Prostaglandin inhibition of acid is cAMP dependent

Karl A. Zucker, Michael J. Zdon, Thomas E. Adrian, Garth H. Ballantyne, Irvin M. Modlin

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

Prostaglandin E (PGE) potently inhibits acid secretion stimulated by histamine, but not by acetylcholine or gastrin, and is accompanied by decreased intracellular cAMP. Adenylate cyclase receptor systems are composed of three complex proteins: cell receptor, nucleotide binding protein, and the catalytic subunit. The exact mechanism of PGE interaction with this complex remains unclear and elucidation of this site of action is the purpose of this study. We utilized molecular probes directed at the various components of adenylate cyclase. Cholera toxin alters the stimulatory subunit of the nucleotide binding proteins (Ns), rendering it resistant to normal deactivation, whereas N-ethylmaleimide (NEM) blocks the inhibitory subunit (Ni). Forskolin acts as a direct activator of the catalytic subunit of adenylate cyclase and 8-bromo-cAMP acts as a cyclic AMP mimetic. We measured in vitro acid secretion in isolated parietal cells by the assessment of [14C]aminopyrine (AP) accumulation. The PGE1 analog (miso) and the PGE2 analog (DMPG) were incubated in graded doses (10-11 to 10-6 M) with histamine (10-6 M). Miso (10-7 M) reduced AP accumulation to 21 ± 8% of histamine alone (100%) and DMPG (10-6 M) reduced AP to 61 ± 9% (P < 0.005 for both). AP accumulation stimulated by 8-Br-cAMP (10-6 M) and forskolin (10-6 M) was not significantly affected by either PGE analog (P > 0.05) suggesting that the site of PGE interaction is proximal to the activation of the catalytic subunit. Cholera toxin (2.0 μg/ml)- and histamine (10-6 M)-induced AP accumulation was not affected by either PGE analog (P > 0.05), suggesting the requirement of an intact Ns for PGE inhibition. Inactivation of Ni by NEM (1 mM) in parietal cells stimulated by histamine (10-6 M) resulted in a diminished inhibition of AP accumulation induced by miso and DMPG (78 ± 11 and 58 ± 13%) (P < 0.05). These data are consistent with the hypothesis that PGE may modify the inhibitory receptor signal by interacting with the nucleotide regulatory proteins.

Original languageEnglish
Pages (from-to)513-520
Number of pages8
JournalJournal of Surgical Research
Volume42
Issue number5
DOIs
Publication statusPublished - May 1987
Externally publishedYes

ASJC Scopus subject areas

  • Surgery

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