Histamine stimulation of rat gastric parietal cell adenylyl cyclase: Modulation by guanine nucleotides

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Abstract

Histamine activation of adenylyl cyclase activity in sonicated enriched rat gastric parietal cells showed a time, temperature, and concentration dependence upon guanine diphosphoimide (Gpp(NH)p). Enzyme activation was first order with Gpp(NH)p alone or Gpp(NH)p plus histamine. The Ka for Gpp(NH)p was ~2 μm and was not influenced by histamine. GTP and GDP were inactive alone or with histamine and were competitive with Gpp(NH)p, showing apparent Ki's of near 0.4 and 0.3 μm, respectively. In the presence of Gpp(NH)p, parietal cell adenylyl cyclase was activated by histamine with an EC50 of 24 μm, the most potent in a series of histamine analogs, further substantiating an H2-receptor classification for this response. H2-Receptor antagonists were competitive inhibitors with submicromolar Ki's. Preincubation of parietal cells with histamine and Gpp(NH)p resulted in adenylyl cyclase activity up to 15 times the basal level. The activated state was retained after washing the cells free of histamine and Gpp(NH)p and was not reversed by the subsequent addition of either histamine, cimetidine, or GTP. The other gastric acid secretagogues, pentagastrin and carbamylcholine, were without effect upon histamine activation or the activated state of adenylyl cyclase. These results describe a level of control of histamine-sensitive adenylyl cyclase that requires consideration in the activation of the parietal cell H2-receptor system by histamine to modulate acid secretion.

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    This research was supported by USPHS Grants Am 20431 and GM 21361 and a grant from the Upjohn Company.

    1

    Gary C. Rosenfeld is supported by Research Career Development Award AM 00456.

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