Membrane-delimited stimulation of heart cell calcium current by beta-adrenergic signal-transducing Gs protein

A several-fold increase in calcium current (Ica) is a signal feature of the maximal beta-adrenergic response of the heart. It is generally ascribed to enhanced adenosine 3’,5’-cyclic monophosphate (cAMP)dependent phosphorylation of calcium (Ca) channels following beta-receptor activation of the guanosine nucleotide-binding (G) protein Gs, and Gs-activation of the adenylyl cyclase cascade. We blocked phosphorylation pathways in guinea pig ventricular cardiomyocytes to unmask other possible Ica-stimulatory modes. In blocked cells, Ica increased by approximately 50% during (i) beta-receptor activation of Gs, (ii) intracellular activation of Gs, and (iii) intracellular application of preactivated Gs. We conclude that fast, membrane-delimited Gs modulation participates in the physiological regulation of cardiac Ica. Additionally, membrane-delimited action by activated Gs seems to hinder Ca channel inhibition by D600 and may prime Ca channels for up-regulation by cAMP-dependent phosphorylation.