Oxyntomodulin: a cAMP-dependent stimulus of rat parietal cell function via the receptor for glucagon-like peptide-1 (7-36)NH2.
We have previously shown that in highly enriched rat gastric parietal cells the intestinal peptide hormones oxyntomodulin and glucagon-like peptide-2 (GLP-2) compete for receptor-binding with glucagon-like peptide-1 (GLP-1), a potent cAMP-dependent stimulus of H+ production in vitro. It is, however, unknown whether oxyntomodulin and GLP-2 elicit a biological response by interacting with the GLP-1 receptor. Therefore, we used enriched rat parietal cells to investigate the effects of both hormones on the production of cAMP and H+ ([14C]aminopyrine accumulation). Both parameters were stimulated by oxyntomodulin in a concentration-dependent manner. EC50 values were 6.2.10(-8) and 2.5.10(-7) M oxyntomodulin for stimulation of H+ and cAMP production, respectively. The maximally effective concentrations for stimulation of [14C]aminopyrine accumulation and cAMP production were 1.10(-6) and 1.10(-5) M oxyntomodulin, respectively. At these concentrations oxyntomodulin was nearly as effective as 10(-4) M histamine and equally effective as 10(-8) M GLP-1 (7-36)NH2. In the enriched parietal cell preparation there was no immunocytochemical evidence of contaminating D cells. Accordingly, the responses to oxyntomodulin and GLP-1 (7-36)NH2 were not augmented by incubating the cells in the presence of a polyclonal anti-somatostatin antibody. [14C]Aminopyrine accumulation in response to oxyntomodulin was inhibited by the GLP-1 (7-36)NH2 receptor antagonist, exendin (9-39)NH2, but not by the H2-receptor antagonist, ranitidine. Oxyntomodulin and carbachol acted additively to stimulate [14C]aminopyrine accumulation. GLP-2 (10(-7) to 10(-5)M) was without effect on basal H+ and cAMP production; however, at 10(-5) M GLP-2 markedly inhibited oxyntomodulin-stimulated [14C]aminopyrine accumulation. It is concluded that, by interacting with parietal cell receptors for GLP-1 (7-36)NH2, oxyntomodulin, but not GLP-2, directly stimulates H+ production by activating the adenylate cyclase.
Department of Internal Medicine II, Technical University of Munich, Germany.
W
W
Schepp
K
K
Dehne
T
T
Riedel
J
J
Schmidtler
K
K
Schaffer
M
M
Classen
D000632:Aminopyrine / Q000378:metabolism; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005934:Glucagon / Q000494:pharmacology / Q000502:physiology*; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D004763:Glucagon-Like Peptides / Q000494:pharmacology / Q000502:physiology*; D006632:Histamine / Q000494:pharmacology; D006635:Histamine H2 Antagonists / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D053772:Oxyntomodulin; D010295:Parietal Cells, Gastric / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology / Q000502:physiology*; D011899:Ranitidine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors / Q000378:metabolism; D013004:Somatostatin / Q000378:metabolism
C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D006635:Histamine H2 Antagonists; D053772:Oxyntomodulin; D010446:Peptide Fragments; D018027:Receptors, Glucagon; D000632:Aminopyrine; C055453:glucagon-like peptide 1 (7-36)amide; D013004:Somatostatin; C083773:exendin (9-39); D004763:Glucagon-Like Peptides; D006632:Histamine; D011899:Ranitidine; D052216:Glucagon-Like Peptide 1; D002217:Carbachol; D005934:Glucagon; D000242:Cyclic AMP