Identifying a role of the actin capping protein CapZ in β-adrenergic receptor signalling.

AIM:β-Adrenergic receptor activation increases myocardial contractility, in part through protein kinase A modification of cardiac myofilaments. regulation of cardiac myofilaments is contingent influenced by protein kinase C phosphorylation of troponin I (TnI). Reductions in the cardiac Z-disc protein CapZ attenuate regulation of myofilament activation. We hypothesized that CapZ-deficient transgenic mouse hearts respond poorly to β-adrenergic receptor activation, as a result of impaired duanyu1531 activation. METHODS:Wild-type and CapZ-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 MgATPase assay and protein phosphorylation gels. RESULTS:CapZ-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 TnI phosphorylation. CapZ-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. TnI phosphorylation was similarly increased in wild-type and transgenic mice following ISO treatment, while CapZ-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.

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