title: Glucagon desensitization of adenylate cyclase and stimulation of inositol phospholipid metabolism does not involve the inhibitory guanine nucleotide regulatory protein Gi, which is inactivated upon challenge of hepatocytes with glucagon.
abstract: Brief exposure of hepatocytes to glucagon, angiotensin or the protein kinase C activator TPA (12-O-tetradecanoylphorbol 13-acetate) caused the inactivation of the inhibitory guanine nucleotide regulatory protein Gi. Glucagon-mediated desensitization of glucagon-stimulated adenylate cyclase activity was seen in hepatocytes from both normal rats and those made diabetic with streptozotocin, where Gi is not functionally expressed. Normal glucagon desensitization was seen in hepatocytes from young animals, 6 weeks of age, which had amounts of Gi in their hepatocyte membranes which were some 45% of that seen in mature animals (3.4 pmol/mg of plasma-membrane protein). Streptozotocin-induced diabetes in young animals abolished the appearance of functional Gi in hepatocyte plasma membranes. Pertussis-toxin treatment of hepatocytes from both normal mature animals and those made diabetic, with streptozotocin, blocked the ability of glucagon or angiotensin or TPA to elicit desensitization of adenylate cyclase. The isolated B (binding)-subunit of pertussis toxin was ineffective in blocking desensitization. Neither induction of diabetes nor treatment of hepatocytes with pertussis toxin inhibited the ability of glucagon and angiotensin to stimulate the production of inositol phosphates in intact hepatocytes. Thus (i) Gi does not appear to play a role in the molecular mechanism of glucagon desensitization in hepatocytes, (ii) the G-protein concerned with receptor-stimulated inositol phospholipid metabolism in hepatocytes appears not to be a substrate for the action of pertussis toxin, (iii) in intact hepatocytes, treatment with glucagon and/or angiotensin can elicit the inactivation of the inhibitory G-protein Gi, and (iv) pertussis toxin blocks desensitization by a process which does not involve Gi.
authors.affiliation: Institute of Biochemistry, University of Glasgow, Scotland, U.K.
authors.forename: G J
authors.initials: GJ
authors.lastname: Murphy
authors.forename: D J
authors.initials: DJ
authors.lastname: Gawler
authors.forename: G
authors.initials: G
authors.lastname: Milligan
authors.forename: M J
authors.initials: MJ
authors.lastname: Wakelam
authors.forename: N J
authors.initials: NJ
authors.lastname: Pyne
authors.forename: M D
authors.initials: MD
authors.lastname: Houslay
mesh_terms: D037361:Adenylate Cyclase Toxin; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology; D019204:GTP-Binding Proteins / Q000378:metabolism*; D005934:Glucagon / Q000502:physiology*; D007295:Inositol Phosphates / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000201:enzymology*; D037342:Pertussis Toxin; D051381:Rats; D011919:Rats, Inbred Strains; D013403:Sugar Phosphates / Q000378:metabolism*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D037361:Adenylate Cyclase Toxin; D007295:Inositol Phosphates; D013403:Sugar Phosphates; D010566:Virulence Factors, Bordetella; D005934:Glucagon; D037342:Pertussis Toxin; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases