The rapid desensitization of glucagon-stimulated adenylate cyclase is a cyclic AMP-independent process that can be mimicked by hormones which stimulate inositol phospholipid metabolism

C. J. Murphy, Victor J Hruby, D. Trivedi, M. J. Wakelam, M. D. Houslay

Research output: Contribution to journalArticle

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Abstract

Treatment of intact hepatocytes with glucagon, TH-glucagon ([1-N-α-trinitrophenylhistidine, 12-homo-arginine]glucagon), angiotensin or vasopressin led to a rapid time- and dose-dependent loss of the glucagon-stimulated response of the adenylate cyclase activity seen in membrane fractions isolated from these cells. Intracellular cyclic AMP concentrations were only elevated with glucagon. All ligands were capable of causing both desensitization/logg of glucagon-stimulated adenylate cyclase activity and stimulation of inositol phospholipid metabolism in the intact hepatocytes. Maximally effective doses of angiotensin precluded any further inhibition/desensitizing action when either glucagon or TH-glucagon was subsequently added to these intact cells, as has been shown previously for the phorbol ester TPA (12-O-tetradecanoylphorbol 13-acetate) [Heyworth, Wilson, Gawler & Houslay (1985) FEBS Lett. 187, 196-200]. Treatment of intact hepatocytes with these various ligands caused a selective loss of the glucagon-stimulated adenylate cyclase activity in washed membrane fraction and did not alter the basal, GTP-, NaF- and forskolin-stimulated responses. Angiotensin failed to inhibit glucagon-stimulated adenylate cyclase activity when added directly to a washed membrane fraction from control cells. Glucagon GR2 receptor-stimulated adenylate cyclase is suggested to undergo desensitization/uncoupling through a cyclic AMP-independent process, which involves the stimulation of inositol phospholipid metabolism by glucagon acting through GR1 receptors. This action can be mimicked by other hormones which act on the liver to stimulate inositol phospholipid metabolism. As the phorbol ester TPA also mimics this process, it is proposed that protein kinase C activation plays a pivotal role in the molecular mechanism of desensitization of glucagon-stimulated adenylate cyclase. The site of the lesion in desensitization is shown to be at the level of coupling between the glucagon receptor and the stimulatory guanine nucleotide regulatory protein G(s), and it is suggested that one or both of these components may provide a target for phosphorylation by protein kinase C.

Original languageEnglish (US)
Pages (from-to)39-46
Number of pages8
JournalBiochemical Journal
Volume243
Issue number1
StatePublished - 1987
Externally publishedYes

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Phosphatidylinositols
Glucagon
Adenylyl Cyclases
Metabolism
Cyclic AMP
Hormones
Angiotensins
Glucagon Receptors
Hepatocytes
Phorbol Esters
Tetradecanoylphorbol Acetate
Protein Kinase C
Membranes
Arginine
Acetates
Ligands
Phosphorylation
Colforsin
Guanosine Triphosphate
Vasopressins

ASJC Scopus subject areas

  • Biochemistry

Cite this

The rapid desensitization of glucagon-stimulated adenylate cyclase is a cyclic AMP-independent process that can be mimicked by hormones which stimulate inositol phospholipid metabolism. / Murphy, C. J.; Hruby, Victor J; Trivedi, D.; Wakelam, M. J.; Houslay, M. D.

In: Biochemical Journal, Vol. 243, No. 1, 1987, p. 39-46.

Research output: Contribution to journalArticle

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