Beta-adrenergic regulation of the heart expressing the Ser1700A/Thr1704A mutated Cav1.2 channel. (October 2017)

• Record Type: Journal Article
• Authors: Poomvanicha, Montatip; Matthes, Jan; Domes, Katrin; Patrucco, Enrico; Angermeier, Elisabeth; Laugwitz, Karl-Ludwig; Schneider, Toni; Hofmann, Franz
• Is Part Of: Journal of molecular and cellular cardiology. Volume 111(2017)
• Page Start: 10
• Page End: 16
• Publication Date: 2017-10
• Subjects: Heart -- β-adrenergic regulation -- Calcium channel -- Cardiac Cav1.2 -- Gene mutation; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2017.07.119
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Beta-adrenergic stimulation of the heart increases I Ca . PKA dependent phosphorylation of several amino acids (among them Ser 1700 and Thr 1704 in the carboxy-terminus of the Cav1.2 α1 c subunit) has been implicated as decisive for the β-adrenergic up-regulation of cardiac I Ca . 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 Ca in isolated cardiomyocytes (CM) are stimulated by isoproterenol. Cardiac specific expression of the mutated Cav1.2PKA_P2 −/− gene reduces Cav1.2 α1 c protein concentration, I Ca, and the β-adrenergic stimulation of L-type I Ca 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 Ca in Cav1.2PKA_P2 −/− CMs. Highlights: Phosphorylation of S1700/T1704 may mediate up-regulation of heart calcium channel. The mutation S1700A/T1704A reduces cardiac I Ca, Cav1.2 protein, FS, and EF. Electrophysiological properties of I Ca are unchanged by the mutation. The mutated channel is upregulated by isoproterenol. Compensatory mechanisms obscure the impact of the S1700A/T1704A mutation.