Cardiac-specific overexpression of the α1 subunit of the L-type voltage-dependent Ca2+ channel in transgenic mice. Loss of isoproterenol- induced contraction

Abstract

The L-type voltage-dependent calcium channel (LVDCC) regulates calcium influx in cardiac myocytes. Activation of the β-adrenergic receptor (βAR) pathway causes phosphorylation of the L-VDCC and that in turn increases Ca2+ influx. Targeted expression of the L-VDCC α1 subunit in transgenic (Tg) mouse ventricles resulted in marked blunting of the βAR pathway. Inotropic and lusitropic responses to isoproterenol and forskolin in Tg hearts were significantly reduced. Likewise, Ca2+ current augmentation induced by isoproterenol and forskolin was markedly depressed in Tg cardiomyocytes. Despite no change in βAR number, isoproterenol-stimulated adenylyl cyclase activity was absent in Tg membranes and NaF and forskolin responses were reduced. We postulate an important pathway for regulation of the βAR by Ca2+ channels.