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Identifying a role of the actin capping protein C ap Z in β‐adrenergic receptor signalling
Author(s) -
Gaikis L.,
Stewart D.,
Johnson R.,
Pyle W. G.
Publication year - 2013
Publication title -
acta physiologica
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.591
H-Index - 116
eISSN - 1748-1716
pISSN - 1748-1708
DOI - 10.1111/j.1748-1716.2012.02470.x
Subject(s) - myofilament , phosphorylation , contractility , medicine , endocrinology , protein kinase a , protein kinase c , genetically modified mouse , microbiology and biotechnology , biology , chemistry , transgene , myosin , biochemistry , gene
Aim β‐Adrenergic receptor activation increases myocardial contractility, in part through protein kinase A ( PKA )‐dependent modification of cardiac myofilaments. PKA regulation of cardiac myofilaments is contingent influenced by protein kinase C ( PKC ) phosphorylation of troponin I ( T n I ). Reductions in the cardiac Z ‐disc protein C ap Z attenuate PKC regulation of myofilament activation. We hypothesized that C ap Z ‐deficient transgenic mouse hearts respond poorly to β‐adrenergic receptor activation, as a result of impaired PKC activation. Methods Wild‐type and C ap Z ‐deficient transgenic mice were treated with the β‐adrenergic receptor agonist isoproterenol ( ISO ) and whole heart function assessed by echocardiography. Cardiac myofilaments were isolated post‐ ISO treatment and subjected to an actomyosin M g ATP ase assay and protein phosphorylation gels. Results C ap Z ‐deficient transgenic mouse hearts exhibited increased contractility and myofilament calcium sensitivity at baseline, as compared to wild‐type mice. In wild‐type mice, ISO increased myocardial contractility and decreased myofilament calcium sensitivity, along with an increase in T n I phosphorylation. C ap Z ‐deficient transgenic mice responded to ISO treatment, and myocardial functional differences between transgenic and wild‐type mice were abolished. ISO ‐dependent changes in myofilament activation in transgenic mice were similar to those observed in wild‐type. T n I phosphorylation was similarly increased in wild‐type and transgenic mice following ISO treatment, while C ap Z ‐deficient transgenic mouse myofilaments also exhibited increased myosin‐binding protein C phosphorylation. Differences in myofilament protein phosphorylation patterns suggest the intracellular mechanisms utilized by β‐adrenergic receptor activation are different than that seen in wild‐type hearts. Conclusions These data further support the concept that the cardiac Z ‐disc protein is a regulator of myofilament function and intracellular signalling transduction.