Abolition of the expression of inhibitory guanine nucleotide regulatory protein Gi activity in diabetes

Debra Gawler, Graeme Milligan, Allen M. Spiegel, Cecilia G. Unson, Miles D. Houslay

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Abstract

Many cell-surface receptors for hormones appear to exert their effects on target cells by interacting with specific guanine nucleotide binding regulatory proteins (G-proteins) which couple receptors to their second-messenger signal generation systems. A common intracellular second messenger, which is used by many hormones, is cyclic AMP. This is produced by adenylate cyclase, whose activity is controlled by two G-proteins, Gs which mediates stimulatory effects and Gi inhibitory effects on adenylate cyclase activity1. In liver, the hormone glucagon increases intracellular cAMP concentrations by activating adenylate cyclase by a Gs-mediated process. This effect of glucagon is antagonised by the hormone insulin, although the molecular mechanism by which insulin elicits its actions is obscure. However, insulin receptors exhibit a tyrosyl kinase activity2 and appear to interact with G-proteins2,3, perhaps by causing phosphorylation of them4. In type I diabetes, circulating insulin levels are abnormally low, giving rise to gross perturbations of metabolism as well as to a variety of complications such as ionic disturbances, neuropathies of the nervous system, respiratory and cardiovascular aberrations and predispostion to infection5. We show here that experimentally-induced type I diabetes leads to the loss of expression of G{ in rat liver. As it has been suggested that Gi may couple receptors to K+- channels6,7 as well as mediating the inhibition of adenylate cyclase, aberrations in the control of expression of this key regulatory protein in type I diabetes may be expected to lead to pleiotropic effects.

Original languageEnglish (US)
Pages (from-to)229-232
Number of pages4
JournalNature
Volume327
Issue number6119
DOIs
StatePublished - Jan 1 1987
Externally publishedYes

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