Metabotropic Regulation of RhoA/Rho-Associated Kinase by L-Type Ca 2+ Channels

Sustained vascular smooth muscle contraction can be mediated by several mechanisms, including the influx of extracellular Ca 2+ through L-type voltage-gated Ca 2+ channels (LTCCs) and by RhoA/Rho-associated kinase (ROCK)-dependent Ca 2+ 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 Ca 2+ release from the sarcoplasmic reticulum (SR) (calcium channel-induced Ca 2+ release or calcium channel-induced calcium release [CCICR]). In this review, we summarize recent data suggesting that LTCC activation and subsequent metabotropic Ca 2+ 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 Ca 2+ 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 Ca 2+ release and RhoA/ROCK stimulation. © 2012 Elsevier Inc.This study was supported by grant PI060137 and Red RECAVA from the Spanish Ministry of Health and by the “Proyecto de Excelencia” (P08-CTS-03530) of the “Consejería de Innovación y Ciencia de la Junta de Andalucía and European Union.” Support was also provided by the Spanish Ministry of Science and Innovation. This material is based on work supported by the Botín Foundation.Peer Reviewe