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Interaction of the Joining Region in Junctophilin-2 With the L-Type Ca2+ Channel Is Pivotal for Cardiac Dyad Assembly and Intracellular Ca2+ Dynamics.
Gross, Polina; Johnson, Jaslyn; Romero, Carlos M; Eaton, Deborah M; Poulet, Claire; Sanchez-Alonso, Jose; Lucarelli, Carla; Ross, Jean; Gibb, Andrew A; Garbincius, Joanne F; Lambert, Jonathan; Varol, Erdem; Yang, Yijun; Wallner, Markus; Feldsott, Eric A; Kubo, Hajime; Berretta, Remus M; Yu, Daohai; Rizzo, Victor; Elrod, John; Sabri, Abdelkarim; Gorelik, Julia; Chen, Xiongwen; Houser, Steven R.
Afiliação
  • Gross P; Department of Physiology, Cardiovascular Research Center (P.G., J.J., C.M.R., D.M.E., Y.Y., M.W., E.A.F., H.K., R.M.B., V.R., A.S., X.C., S.R.H.), Lewis Katz Temple University School of Medicine, Philadelphia, PA.
  • Johnson J; Department of Physiology, Cardiovascular Research Center (P.G., J.J., C.M.R., D.M.E., Y.Y., M.W., E.A.F., H.K., R.M.B., V.R., A.S., X.C., S.R.H.), Lewis Katz Temple University School of Medicine, Philadelphia, PA.
  • Romero CM; Department of Physiology, Cardiovascular Research Center (P.G., J.J., C.M.R., D.M.E., Y.Y., M.W., E.A.F., H.K., R.M.B., V.R., A.S., X.C., S.R.H.), Lewis Katz Temple University School of Medicine, Philadelphia, PA.
  • Eaton DM; Department of Physiology, Cardiovascular Research Center (P.G., J.J., C.M.R., D.M.E., Y.Y., M.W., E.A.F., H.K., R.M.B., V.R., A.S., X.C., S.R.H.), Lewis Katz Temple University School of Medicine, Philadelphia, PA.
  • Poulet C; NIHR Imperial Biomedical Research Centre, National Heart and Lung Institute, Imperial College London, London, United Kingdom (C.P., J.S.-A., C.L., J.G.).
  • Sanchez-Alonso J; NIHR Imperial Biomedical Research Centre, National Heart and Lung Institute, Imperial College London, London, United Kingdom (C.P., J.S.-A., C.L., J.G.).
  • Lucarelli C; NIHR Imperial Biomedical Research Centre, National Heart and Lung Institute, Imperial College London, London, United Kingdom (C.P., J.S.-A., C.L., J.G.).
  • Ross J; Cardiovascular Science, University of Verona, Verona, Italy (C.L.).
  • Gibb AA; Bioimaging Center Research, Delaware Biotechnology Institute, Newark, DE (J.R.).
  • Garbincius JF; Department of Pharmacology, Center for Translational Medicine (A.A.G., J.F.G., J.L., J.E.), Lewis Katz Temple University School of Medicine, Philadelphia, PA.
  • Lambert J; Department of Pharmacology, Center for Translational Medicine (A.A.G., J.F.G., J.L., J.E.), Lewis Katz Temple University School of Medicine, Philadelphia, PA.
  • Varol E; Department of Pharmacology, Center for Translational Medicine (A.A.G., J.F.G., J.L., J.E.), Lewis Katz Temple University School of Medicine, Philadelphia, PA.
  • Yang Y; Department of Statistics, Center for Theoretical Neuroscience, Columbia University, New York, NY (E.V.).
  • Wallner M; Department of Physiology, Cardiovascular Research Center (P.G., J.J., C.M.R., D.M.E., Y.Y., M.W., E.A.F., H.K., R.M.B., V.R., A.S., X.C., S.R.H.), Lewis Katz Temple University School of Medicine, Philadelphia, PA.
  • Feldsott EA; Department of Physiology, Cardiovascular Research Center (P.G., J.J., C.M.R., D.M.E., Y.Y., M.W., E.A.F., H.K., R.M.B., V.R., A.S., X.C., S.R.H.), Lewis Katz Temple University School of Medicine, Philadelphia, PA.
  • Kubo H; Division of Cardiology, Medical University of Graz, Austria (M.W.).
  • Berretta RM; Center for Biomarker Research in Medicine, CBmed GmbH, Graz, Austria (M.W.).
  • Yu D; Department of Physiology, Cardiovascular Research Center (P.G., J.J., C.M.R., D.M.E., Y.Y., M.W., E.A.F., H.K., R.M.B., V.R., A.S., X.C., S.R.H.), Lewis Katz Temple University School of Medicine, Philadelphia, PA.
  • Rizzo V; Department of Physiology, Cardiovascular Research Center (P.G., J.J., C.M.R., D.M.E., Y.Y., M.W., E.A.F., H.K., R.M.B., V.R., A.S., X.C., S.R.H.), Lewis Katz Temple University School of Medicine, Philadelphia, PA.
  • Elrod J; Department of Physiology, Cardiovascular Research Center (P.G., J.J., C.M.R., D.M.E., Y.Y., M.W., E.A.F., H.K., R.M.B., V.R., A.S., X.C., S.R.H.), Lewis Katz Temple University School of Medicine, Philadelphia, PA.
  • Sabri A; Department of Clinical Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA (D.Y.).
  • Gorelik J; Department of Physiology, Cardiovascular Research Center (P.G., J.J., C.M.R., D.M.E., Y.Y., M.W., E.A.F., H.K., R.M.B., V.R., A.S., X.C., S.R.H.), Lewis Katz Temple University School of Medicine, Philadelphia, PA.
  • Chen X; Department of Pharmacology, Center for Translational Medicine (A.A.G., J.F.G., J.L., J.E.), Lewis Katz Temple University School of Medicine, Philadelphia, PA.
  • Houser SR; Department of Physiology, Cardiovascular Research Center (P.G., J.J., C.M.R., D.M.E., Y.Y., M.W., E.A.F., H.K., R.M.B., V.R., A.S., X.C., S.R.H.), Lewis Katz Temple University School of Medicine, Philadelphia, PA.
Circ Res ; 128(1): 92-114, 2021 01 08.
Article em En | MEDLINE | ID: mdl-33092464
ABSTRACT
RATIONALE Ca2+-induced Ca2+ release (CICR) in normal hearts requires close approximation of L-type calcium channels (LTCCs) within the transverse tubules (T-tubules) and RyR (ryanodine receptors) within the junctional sarcoplasmic reticulum. CICR is disrupted in cardiac hypertrophy and heart failure, which is associated with loss of T-tubules and disruption of cardiac dyads. In these conditions, LTCCs are redistributed from the T-tubules to disrupt CICR. The molecular mechanism responsible for LTCCs recruitment to and from the T-tubules is not well known. JPH (junctophilin) 2 enables close association between T-tubules and the junctional sarcoplasmic reticulum to ensure efficient CICR. JPH2 has a so-called joining region that is located near domains that interact with T-tubular plasma membrane, where LTCCs are housed. The idea that this joining region directly interacts with LTCCs and contributes to LTCC recruitment to T-tubules is unknown.

OBJECTIVE:

To determine if the joining region in JPH2 recruits LTCCs to T-tubules through direct molecular interaction in cardiomyocytes to enable efficient CICR. METHODS AND

RESULTS:

Modified abundance of JPH2 and redistribution of LTCC were studied in left ventricular hypertrophy in vivo and in cultured adult feline and rat ventricular myocytes. Protein-protein interaction studies showed that the joining region in JPH2 interacts with LTCC-α1C subunit and causes LTCCs distribution to the dyads, where they colocalize with RyRs. A JPH2 with induced mutations in the joining region (mutPG1JPH2) caused T-tubule remodeling and dyad loss, showing that an interaction between LTCC and JPH2 is crucial for T-tubule stabilization. mutPG1JPH2 caused asynchronous Ca2+-release with impaired excitation-contraction coupling after ß-adrenergic stimulation. The disturbed Ca2+ regulation in mutPG1JPH2 overexpressing myocytes caused calcium/calmodulin-dependent kinase II activation and altered myocyte bioenergetics.

CONCLUSIONS:

The interaction between LTCC and the joining region in JPH2 facilitates dyad assembly and maintains normal CICR in cardiomyocytes.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Cálcio / Hipertrofia Ventricular Esquerda / Sinalização do Cálcio / Canais de Cálcio Tipo L / Miócitos Cardíacos / Proteínas de Membrana / Proteínas Musculares Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male 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: Cálcio / Hipertrofia Ventricular Esquerda / Sinalização do Cálcio / Canais de Cálcio Tipo L / Miócitos Cardíacos / Proteínas de Membrana / Proteínas Musculares Tipo de estudo: Prognostic_studies Limite: Animals / Humans / Male Idioma: En Ano de publicação: 2021 Tipo de documento: Article