title: Mediators of postreceptor action of insulin.
abstract: Intracellular insulin action has been investigated in terms of the control of glycogen synthesis. The action was systematically traced back to the initial action of insulin at the cell membrane. Insulin activates the rate-controlling enzyme, glycogen synthase. The mechanism of this activation was found to be the control of glycogen synthase by covalent phosphorylation and dephosphorylation. Insulin brought about dephosphorylation and enzyme activation, which led to increased glycogen synthesis. A study of the interconversion reactions led to the discovery of the cyclic adenosine monophosphate dependent (cAMP-dependent) protein kinase which phosphorylates glycogen synthase and inactivates the enzyme, and a phosphoprotein phosphatase which dephosphorylates glycogen synthase and activates it. Studies revealed that insulin does not act on glycogen synthase by decreasing basal tissue concentrations of cAMP (or by altering cyclic guanosine monophosphate (cGMP) tissue concentrations); rather, insulin acts more directly on the cAMP-dependent protein kinase to inactivate the kinase and to desensitize it to the activating action of cAMP. An intracellular mediator of insulin action was hypothesized to carry out this effect on the kinase; therefore, the kinase was used as an assay to search for the putative mediator. Such an insulin-generated mediator was found to be present initially in skeletal muscle and more recently in several insulin-sensitive tissues. Present evidence, although indirect, strongly suggests (1) that the mediator is a small peptide or peptide-like molecule, (2) that probably several mediators (or a family of mediators) are formed rapidly with insulin action; and (3) that they are formed from cell-membrane proteins by a process of limited proteolysis, which is initiated by the binding of insulin to its receptor. The present status of the rapidly developing area of hormone-induced transmembrane signaling via mediators is reviewed.
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D006006:Glycogen Synthase / Q000378:metabolism; D007328:Insulin / Q000502:physiology*; D008954:Models, Biological; D010455:Peptides / Q000502:physiology; D010766:Phosphorylation; D010770:Phosphotransferases / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D011972:Receptor, Insulin / Q000502:physiology*; D014107:Tosyllysine Chloromethyl Ketone / Q000494:pharmacology; D014357:Trypsin / Q000494:pharmacology
chemical_list: D007328:Insulin; D010455:Peptides; D014107:Tosyllysine Chloromethyl Ketone; D000242:Cyclic AMP; D006006:Glycogen Synthase; D010770:Phosphotransferases; D011494:Protein Kinases; D011972:Receptor, Insulin; D014357:Trypsin