Figure 1
From: Muscarinic receptor signaling in the pathophysiology of asthma and COPD
Pathways central in muscarinic receptor mediated airway smooth muscle contraction. Muscarinic receptor (MR) agonists induce contraction of airway smooth muscle by Ca2+ dependent and Ca2+ independent pathways. Through associated Gq alpha subunits, the muscarinic M3 receptor activates phospholipase C (PLC), which releases inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) after hydrolytic conversion of phosphatidylinositol-4,5-bisphosphate (PIP2). IP3 induces the release of Ca2+ from internal sarcoplasmatic reticulum (SR) stores. Coupling of M3 receptor to CD38 through as yet undefined mechanisms contributes to the production of cyclic ADP ribose (cADPR) and the release of Ca2+ through ryanodine receptor channels in the SR. Ca2+ release increases free cytosolic Ca2+ and promotes calmodulin-dependent activation of myosin light chain kinase (MLCK). MLCK mediated phosphorylation of 20 kDa regulatory myosin light chain (MLC) in the contractile apparatus is an obligatory event to induce smooth muscle contraction. MLC phosphorylation level is also controlled by pathways that inhibit myosin light chain phosphatase (MLCP) and, thus enhance Ca2+ sensitivity. PLC-derived DAG activates protein kinase C (PKC), leading to CPI-17 phosphorylation and downstream MLCP inhibition. Rho-kinase, which is activated by the monomeric G protein RhoA, both phosphorylates CPI-17 and inhibits MLCP directly. The expression and function of RhoA, CPI-17 and CD38 are increased by pro-inflammatory cytokines in vitro and in animal models of asthma and COPD ex vivo (see text).