Metabotropic Regulation of RhoA/Rho–Associated Kinase by L-Type Ca2+ Channels

Sustained vascular smooth muscle contraction can be mediated by several mechanisms, including the influx of extracellular Ca2+ through L-type voltage-gated Ca2+ channels (LTCCs) and by RhoA/Rho–associated kinase (ROCK)-dependent Ca2+ sensitization of the contractile machinery. Conformational changes in the LTCC following depolarization can also trigger an ion-independent metabotropic pathway that involves G protein/phospholipase C activation, giving rise to inositol 1,4,5-trisphosphate synthesis and subsequent Ca2+ release from the sarcoplasmic reticulum (SR) (calcium channel–induced Ca2+ release or calcium channel–induced calcium release [CCICR]). In this review, we summarize recent data suggesting that LTCC activation and subsequent metabotropic Ca2+ release from the SR participate in depolarization-evoked RhoA/ROCK activity and sustained arterial contraction. During protracted depolarizations, refilling of the SR stores by a residual influx of extracellular Ca2+ through LTCCs helps maintain RhoA activity and contractile activation. These findings suggest that CCICR plays a major role in tonic vascular smooth muscle contraction, providing a link between membrane depolarization–induced LTCC activation and metabotropic Ca2+ release and RhoA/ROCK stimulation.