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

Am J Physiol. 1992 Apr;262(4 Pt 1):G660-8. doi: 10.1152/ajpgi.1992.262.4.G660.

Abstract

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.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylate Cyclase Toxin*
  • Aminopyrine / metabolism
  • Animals
  • Cyclic AMP / analogs & derivatives
  • Cyclic AMP / antagonists & inhibitors
  • Cyclic AMP / pharmacology
  • Dinoprostone / pharmacology
  • Drug Resistance
  • Glucagon / pharmacology*
  • Glucagon-Like Peptide 1
  • Histamine / pharmacology*
  • Osmolar Concentration
  • Parietal Cells, Gastric / drug effects*
  • Peptide Fragments / pharmacology*
  • Pertussis Toxin*
  • Protein Kinase Inhibitors
  • Protein Precursors / pharmacology*
  • Somatostatin / pharmacology
  • Thionucleotides / pharmacology
  • Virulence Factors, Bordetella / pharmacology*

Substances

  • Adenylate Cyclase Toxin
  • Peptide Fragments
  • Protein Kinase Inhibitors
  • Protein Precursors
  • Thionucleotides
  • Virulence Factors, Bordetella
  • Aminopyrine
  • adenosine-3',5'-cyclic phosphorothioate
  • Somatostatin
  • Histamine
  • Glucagon-Like Peptide 1
  • Glucagon
  • Cyclic AMP
  • Pertussis Toxin
  • Dinoprostone