Membrane depolarization causes a direct activation of G protein-coupled receptors leading to local Ca2+ release in smooth muscle

Membrane depolarization activates voltage-dependent Ca2+ channels (VDCCs) inducing Ca2+ release via ryanodine receptors (RyRs), which is obligatory for skeletal and cardiac muscle contraction and other physiological responses. However, depolarization-induced Ca2+ release and its functional importance as well as underlying signaling mechanisms in smooth muscle cells (SMCs) are largely unknown. Here we report that membrane depolarization can induce RyR-mediated local Ca2+ release, leading to a significant increase in the activity of Ca2+ sparks and contraction in airway SMCs. The increased Ca2+ sparks are independent of VDCCs and the associated extracellular Ca2+ influx. This format of local Ca2+ release results from a direct activation of G protein-coupled, M-3 muscarinic receptors in the absence of exogenous agonists, which causes activation of Gq proteins and phospholipase C, and generation of inositol 1,4,5-triphosphate (IP3), inducing initial Ca2+ release through IP3 receptors and then further Ca2+ release via RyR2 due to a local Ca2+-induced Ca2+ release process. These findings demonstrate an important mechanism for Ca2+ signaling and attendant physiological function in SMCs.