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

- Phosphorylation of S1700/T1704 may mediate up-regulation of heart calcium channel.
- The mutation S1700A/T1704A reduces cardiac ICa, Cav1.2 protein, FS, and EF.
- Electrophysiological properties of ICa are unchanged by the mutation.
- The mutated channel is upregulated by isoproterenol.
- Compensatory mechanisms obscure the impact of the S1700A/T1704A mutation.

Beta-adrenergic stimulation of the heart increases ICa. PKA dependent phosphorylation of several amino acids (among them Ser 1700 and Thr 1704 in the carboxy-terminus of the Cav1.2 α1c subunit) has been implicated as decisive for the β-adrenergic up-regulation of cardiac ICa. 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 ICa in isolated cardiomyocytes (CM) are stimulated by isoproterenol. Cardiac specific expression of the mutated Cav1.2PKA_P2−/− gene reduces Cav1.2 α1c protein concentration, ICa, and the β-adrenergic stimulation of L-type ICa 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 ICa in Cav1.2PKA_P2−/− CMs.