Genetic Ablation of L-Type Ca2+ Channels Abolishes Depolarization-Induced Ca2+ Release in Arterial Smooth Muscle

Abstract

Rationale: In arterial myocytes, membrane depolarization-induced Ca2 release (DICR) from the sarcoplasmic reticulum (SR) occurs through a metabotropic pathway that leads to inositol trisphosphate synthesis independently of extracellular Ca2 influx. Despite the fundamental functional relevance of DICR, its molecular bases are not well known. Objective: Biophysical and pharmacological data have suggested that L-type Ca2 channels could be the sensors coupling membrane depolarization to SR Ca2 release. This hypothesis was tested using smooth muscle–selective conditional Cav1.2 knockout mice. Methods and Results: In aortic myocytes, the decrease of Ca2 channel density was paralleled by the disappearance of SR Ca2 release induced by either depolarization or Ca2 channel agonists. Cav1.2 channel deficiency resulted in almost abolition of arterial ring contraction evoked by DICR. Ca2 channel–null cells showed unaltered caffeine-induced Ca2 release and contraction. Conclusion: These data suggest that Cav1.2 channels are indeed voltage sensors coupled to the metabolic cascade, leading to SR Ca2 release. These findings support a novel, ion-independent, functional role of L-type Ca2 channels linked to intracellular signaling pathways in vascular myocytes.