TY - JOUR
T1 - Pertussis toxin-sensitive inhibition of glucagon-like peptide 1-stimulated acid production by epidermal growth factor and transforming growth factor α in rat parietal cells
AU - Schmidtler, Johanna
AU - Dehne, Kerstin
AU - Schusdziarra, Volker
AU - Classen, Meinhard
AU - Schepp, Wolfgang
PY - 1993/6/15
Y1 - 1993/6/15
N2 - We have recently shown that the intestinal hormone glucagon-like peptide-1 (GLP-1)-7-36) amideis a cAMP-dependent stimulant of rat parietal cell H+ production. Epidermal growth factor (EGF) and transforming growth factor-α (TGFα) are known to inhibit histamine-stimulated parietal cell function by reducing cAMP productions in a pertussis toxin-sensitive manner. Pertussis toxin blocks Giα, the inhibitory subunit of adenylate cyclase, thereby preventing inhibitors from acting via Giα. Therefore, we used pertussis toxin as a tool to determine whether EGF and TGFα inhibit GLP-1-stimulated parietal cell function via Giα. 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 TGFα (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 TGFα, respectively. There was a close correlation (r = 0.83; P < 0.05; n = 7) between the inhibition by EGF and TGFα 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%. Thus, the effect of EGF and TGFα on the response to GLP-1 closely resembles that on histamine-induced parietal cell function. Pretreatment with pertussis toxin (300 ng/ml; 37°C; 4 h) completely reversed inhibition by EGF and TGFα of aminopyrine accumulation and cAMP production following stimulation by either GLP-1 or histamine. In crude membranes prepared from enriched parietal cells, GLP-1-induced adenylate cyclase activity was inhibited by EGF (10-8 M) and TGFα (10-9 M) in a pertussis toxin-sensitive manner. We conclude that EGF and TGFα inhibit GLP-1-(7-36)-stimulated parietal cell function via a pertussis toxin-sensitive substrate, presumably Giα, the inhibitory subunit of adenylate cyclase.
AB - We have recently shown that the intestinal hormone glucagon-like peptide-1 (GLP-1)-7-36) amideis a cAMP-dependent stimulant of rat parietal cell H+ production. Epidermal growth factor (EGF) and transforming growth factor-α (TGFα) are known to inhibit histamine-stimulated parietal cell function by reducing cAMP productions in a pertussis toxin-sensitive manner. Pertussis toxin blocks Giα, the inhibitory subunit of adenylate cyclase, thereby preventing inhibitors from acting via Giα. Therefore, we used pertussis toxin as a tool to determine whether EGF and TGFα inhibit GLP-1-stimulated parietal cell function via Giα. 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 TGFα (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 TGFα, respectively. There was a close correlation (r = 0.83; P < 0.05; n = 7) between the inhibition by EGF and TGFα 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%. Thus, the effect of EGF and TGFα on the response to GLP-1 closely resembles that on histamine-induced parietal cell function. Pretreatment with pertussis toxin (300 ng/ml; 37°C; 4 h) completely reversed inhibition by EGF and TGFα of aminopyrine accumulation and cAMP production following stimulation by either GLP-1 or histamine. In crude membranes prepared from enriched parietal cells, GLP-1-induced adenylate cyclase activity was inhibited by EGF (10-8 M) and TGFα (10-9 M) in a pertussis toxin-sensitive manner. We conclude that EGF and TGFα inhibit GLP-1-(7-36)-stimulated parietal cell function via a pertussis toxin-sensitive substrate, presumably Giα, the inhibitory subunit of adenylate cyclase.
KW - Acid production
KW - Epidermal growth factor
KW - GTP-binding proteins
KW - Glucagon-like peptide 1-(7-36) amide
KW - Parietal cell rat
KW - Transforming growth factor-α
UR - http://www.scopus.com/inward/record.url?scp=0027158210&partnerID=8YFLogxK
U2 - 10.1016/0922-4106(93)90010-7
DO - 10.1016/0922-4106(93)90010-7
M3 - Article
C2 - 8394819
AN - SCOPUS:0027158210
SN - 0922-4106
VL - 246
SP - 59
EP - 66
JO - European Journal of Pharmacology: Molecular Pharmacology
JF - European Journal of Pharmacology: Molecular Pharmacology
IS - 1
ER -