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

J Mol Cell Cardiol. 2017 Oct:111:10-16. doi: 10.1016/j.yjmcc.2017.07.119. Epub 2017 Aug 1.

Abstract

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.

Keywords: Calcium channel; Cardiac Cav1.2; Gene mutation; Heart; β-adrenergic regulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium Channels, L-Type / genetics*
  • Ion Channel Gating / drug effects
  • Isoproterenol / pharmacology
  • Mice, Inbred C57BL
  • Mutation / genetics*
  • Myocardium / metabolism*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Phenotype
  • Receptors, Adrenergic, beta / metabolism*
  • Tamoxifen / pharmacology

Substances

  • Calcium Channels, L-Type
  • L-type calcium channel alpha(1C)
  • Receptors, Adrenergic, beta
  • Tamoxifen
  • Isoproterenol