SIGNAL-TRANSDUCTION PATHWAYS IN ESOPHAGEAL AND LOWER ESOPHAGEAL SPHINCTER CIRCULAR MUSCLE

Esophageal reflux is a common condition that affects children and 1 in 10 adults, and if untreated may result in chronic esophagitis, aspira tion pneumonia, esophageal strictures, and Barrett's esophagus, a prem alignant condition. Although esophagitis is a multifactorial disease t hat may depend on transient lower esophageal sphincter (LES) relaxatio n, speed of esophageal clearance, mucosal resistance, and other factor s, impairment of LES pressure is a common finding in patients complain ing of chronic heartburn. Our data suggest that esophageal and LES cir cular muscle utilize distinct Ca2+ sources, phospholipid pools, and si gnal transduction pathways to contract in response to acetylcholine (A Ch): (1) In esophageal muscle ACh-induced contraction requires influx of extracellular Ca2+ and may be linked to phosphatidylcholine metabol ism, production of diacylglycerol (DAG) and arachidonic acid, and acti vation of a protein kinase C (PKC)dependent pathway. (2) In LES muscle ACh-induced contraction utilizes intracellular Ca2+ release arising f rom metabolism of phosphatidylinositol (PI), and a calmodulin-myosin l ight chain kinase-dependent pathway. Resting LES tone, on the other ha nd, may be due to relatively low basal PI hydrolysis resulting in subm aximal levels of inositol triphosphate (IP3)-induced calcium release a nd interaction with DAG to activate PKC. (3) After induction of experi mental esophagitis, basal levels of PI hydrolysis and intracellular ca lcium stores are substantially reduced, resulting in a reduction of ve sting tone. In addition the signal transduction pathway responsible fo r LES contraction in response to ACh changes from one that depends on IF, production, calcium release, and calmodulin activation to one that relies on influx of extracellular calcium and activation of PKC. (C) 1997 by Excerpta Medica, Inc.