AbstractAimβ‐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 (TnI). Reductions in the cardiac Z‐disc protein CapZ attenuate PKC regulation of myofilament activation. We hypothesized that CapZ‐deficient transgenic mouse hearts respond poorly to β‐adrenergic receptor activation, as a result of impaired PKC activation.MethodsWild‐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.ResultsCapZ‐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.ConclusionsThese data further support the concept that the cardiac Z‐disc protein is a regulator of myofilament function and intracellular signalling transduction.