Fig. 4.

Illustration of the cellular mechanisms by which M3 receptors regulate BK channel function in UBSM cells. Activation of M3 receptors leads to IP₃ and DAG production, via a pathway involving phospholipase-C (PLC) and PIP₂. IP₃ activates IP₃ receptors, which releases Ca²⁺ from the SR. This IP₃-induced Ca²⁺ release transiently activates the BK channels. Over time, depletion of SR Ca²⁺ upon activation of M3 receptors reduces Ca²⁺ spark activity, which leads to inhibition of TBKCs and depolarization of UBSM cell resting membrane potential causing activation of VDCC and thus increases UBSM contractility. DAG activates PKC, which may lead to direct inhibition of the SR Ca²⁺ pump and RyRs resulting in suppression of Ca²⁺ sparks and TBKCs. Pharmacological tools used in this study to inhibit cellular sources of Ca²⁺ are indicated. BK, large-conductance voltage- and Ca²⁺-activated K⁺ channel; DAG, 1,2-diacylglycerol; IP₃, inositol triphosphate; M3 receptors, muscarinic receptors type 3; PIP₂, phosphatidylinositol 4,5-bisphosphate; PKC, protein kinase-C; PLC, phospholipase-C; Ryr, ryanodine receptor; TBKCs, transient BK currents; SR, sarcoplasmic reticulum; UBSM, urinary bladder smooth muscle; VDCC, L-type voltage-dependent Ca²⁺ channel. This figure is based on information from (62, 112, 114).