SIGNAL-TRANSDUCTION IN GASTROINTESTINAL SMOOTH-MUSCLE

Signal transduction in gastric and intestinal smooth muscle is mediate d by receptors coupled via distinct G proteins to various effector enz ymes, including PI-specific PLC beta 1 and PLC-beta 3, and phosphatidy lcholine (PC)-specific PLC, PLD and PLA(2). Activation of these enzyme s is different in circular and longitudinal muscle cells, generating C a2+ mobilizing (IP3, AA, cADPR) and other (DAG) messengers responsible for the initial and sustained phases of contraction, respectively. IP 3-dependent Ca2+ release occurs only in circular muscle. Ca2+ mobiliza tion in longitudinal muscle involves a cascade initiated by agonist in duced transient activation of PLA(2) and formation of AA, AA dependent depolarization of the plasma membrane and opening of voltage-sensitiv e Ca2+ channels. The influx of Ca2+ induces Ca2+ release by activating sarcoplasmic ryanodine receptor/Ca2+ channel and stimulates cADPR for mation which enhances Ca2+-induced Ca2+ release. The initial [Ca2+](i) transient in both muscle cell types results in Ca2+/calmodulin-depend ent activation of MLC kinase, phosphorylation of MLC20 and interaction of actin and myosin. The sustained phase is mediated by a Ca2+-indepe ndent isoform of PKC, PKC-epsilon. DAG for this process is generated b y PLC- and PLD-mediated hydrolysis of PC. Relaxation is mediated by cA MP- and/or cGMP-dependent protein kinase which inhibit the initial [Ca 2+](i) transient and reduce the sensitivity of MLC kinase to [Ca2+](i) . Relaxation induced by the main enteric relaxant neurotransmitters, V IP and PACAP, involves two cascades, one of which reflects activation of adenylyl cyclase. A distinct cascade involves G-protein dependent s timulation of Ca2+ influx leading to Ca2+/calmodulin-dependent activat ion of a constitutive eNOS in muscle cells; the generation of NO activ ates soluble guanylyl cyclase. The resultant activation of PKA and PKG is jointly responsible for muscle relaxation. (C) 1997 Elsevier Scien ce Inc.