Beta-adrenergic regulation of the heart expressing the Ser1700A/Thr1704A mutated Cav1.2 channel.

Beta-adrenergic stimulation of the heart increases I. PKA dependent phosphorylation of several amino acids (among them Ser 1700 and Thr 1704 in the carboxy-terminus of the Cav1.2 αc subunit) has been implicated as decisive for the β-adrenergic up-regulation of cardiac I. Mutation of Ser 1700 and Thr 1704 to alanine results in the Cav1.2PKA_P2 mice. Cav1.2PKA_P2 mice display reduced cardiac L-type current. Fractional shortening and ejection fraction in the intact animal and I in isolated cardiomyocytes (CM) are stimulated by isoproterenol. Cardiac specific expression of the mutated Cav1.2PKA_P2 gene reduces Cav1.2 αc protein concentration, I, and the β-adrenergic stimulation of L-type I in CMs. Single channels were not detected on the CM surface of the cCav1.2PKA_P2 hearts. This outcome supports the notion that S1700/1704 is essential for expression of the Cav1.2 channel and that isoproterenol stimulates I in Cav1.2PKA_P2 CMs.