA biosensor targeted at either the plasma membrane (PM) or SR. Compared with wild-type, myocytes lacking OCT3 (OCT3-KO [OCT3 knockout]) responded identically to the membrane-permeant ßAR agonist isoproterenol in PKA activation at both PM and SR. The same was true at the PM for membrane-impermeant norepinephrine, but the SR response to norepinephrine was suppressed in OCT3-KO myocytes. This differential effect was recapitulated in phosphorylation of the SR-pump regulator phospholamban. Similarly, OCT3-KO selectively suppressed calcium transients and contraction responses to norepinephrine but not isoproterenol. Furthermore, sotalol, a membrane-impermeant ßAR-blocker, suppressed isoproterenol-induced PKA activation at the PM but permitted PKA activation at the SR, phospholamban phosphorylation, and contractility. Moreover, pretreatment with sotalol in OCT3-KO myocytes prevented norepinephrine-induced PKA activation at both PM and the SR and contractility.

CONCLUSIONS:

Functional ß1ARs exists at the SR and is critical for PKA-mediated phosphorylation of phospholamban and cardiac contractility upon catecholamine stimulation. Activation of these intracellular ß1ARs requires catecholamine transport via OCT3.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas de Ligação ao Cálcio / Receptores Adrenérgicos beta 2 / Receptores Adrenérgicos beta 1 / Proteínas de Transporte de Cátions Orgânicos / Miócitos Cardíacos / Contração Miocárdica Idioma: En Ano de publicação: 2021 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Proteínas de Ligação ao Cálcio / Receptores Adrenérgicos beta 2 / Receptores Adrenérgicos beta 1 / Proteínas de Transporte de Cátions Orgânicos / Miócitos Cardíacos / Contração Miocárdica Idioma: En Ano de publicação: 2021 Tipo de documento: Article