Study of the functional organization of a novel adenylate cyclase signaling mechanism of insulin action.
In this study we continued decoding the adenylate cyclase signaling mechanism that underlies the effect of insulin and related peptides. We show for the first time that insulin signal transduction via an adenylate cyclase signaling mechanism, which is attended by adenylate cyclase activation, is blocked in the muscle tissues of the rat and the mollusk Anodonta cygnea in the presence of: 1) pertussis toxin, which impairs the action of the inhibitory GTP-binding protein (Gi); 2) wortmannin, a specific blocker of phosphatidylinositol 3-kinase; and 3) calphostin C, an inhibitor of different isoforms of protein kinase C. The treatment of sarcolemmal membrane fraction with cholera toxin increases basal adenylate cyclase activity and decreases the sensitivity of the enzyme to insulin. We suggest that the stimulating effect of insulin on adenylate cyclase involves the following stages of hormonal signal transduction cascade: receptor tyrosine kinase --> Gi protein (betagamma) --> phosphatidylinositol 3-kinase --> protein kinase C (zeta?) --> Gs protein --> adenylate cyclase --> cAMP.
Shpakov
A O
AO
Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, pr. Morisa Toreza 44, St. Petersburg, 194223 Russia. shpakov@hormone.ief.spb.su
Plesneva
S A
SA
Kuznetsova
L A
LA
Pertseva
M N
MN
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006728:Hormones / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D007329:Insulin Antagonists / Q000494:pharmacology; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008974:Mollusca; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000201:enzymology; D009130:Muscle, Smooth / Q000187:drug effects* / Q000201:enzymology; D009281:Naphthalenes / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D000077191:Wortmannin
D000730:Androstadienes; D001427:Bacterial Toxins; D004791:Enzyme Inhibitors; D006728:Hormones; D007328:Insulin; D007329:Insulin Antagonists; D009281:Naphthalenes; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C; D000262:Adenylyl Cyclases; C058819:calphostin C; D013755:Tetradecanoylphorbol Acetate; D000077191:Wortmannin