Figure 3.

Solidification mediated by force generation pathways in ASM. Contraction-inducing mediators (CCh, histamine) activate GPCRs coupled to Gαq and/or Gα12. G protein activation stimulates activity of phospholipase Cβ (PLCβ), which generates an inositol 1,4,5-trisphosphate (Ins_P3) and diacylglycerol (DAG). Ins_P3 induces release of Ca²⁺ from sarcoplasmic reticulum stores. Cytosolic Ca²⁺ binds calmodulin and activates myosin light chain kinase (MLCK). MLC phosphorylation on Ser19 by MLCK causes crossbridging of myosin filaments (black) with actin (red) and cell shortening along the longitudinal axis. Extracellular Ca²⁺ enters the cell through membrane-embedded channels (Orai1). In collaboration with the Ca²⁺ sensor STIM1, Orai1 mediates oscillations in intracellular Ca²⁺ levels that are required to sustain contraction. GPCRs also stimulate activity of guanine nucleotide exchange factors (GEFs) for RhoA. Activated RhoA stimulates ROCK-mediated inhibitory phosphorylation of MYPT1, which prevents MLC dephosphorylation and prolongs contraction. Other inhibitors of MYPT1 activity include CPI-17 and p116Rip. ASM, airway smooth muscle; CCh, carbachol; GPCR, G protein-coupled receptor.