The AKAP Cypher/Zasp contributes to β-adrenergic/PKA stimulation of cardiac Ca_V1.2 calcium channels.

Stimulation of the L-type Ca²⁺ current conducted by Ca_V1.2 channels in cardiac myocytes by the β-adrenergic/protein kinase A signaling pathway requires anchoring of to the Ca_V1.2 channel by an A-kinase anchoring protein (AKAP). However, the AKAP(s) responsible for regulation in vivo remain unknown. Here, we test the role of the AKAP Cypher/Zasp in β-adrenergic regulation of Ca_V1.2 channels using physiological studies of cardiac ventricular myocytes from young-adult mice lacking the long form of Cypher/Zasp (LCyphKO mice). These myocytes have increased protein levels of Ca_V1.2, and calcineurin. In contrast, the cell surface density of Ca_V1.2 channels and the basal Ca²⁺ current conducted by Ca_V1.2 channels are significantly reduced without substantial changes to kinetics or voltage dependence. β-adrenergic regulation of these L-type Ca²⁺ currents is also significantly reduced in myocytes from LCyphKO mice, whether calculated as a stimulation ratio or as net-stimulated Ca²⁺ current. At 100 nM isoproterenol, the net β-adrenergic-Ca²⁺ current conducted by Ca_V1.2 channels was reduced to 39 ± 12% of wild type. However, concentration-response curves for β-adrenergic stimulation of myocytes from LCyphKO mice have concentrations that give a half-maximal response similar to those for wild-type mice. These results identify Cypher/Zasp as an important AKAP for β-adrenergic regulation of cardiac Ca_V1.2 channels. Other AKAPs may work cooperatively with Cypher/Zasp to give the full magnitude of β-adrenergic regulation of Ca_V1.2 channels observed in vivo.

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