Guanosine-5'-O-thiodiphosphate functions as a partial agonist for the receptor-independent stimulation of neural adenylate cyclase.
GTP-binding proteins (G proteins) have been implicated as mediators of several aspects of neuronal signal transduction including ion channels, phosphatidyl inositol turnover and the stimulation or inhibition of adenylate cyclase. Several investigators have employed the stable guanosine diphosphate (GDP) analog, guanosine 5'-O-thiodiphosphate (GDP beta S) to block putative G protein-mediated processes. Although GDP beta S is assumed to block G protein function, some investigators have reported partial activation of G protein-mediated processes by this compound. In this study we demonstrate that GDP beta S functions as a partial agonist for the adenylate cyclase system. In rat cerebral cortex membranes, GDP beta S activates adenylate cyclase with an EC50 similar to the hydrolysis resistant GTP analog, guanylylimidodiphosphate (GppNHp), but to a far lower extent. Further, GDP beta S antagonizes the activation of adenylate cyclase by high doses of GppNHp or GTP gamma S (another stable GTP analog) but potentiates adenylate cyclase activation by low doses of these nucleotides. High doses of GDP beta S provoke, only partially, exchange of nucleotides among G proteins, as measured by the transfer of the photoaffinity GTP analog, azidoanilido-GTP, between the inhibitory and stimulatory GTP-binding proteins. In the presence of the beta-adrenergic agonist, isoproterenol, GDP beta S fails to support stimulation of C6 glioma membrane adenylate cyclase and inhibits GppNHp- or GTP gamma S-mediated stimulation of that enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)
Rasenick
M M
MM
Department of Physiology and Biophysics, University of Illinois College of Medicine, Chicago 60680.
Hughes
J M
JM
Wang
N
N
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects / Q000201:enzymology*; D006150:Guanine Nucleotides / Q000031:analogs & derivatives*; D006153:Guanosine Diphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D015290:Second Messenger Systems; D013574:Synaptosomes / Q000378:metabolism; D013873:Thionucleotides / Q000494:pharmacology*
D006150:Guanine Nucleotides; D013873:Thionucleotides; D006153:Guanosine Diphosphate; C023427:guanosine 5'-O-(2-thiodiphosphate); D000262:Adenylyl Cyclases