Figure 5
From: Signaling and regulation of G protein-coupled receptors in airway smooth muscle
Model of aberrant G protein-coupled receptor signaling in airway smooth muscle contributing to elevated airway smooth muscle tone. Within the context of airway remodeling, G protein-coupled receptor (GPCR) signaling leading to airway smooth muscle (ASM) contraction may be altered at 3 different levels in the asthmatic airway. First, ASM may be exposed to greater levels of GPCR agonists that promote contraction (i.e., those activating Gq- or Gi-coupled receptors), or to lower levels of GPCR agonists that mediate prorelaxant signaling (Gs-coupled receptors). Increased levels of procontractile agonists can augment contraction, whereas combined stimulation of ASM with multiple Gq/Gi -coupled receptor agonists has a synergistic effect on contraction [277]. The sources of both procontractile and prorelaxant agonists include infiltrating inflammatory cells (e.g., mast cells releasing histamine, platelets releasing thrombin), postganglionic neurons with exaggerated cholinergic discharge resulting from stimulated reflex arcs or dysregulated m2 muscarinic acetylcholine receptor (mAChR) -mediated feedback inhibition [281], and resident airway cells such as epithelium, fibroblasts, and ASM itself. Access of these agonists to ASM may be increased by sloughing of airway epithelium. Second, Gq- or Gi-coupled receptor signaling may be sensitized, or Gs-coupled receptor signaling desensitized, resulting in an imbalance of signaling promoting increased phosphoinositide generation and increased calcium mobilization. Third, the contractile response to calcium may be exaggerated due to "augmented sensitization" manifested in increased myosin light chain phosphorylation caused by: 1) an imbalance of GPCR-derived signals; and 2) increased expression and activity of myosin light chain kinase (MLCK) associated with inhibited myosin light chain phosphatase (MLCP) activity, the latter a result of increased RhoA activity mediated by upregulated G12/13 and RhoA expression. Not included in this model (for the sake of simplicity) are other potential regulatory features of ASM contraction including ASM strain and load, direct contribution of non-GPCR signaling pathways to phospholipase C (PLC) activation and calcium mobilization, calcium loading in intracellular stores, compartmentalization of calcium and calcium signaling, and ion channel and membrane pump activity that directly and indirectly affect intracellular calcium levels.