Dataset Information

PKC?II modulation of myocyte contractile performance.

ABSTRACT: Significant up-regulation of the protein kinase C?(II) (PKC?(II)) develops during heart failure and yet divergent functional outcomes are reported in animal models. The goal here is to investigate PKC?(II) modulation of contractile function and gain insights into downstream targets in adult cardiac myocytes. Increased PKC?(II) protein expression and phosphorylation developed after gene transfer into adult myocytes while expression remained undetectable in controls. The PKC?(II) was distributed in a peri-nuclear pattern and this expression resulted in diminished rates and amplitude of shortening and re-lengthening compared to controls and myocytes expressing dominant negative PKC?(II) (PKC?DN). Similar decreases were observed in the Ca(2+) transient and the Ca(2+) decay rate slowed in response to caffeine in PKC?(II)-expressing myocytes. Parallel phosphorylation studies indicated PKC?(II) targets phosphatase activity to reduce phospholamban (PLB) phosphorylation at residue Thr17 (pThr17-PLB). The PKC? inhibitor, LY379196 (LY) restored pThr17-PLB to control levels. In contrast, myofilament protein phosphorylation was enhanced by PKC?(II) expression, and individually, LY and the phosphatase inhibitor, calyculin A each failed to block this response. Further work showed PKC?(II) increased Ca(2+)-activated, calmodulin-dependent kinase II? (CaMKII?) expression and enhanced both CaMKII? and protein kinase D (PKD) phosphorylation. Phosphorylation of both signaling targets also was resistant to acute inhibition by LY. These later results provide evidence PKC?(II) modulates contractile function via intermediate downstream pathway(s) in cardiac myocytes.

SUBMITTER: Hwang H

PROVIDER: S-EPMC3418922 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

PKCβII modulation of myocyte contractile performance.

Hwang Hyosook H Robinson Dustin A DA Stevenson Tamara K TK Wu Helen C HC Kampert Sarah E SE Pagani Francis D FD Dyke D Brad DB Martin Jody L JL Sadayappan Sakthival S Day Sharlene M SM Westfall Margaret V MV

Journal of molecular and cellular cardiology 20120514 2

Significant up-regulation of the protein kinase Cβ(II) (PKCβ(II)) develops during heart failure and yet divergent functional outcomes are reported in animal models. The goal here is to investigate PKCβ(II) modulation of contractile function and gain insights into downstream targets in adult cardiac myocytes. Increased PKCβ(II) protein expression and phosphorylation developed after gene transfer into adult myocytes while expression remained undetectable in controls. The PKCβ(II) was distributed i ...[more]

PMID: 22587992

Similar Datasets

Project description:Voltage-dependent Na+ channel activation underlies action potential generation fundamental to cellular excitability. In skeletal and cardiac muscle this triggers contraction via ryanodine-receptor (RyR)-mediated sarcoplasmic reticular (SR) Ca2+ release. We here review potential feedback actions of intracellular [Ca2+] ([Ca2+]i) on Na+ channel activity, surveying their structural, genetic and cellular and functional implications, translating these to their possible clinical importance. In addition to phosphorylation sites, both Nav1.4 and Nav1.5 possess potentially regulatory binding sites for Ca2+ and/or the Ca2+-sensor calmodulin in their inactivating III-IV linker and C-terminal domains (CTD), where mutations are associated with a range of skeletal and cardiac muscle diseases. We summarize in vitro cell-attached patch clamp studies reporting correspondingly diverse, direct and indirect, Ca2+ effects upon maximal Nav1.4 and Nav1.5 currents (Imax) and their half-maximal voltages (V1/2) characterizing channel gating, in cellular expression systems and isolated myocytes. Interventions increasing cytoplasmic [Ca2+]i down-regulated Imax leaving V1/2 constant in native loose patch clamped, wild-type murine skeletal and cardiac myocytes. They correspondingly reduced action potential upstroke rates and conduction velocities, causing pro-arrhythmic effects in intact perfused hearts. Genetically modified murine RyR2-P2328S hearts modelling catecholaminergic polymorphic ventricular tachycardia (CPVT), recapitulated clinical ventricular and atrial pro-arrhythmic phenotypes following catecholaminergic challenge. These accompanied reductions in action potential conduction velocities. The latter were reversed by flecainide at RyR-blocking concentrations specifically in RyR2-P2328S as opposed to wild-type hearts, suggesting a basis for its recent therapeutic application in CPVT. We finally explore the relevance of these mechanisms in further genetic paradigms for commoner metabolic and structural cardiac disease.

Dataset Information

PKC?II modulation of myocyte contractile performance.

Publications

PKCβII modulation of myocyte contractile performance.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets