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Genetically Encoded Biosensors Reveal PKA Hyperphosphorylation on the Myofilaments in Rabbit Heart Failure.
Barbagallo, Federica; Xu, Bing; Reddy, Gopireddy R; West, Toni; Wang, Qingtong; Fu, Qin; Li, Minghui; Shi, Qian; Ginsburg, Kenneth S; Ferrier, William; Isidori, Andrea M; Naro, Fabio; Patel, Hemal H; Bossuyt, Julie; Bers, Donald; Xiang, Yang K.
Afiliación
  • Barbagallo F; From the Department of Pharmacology, University of California at Davis (F.B., B.X., G.R.R., T.W., Q.W., Q.F., M.L., Q.S., K.S.G., J.B., D.B., Y.K.X.); Department of Experimental Medicine (F.B., A.M.I.) and Department of Anatomical, Histological, Forensic, and Orthopedic Sciences (F.N.), Sapienza Uni
  • Xu B; From the Department of Pharmacology, University of California at Davis (F.B., B.X., G.R.R., T.W., Q.W., Q.F., M.L., Q.S., K.S.G., J.B., D.B., Y.K.X.); Department of Experimental Medicine (F.B., A.M.I.) and Department of Anatomical, Histological, Forensic, and Orthopedic Sciences (F.N.), Sapienza Uni
  • Reddy GR; From the Department of Pharmacology, University of California at Davis (F.B., B.X., G.R.R., T.W., Q.W., Q.F., M.L., Q.S., K.S.G., J.B., D.B., Y.K.X.); Department of Experimental Medicine (F.B., A.M.I.) and Department of Anatomical, Histological, Forensic, and Orthopedic Sciences (F.N.), Sapienza Uni
  • West T; From the Department of Pharmacology, University of California at Davis (F.B., B.X., G.R.R., T.W., Q.W., Q.F., M.L., Q.S., K.S.G., J.B., D.B., Y.K.X.); Department of Experimental Medicine (F.B., A.M.I.) and Department of Anatomical, Histological, Forensic, and Orthopedic Sciences (F.N.), Sapienza Uni
  • Wang Q; From the Department of Pharmacology, University of California at Davis (F.B., B.X., G.R.R., T.W., Q.W., Q.F., M.L., Q.S., K.S.G., J.B., D.B., Y.K.X.); Department of Experimental Medicine (F.B., A.M.I.) and Department of Anatomical, Histological, Forensic, and Orthopedic Sciences (F.N.), Sapienza Uni
  • Fu Q; From the Department of Pharmacology, University of California at Davis (F.B., B.X., G.R.R., T.W., Q.W., Q.F., M.L., Q.S., K.S.G., J.B., D.B., Y.K.X.); Department of Experimental Medicine (F.B., A.M.I.) and Department of Anatomical, Histological, Forensic, and Orthopedic Sciences (F.N.), Sapienza Uni
  • Li M; From the Department of Pharmacology, University of California at Davis (F.B., B.X., G.R.R., T.W., Q.W., Q.F., M.L., Q.S., K.S.G., J.B., D.B., Y.K.X.); Department of Experimental Medicine (F.B., A.M.I.) and Department of Anatomical, Histological, Forensic, and Orthopedic Sciences (F.N.), Sapienza Uni
  • Shi Q; From the Department of Pharmacology, University of California at Davis (F.B., B.X., G.R.R., T.W., Q.W., Q.F., M.L., Q.S., K.S.G., J.B., D.B., Y.K.X.); Department of Experimental Medicine (F.B., A.M.I.) and Department of Anatomical, Histological, Forensic, and Orthopedic Sciences (F.N.), Sapienza Uni
  • Ginsburg KS; From the Department of Pharmacology, University of California at Davis (F.B., B.X., G.R.R., T.W., Q.W., Q.F., M.L., Q.S., K.S.G., J.B., D.B., Y.K.X.); Department of Experimental Medicine (F.B., A.M.I.) and Department of Anatomical, Histological, Forensic, and Orthopedic Sciences (F.N.), Sapienza Uni
  • Ferrier W; From the Department of Pharmacology, University of California at Davis (F.B., B.X., G.R.R., T.W., Q.W., Q.F., M.L., Q.S., K.S.G., J.B., D.B., Y.K.X.); Department of Experimental Medicine (F.B., A.M.I.) and Department of Anatomical, Histological, Forensic, and Orthopedic Sciences (F.N.), Sapienza Uni
  • Isidori AM; From the Department of Pharmacology, University of California at Davis (F.B., B.X., G.R.R., T.W., Q.W., Q.F., M.L., Q.S., K.S.G., J.B., D.B., Y.K.X.); Department of Experimental Medicine (F.B., A.M.I.) and Department of Anatomical, Histological, Forensic, and Orthopedic Sciences (F.N.), Sapienza Uni
  • Naro F; From the Department of Pharmacology, University of California at Davis (F.B., B.X., G.R.R., T.W., Q.W., Q.F., M.L., Q.S., K.S.G., J.B., D.B., Y.K.X.); Department of Experimental Medicine (F.B., A.M.I.) and Department of Anatomical, Histological, Forensic, and Orthopedic Sciences (F.N.), Sapienza Uni
  • Patel HH; From the Department of Pharmacology, University of California at Davis (F.B., B.X., G.R.R., T.W., Q.W., Q.F., M.L., Q.S., K.S.G., J.B., D.B., Y.K.X.); Department of Experimental Medicine (F.B., A.M.I.) and Department of Anatomical, Histological, Forensic, and Orthopedic Sciences (F.N.), Sapienza Uni
  • Bossuyt J; From the Department of Pharmacology, University of California at Davis (F.B., B.X., G.R.R., T.W., Q.W., Q.F., M.L., Q.S., K.S.G., J.B., D.B., Y.K.X.); Department of Experimental Medicine (F.B., A.M.I.) and Department of Anatomical, Histological, Forensic, and Orthopedic Sciences (F.N.), Sapienza Uni
  • Bers D; From the Department of Pharmacology, University of California at Davis (F.B., B.X., G.R.R., T.W., Q.W., Q.F., M.L., Q.S., K.S.G., J.B., D.B., Y.K.X.); Department of Experimental Medicine (F.B., A.M.I.) and Department of Anatomical, Histological, Forensic, and Orthopedic Sciences (F.N.), Sapienza Uni
  • Xiang YK; From the Department of Pharmacology, University of California at Davis (F.B., B.X., G.R.R., T.W., Q.W., Q.F., M.L., Q.S., K.S.G., J.B., D.B., Y.K.X.); Department of Experimental Medicine (F.B., A.M.I.) and Department of Anatomical, Histological, Forensic, and Orthopedic Sciences (F.N.), Sapienza Uni
Circ Res ; 119(8): 931-43, 2016 Sep 30.
Article en En | MEDLINE | ID: mdl-27576469
ABSTRACT
RATIONALE In heart failure, myofilament proteins display abnormal phosphorylation, which contributes to contractile dysfunction. The mechanisms underlying the dysregulation of protein phosphorylation on myofilaments is not clear.

OBJECTIVE:

This study aims to understand the mechanisms underlying altered phosphorylation of myofilament proteins in heart failure. METHODS AND

RESULTS:

We generate a novel genetically encoded protein kinase A (PKA) biosensor anchored onto the myofilaments in rabbit cardiac myocytes to examine PKA activity at the myofilaments in responses to adrenergic stimulation. We show that PKA activity is shifted from the sarcolemma to the myofilaments in hypertrophic failing rabbit myocytes. In particular, the increased PKA activity on the myofilaments is because of an enhanced ß2 adrenergic receptor signal selectively directed to the myofilaments together with a reduced phosphodiesterase activity associated with the myofibrils. Mechanistically, the enhanced PKA activity on the myofilaments is associated with downregulation of caveolin-3 in the hypertrophic failing rabbit myocytes. Reintroduction of caveolin-3 in the failing myocytes is able to normalize the distribution of ß2 adrenergic receptor signal by preventing PKA signal access to the myofilaments and to restore contractile response to adrenergic stimulation.

CONCLUSIONS:

In hypertrophic rabbit myocytes, selectively enhanced ß2 adrenergic receptor signaling toward the myofilaments contributes to elevated PKA activity and PKA phosphorylation of myofilament proteins. Reintroduction of caveolin-3 is able to confine ß2 adrenergic receptor signaling and restore myocyte contractility in response to ß adrenergic stimulation.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Técnicas Biosensibles / Proteínas Quinasas Dependientes de AMP Cíclico / Insuficiencia Cardíaca / Miofibrillas Límite: Animals Idioma: En Revista: Circ Res Año: 2016 Tipo del documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Técnicas Biosensibles / Proteínas Quinasas Dependientes de AMP Cíclico / Insuficiencia Cardíaca / Miofibrillas Límite: Animals Idioma: En Revista: Circ Res Año: 2016 Tipo del documento: Article