Figure 3

Gi-coupled receptor signaling in airway smooth muscle. Gi-coupled receptors have the capacity to initiate or modulate signaling through the actions of both Gi-derived α and βγ subunits. Activated Gαi dissociates from the heterotrimeric complex and binds to adenylyl cyclase (AC) V and VI to act as a negative modulator of Gαs-induced signaling. Gβγ subunits modulate AC activity in an isoform-specific manner, inhibiting AC type I but enhancing Gαs-induced activation of AC II, IV and VII. Gβγ can also activate phospholipase C beta (PLCβ) isoforms, resulting in phosphoinositide generation, protein kinase C (PKC) activation via 1,2-diacylglycerol (DAG), and calcium mobilization. Through ill-defined mechanisms, Gi-coupled receptor activation can also promote airway smooth muscle (ASM) growth [18], and cooperate with both other G protein-coupled receptors (GPCRs) [277, 278] and receptor tyrosine kinases [19, 243] to synergistically stimulate growth. Lastly, Gi activation in ASM can contribute to Rho-dependent changes in actin polymerization [40, 279, 280] and calcium sensitization [273], although the mechanism of Rho activation by Gi in ASM (or other cell types) is not well established.