AJP - Gastrointestinal and Liver Physiology, Vol 262, Issue 4 660-G668, Copyright © 1992 by American Physiological Society

ARTICLES

Pertussis toxin-sensitive and pertussis toxin-insensitive inhibition of parietal cell response to GLP-1 and histamine

W. Schepp, J. Schmidtler, K. Dehne, V. Schusdziarra and M. Classen
Department of Medicine II, Technical University of Munich, Federal Republic of Germany.

We have recently shown that in rat parietal cells the glucagon-like peptide 1 (GLP-1) variants 7-36 amide, 1-37, and 1-36 amide stimulate H+ production as indirectly measured by [14C]aminopyrine (AP) accumulation. This response to the GLP-1 peptides was intracellularly mediated by activation of adenylate cyclase and by adenosine 3',5'-cyclic monophosphate (cAMP) as second messenger. In the present study, we compared prostaglandin (PG)E2, somatostatin, and the protein kinase A antagonist Rp-adenosine-3',5'-monophosphorothioate (Rp-cAMPS) with respect to their inhibitory effects on parietal cell function induced by GLP-1 or histamine. PGE2 and somatostatin noncompetitively inhibited AP accumulation and cAMP production in response to the GLP-1 variants and histamine (IC50): [mean inhibitory concn 5 x 10(-9) M PGE2; 3 x 10(-7) somatostatin]; at their maximal concentrations PGE2 (10(-7) M) and somatostatin (10(-6) M) caused 85 and 65% inhibition, respectively. Treatment with pertussis toxin (PT; 250 ng/ml; 4 h) reversed the inhibitory effect of PGE2 and somatostatin on AP accumulation and cAMP production. At 2 x 10(-3) M (IC50: 3 x 10(-4) M) Rp-cAMPS completely inhibited AP accumulation induced by the GLP-1 variants or histamine; this effect was insensitive to PT. Specificity of Rp-cAMPs as protein kinase A inhibitor is suggested by inhibition of AP accumulation in response to Sp-cAMPS and N6,O2-dibutyryl adenosine 3',5'-cyclic phosphate sodium, and forskolin, activators of protein kinase A and adenylate cyclase, respectively. We conclude that the parietal cell responses to GLP-1 and histamine are inhibited by identical mechanisms. Effects of PGE2 and somatostatin are mediated by the PT-sensitive subunit of adenylate cyclase Gi, whereas Rp-cAMPS interferes with cAMP-dependent mechanisms that are insensitive to PT.

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