G Protein-Coupled Receptor Signaling in Gastrointestinal Smooth Muscle

G Protein-Coupled Receptor Signaling in Gastrointestinal Smooth Muscle

<P> Contraction of smooth muscle is initiated by an increase in cytosolic Ca<SUP>2&#8290;</SUP> leading to activation of Ca<SUP>2&#8290;</SUP>/ calmodulin-dependnet myosin light chain (MLC) kinase and phosphorylation of MLC. The types of contraction and signaling mechanisms mediating contraction differ depending on the region. The involvement of these different mechanisms varies depending on the source of Ca<SUP>2&#8290;</SUP> and the kinetic of Ca<SUP>2&#8290;</SUP> mobilization. Ca<SUP>2&#8290;</SUP> mobilizing agonists stimulate different phospholipases (PLC-β, PLD and PLA<SUB>2</SUB>) to generate one or more Ca<SUP>2&#8290;</SUP> mobilizing messengers (IP<SUB>3</SUB> and AA), and diacylglycerol (DAG), an activator of protein kinase C (PKC). The relative contributions of PLC-β, PLA<SUB>2</SUB> and PLD to generate second messengers vary greatly between cells and types of contraction. In smooth muscle cell derived form the circular muscle layer of the intestine, preferential hydrolysis of PIP<SUB>2</SUB> and generation of IP<SUB>3</SUB> and IP<SUB>3</SUB>-dependent Ca<SUP>2&#8290;</SUP> release initiate the contraction. In smooth muscle cells derived from longitudinal muscle layer of the intestine, preferential hydrolysis of PC by PLA<SUB>2</SUB>, generation of AA and AA-mediated Ca<SUP>2&#8290;</SUP> influx, cADP ribose formation and Ca<SUP>2&#8290;</SUP>-induced Ca<SUP>2&#8290;</SUP> release initiate the contraction. Sustained contraction, however, in both cell types is mediated by Ca<SUP>2&#8290;</SUP>-independent mechanism involving activation of PKC-ε by DAG derived form PLD. A functional linkage between G<SUB>13</SUB>, RhoA, ROCK, PKC-ε, CPI-17 and MLC phosphorylation in sustained contraction has been implicated. Contraction of normal esophageal circular muscle (ESO) in response to acetylcholine (ACh) is linked to M<SUB>2</SUB> muscarinic receptors activating at least three intracellular phospholipases, i.e. phosphatidylcholine-specific phospholipase C (PC-PLC), phospholipase D (PLD) and the high molecular weight (85 kDa) cytosolic phospholipase A<SUB>2</SUB> (cPLA<SUB>2</SUB>) to induce phosphatidylcholine (PC) metabolism, production of diacylglycerol (DAG) and arachidonic acid (AA), resulting in activation of a protein kinase C (PKC)-dependent pathway. In contrast, lower esophageal sphincter (LES) contraction induced by maximally effective doses of ACh is mediated by muscarinic M<SUB>3 </SUB>receptors, linked to pertussis toxin-insensitive GTP-binding proteins of the G<SUB>q/11</SUB> type. They activate phospholipase C, which hydrolyzes phosphatidylinositol bisphosphate (PIP<SUB>2</SUB>), producing inositol 1, 4, 5-trisphosphate (IP<SUB>3</SUB>) and DAG. IP<SUB>3</SUB> causes release of intracellular Ca<SUP>2&#8290;</SUP> and formation of a Ca<SUP>2&#8290;</SUP>-calmodulin complex, resulting in activation of myosin light chain kinase and contraction through a calmodulin-dependent pathway.