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)