Activation of two signal-transduction systems in hepatocytes by glucagon

Michael J.O. Wakelam, Gregory J. Murphy, Victor J. Hruby, Miles D. Houslay

Research output: Contribution to journalArticlepeer-review

281 Scopus citations


The ability of glucagon to stimulate glycogen breakdown in liver played a key part in the classic identification of cyclic AMP and hormonally stimulated adenylate cyclase1. But several observations indicate that glucagon can exert effects independent of elevating intracellular cAMP concentrations2-7. These effects are probably mediated by an elevation8,9 of the intracellular concentration of free Ca 2+ although the mechanism by which this occurs is unknown. We show here that glucagon, at the low concentrations found physiologically, causes both a breakdown of inositol phospholipids and the production of inositol phosphates. Indeed, we show that the glucagon analogue, (1-N-α- trinitrophenylhistidine,12-homo-arginine)glucagon (TH-glucagon), which does not activate adenylate cyclase or cause any increase in cAMP in hepatocytes yet can fully stimulate glycogenolysis, gluconeogenesis and urea synthesis10, stimulates the production of inositol phosphates. This stimulation of inositol phospholipid metabolism by low concentrations of glucagon provides a mechanism11,12 whereby glucagon can exert cAMP-independent actions on target cells. We suggest that hepatocytes possess two distinct receptors for glucagon, a GR-1 receptor coupled to stimulate inositol phospholipid breakdown and a GR-2 receptor coupled to stimulate adenylate cyclase activity.

Original languageEnglish (US)
Pages (from-to)68-71
Number of pages4
Issue number6083
StatePublished - 1986

ASJC Scopus subject areas

  • General


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