Group I secreted PLA2 in the maintenance of human lower esophageal sphincter tone.
OBJECTIVE
In cat spontaneous lower esophageal sphincter (LES), tone is maintained by the activity of group I secreted phospholipase A2 (sPLA2-I) that produces arachidonic acid. Arachidonic acid metabolites activate G proteins linked to phospholipases, producing second messengers and activation of a protein kinase C-dependent pathway to maintain tone. We examined the role of sPLA2-I in the maintenance of tone in human LES samples obtained from organ donors.


METHODS
In vitro LES tone and sPLA2-I-induced contraction of enzymatically isolated LES smooth muscle cells were measured in the absence or presence of inhibitors. Cell permeabilization by saponin allowed use of G-protein antibodies.


RESULTS
In vitro LES tone was reduced by inhibitors of sPLA2-I, by indomethacin, by the phosphatidylcholine-specific phospholipase C inhibitor D609, and by the protein kinase C inhibitor chelerythrine. sPLA2-I-induced contraction of isolated LES smooth muscle cells was reduced by indomethacin, pertussis toxin, Gi3 antibodies, D609, and by chelerythrine.


CONCLUSIONS
Human LES tone is maintained by the activity of sPLA2-I that produces arachidonic acid and metabolites and activation of Gi3-linked receptors and of phosphatidylcholine-specific phospholipase C, resulting in production of diacylglycerol, activation of PKC, and maintenance of tone through a protein kinase C-dependent contractile pathway.
Cao
W
W
Department of Medicine, Rhode Island Hospital and Brown University, Providence, Rhode Island 02903, USA.
Harnett
K M
KM
Behar
J
J
Biancani
P
P
D000293:Adolescent; D000328:Adult; D000368:Aged; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004943:Esophagogastric Junction / Q000187:drug effects / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000502:physiology; D006801:Humans; D008875:Middle Aged; D009119:Muscle Contraction / Q000502:physiology; D009129:Muscle Tonus / Q000187:drug effects / Q000502:physiology*; D010713:Phosphatidylcholines / Q000378:metabolism; D010741:Phospholipases A / Q000378:metabolism / Q000502:physiology*; D054467:Phospholipases A2; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D013379:Substrate Specificity; D010738:Type C Phospholipases / Q000378:metabolism
D016861:Cyclooxygenase Inhibitors; D004791:Enzyme Inhibitors; D010713:Phosphatidylcholines; D011493:Protein Kinase C; D010741:Phospholipases A; D054467:Phospholipases A2; D010738:Type C Phospholipases; D019204:GTP-Binding Proteins