FIGURE 7.

Schematic diagram of receptor-mediated Ca²⁺-signaling pathways in mouse detrusor muscle. CCh activation of muscarinic acetylcholine receptors (mAChRs) stimulates contraction of detrusor muscle by evoking Ca²⁺ release from both SR and acidic (lysosomal) stores. Ca²⁺ binds to calmodulin (CaM), which then activates myosin-light chain kinase (MLCK), which phosphorylates myosin light chains (MLCs), promoting contraction. The three principal Ca²⁺-mobilizing messengers, IP₃, cADPR, and NAADP may all stimulate contractile responses in β-escin permeabilized myocytes, with IP₃ and cADPR mobilizing Ca²⁺ from the SR, by activating IP₃ receptors and RyRs, respectively, and NAADP from acidic stores by activating TPC2 channels. IP₃ production is stimulated by mAChR via G proteins (G) coupling to phospholipase C (PLC), whereas cADPR and NAADP synthesis may be controlled by ADP-ribosyl cyclases such as CD38. mAChRs require the expression of TPC2 and action of NAADP for coupling to Ca²⁺ release from acidic stores (lysosomes). Greater mAChR stimulation was required to effect coupling to Ca²⁺ release from acidic stores when compared with the SR, raising the possibility of weaker coupling to NAADP synthesis or selective coupling of a lower affinity mAChR subtype to NAADP synthases.