Pertussis toxin-sensitive inhibition of glucagon-like peptide 1-stimulated acid production by epidermal growth factor and transforming growth factor alpha in rat parietal cells.
We have recently shown that the intestinal hormone glucagon-like peptide-1 (GLP-1)-(7-36) amide is a cAMP-dependent stimulant of rat parietal cell H+ production. Epidermal growth factor (EGF) and transforming growth factor-alpha (TGF alpha) are known to inhibit histamine-stimulated parietal cell function by reducing cAMP production in a pertussis toxin-sensitive manner. Pertussis toxin blocks Gi alpha, the inhibitory subunit of adenylate cyclase, thereby preventing inhibitors from acting via Gi alpha. Therefore, we used pertussis toxin as a tool to determine whether EGF and TGF alpha inhibit GLP-1-stimulated parietal cell function via Gi alpha. In enriched (76 +/- 4%) rat parietal cells [14C]aminopyrine accumulation and cAMP production were maximally stimulated by GLP-1-(7-36) amide (10(-8) and 10(-7) M, respectively) or by histamine (10(-4) and 10(-3) M, respectively). EGF and TGF alpha (10(-13)-10(-7) M) caused concentration-dependent inhibition of GLP-1-stimulated parietal cell function. Maximal inhibition (33% and 37% of the response to GLP-1-(7-36) amide was observed at 10(-8) M EGF and 10(-9) M TGF alpha, respectively. There was a close correlation (r = 0.83; P < 0.05; n = 7) between the inhibition by EGF and TGF alpha of [14C]aminopyrine accumulation and the fall in cAMP production in GLP-1-stimulated parietal cells. The identical concentrations of both growth factors which maximally reduced GLP-1-stimulated parietal cell function inhibited [14C]aminopyrine accumulation in response to histamine by approximately 30%.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Internal Medicine II, Technical University of Munich, Germany.
J
J
Schmidtler
K
K
Dehne
V
V
Schusdziarra
M
M
Classen
W
W
Schepp
D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism; D000632:Aminopyrine / Q000378:metabolism; D000818:Animals; D000242:Cyclic AMP / Q000096:biosynthesis; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D005260:Female; D005744:Gastric Acid / Q000378:metabolism*; D005753:Gastric Mucosa / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005934:Glucagon / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D052216:Glucagon-Like Peptide 1; D010446:Peptide Fragments / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D037342:Pertussis Toxin; D011498:Protein Precursors / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D016211:Transforming Growth Factor alpha / Q000494:pharmacology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology*
D037361:Adenylate Cyclase Toxin; D010446:Peptide Fragments; D011498:Protein Precursors; D016211:Transforming Growth Factor alpha; D010566:Virulence Factors, Bordetella; D000632:Aminopyrine; D004815:Epidermal Growth Factor; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D000242:Cyclic AMP; D037342:Pertussis Toxin; D000262:Adenylyl Cyclases