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

Membrane depolarization activates voltage-dependent Ca(2+) channels (VDCCs) inducing Ca(2+) release via ryanodine receptors (RyRs), which is obligatory for skeletal and cardiac muscle contraction and other physiological responses. However, depolarization-induced Ca(2+) 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 Ca(2+) release, leading to a significant increase in the activity of Ca(2+) sparks and contraction in airway SMCs. The increased Ca(2+) sparks are independent of VDCCs and the associated extracellular Ca(2+) influx. This format of local Ca(2+) 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 (IP(3)), inducing initial Ca(2+) release through IP(3) receptors and then further Ca(2+) release via RyR2 due to a local Ca(2+)-induced Ca(2+) release process. These findings demonstrate an important mechanism for Ca(2+) signaling and attendant physiological function in SMCs.