Acute experimental esophagitis activates a second signal transduction pathway in cat smooth muscle from the lower esophageal sphincter.
In single cells, isolated by enzymatic digestion from the circular muscle layer of the lower esophageal sphincter (LES), acute experimental esophagitis (AE) alters signal transduction in response to a maximally effective dose of acetylcholine. In normal LES contraction was inhibited by M3 >> M1 or M2 antagonists. In AE inhibition by M2 antagonists increased significantly so that contraction was inhibited by M3 > M2 > M1 antagonists. In normal cells permeabilized by saponin, contraction was antagonized by antibodies against Gq/11, by the phosphatidylinositol-specific phospholipase C (PI-PLC) antagonist U 73122, but not by the phosphatidylcholine-specific phospholipase C (PC-PLC) inhibitor D609, or by the phospholipase D pathway inhibitor propranolol. In AE contraction was reduced by Gq/11 and Gi3 antibodies and by U73122, propranolol and D609. After thapsigargin treatment of normal cells to reduce intracellular Ca++ stores, contraction was inhibited by M2 and M3 antagonists, by antibodies against Gq/11 and Gi3, by U73122, D609 and propranolol, suggesting that depletion of Ca++ stores reproduces the changes induced by AE. We conclude that in normal LES smooth muscle cells acetylcholine-induced contraction is mediated by M3 receptors linked to Gq/11 and PI-PLC, whereas in AE, contraction through this pathway is reduced, perhaps because of reduction in Ca++ stores, and a second pathway is activated by M2 receptors linked to Gi3, PC-PLC and phospholipase D.
Sohn
U D
UD
Department of Pharmacology, Chung Ang University Pharmacy College, Seoul 156-756, Korea.
Harnett
K M
KM
Cao
W
W
Rich
H
H
Kim
N
N
Behar
J
J
Biancani
P
P
D000109:Acetylcholine / Q000494:pharmacology; D000208:Acute Disease; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002415:Cats; D004941:Esophagitis / Q000503:physiopathology*; D004943:Esophagogastric Junction / Q000503:physiopathology*; D005260:Female; D019204:GTP-Binding Proteins / Q000502:physiology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000503:physiopathology*; D010740:Phospholipases / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D011976:Receptors, Muscarinic / Q000502:physiology; D015398:Signal Transduction
D011976:Receptors, Muscarinic; D011493:Protein Kinase C; D010740:Phospholipases; D019204:GTP-Binding Proteins; D000109:Acetylcholine; D002118:Calcium