Reversible activation of hepatic adenylate cyclase by guanyl-5'-yl-(alpha,beta-methylene)diphosphonate and guanyl-5'-yl imidodiphosphate.
Guanyl-5'-yl-(alpha,beta-methylene)di[gamma-32P]phosphonate (Gp-(CH2)pp) is not hydrolyzed by rat liver membranes under conditions in which GTP and guanyl-5'-yl imidodiphosphate (Gpp(NH)p) are hydrolyzed. Gp(CH2)pp activates adenylate cyclase in hepatic membranes with characteristics similar to those of Gpp(NH)p activation but with lower potency and effectiveness. The analogs, although with lower potency than GTP, also share the ability to change the glucagon receptor from a high to a low affinity state. Both Gp(CH2)pp and Gpp(NH)p stimulate adenylate cyclase activity following a lag period of about 1 min addition of GTP after steady state rates are achieved results in reduction in the rate following a lag period of 6 min from the time of addition of GTP. Pretreatment of the enzyme with Gpp(NH)p or Gp(CH2)pp, followed by washing the membranes, leads to a high activity state of the enzyme which slowly decays in rate unless the analogs are continuously present in the medium. These data suggest that the guanosyl nucleotide analogs act on the enzyme system by a slowly reversible process that possibly reflects slow binding and dissociation from different transition states of the enzyme system and suggest that activation of adenylate cyclase by GTP, Gpp(NH)p, and Gp(CH2)pp does not involve covalent modification of the enzyme.
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000201:enzymology; D004164:Diphosphonates / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005934:Glucagon / Q000378:metabolism; D006150:Guanine Nucleotides / Q000494:pharmacology*; D006160:Guanosine Triphosphate / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D011485:Protein Binding; D051381:Rats
D004164:Diphosphonates; D006150:Guanine Nucleotides; D006160:Guanosine Triphosphate; D005934:Glucagon; D000262:Adenylyl Cyclases