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Regulation of hormone receptor coupling to adenylate cyclase effects of gtp and gdp

, : Regulation of hormone receptor coupling to adenylate cyclase effects of gtp and gdp. Journal of Biological Chemistry 255(21): 10312-10321

GDP and GTP regulation of receptor-mediated stimulation of adenylate cyclase [AC] in membranes of murine lymphoma cells (S49), NS-20 murine neuroblastoma cells (NS-20), rabbit corpora lutea (CL) and turkey erythrocytes were studied under assay conditions, which minimized conversion of added GTP to GDP and of added GDP to GTP. Hormonal stimulation in all systems required guanine nucleotide addition. In the presence of GTP, AC activity in S49, NS-20, and CL was stimulated, respectively, by isoproterenol and prostaglandin E1 (PGE1); by PGE1 and the adenosine analog, phenylisopropyladenosine; and by PGE1 and isoproterenol.sbd.the first of the listed stimulants eliciting higher activities than the second. Activity in turkey erythrocyte membranes was stimulated by isoproterenol. GDP was partially effective in promoting hormonal stimulation, being able to sustain stimulation by isoproterenol and PGE1 in S49 cell membranes, and by PGE1 in CL membranes. In NS-20 membranes, both GDP and guanosine-5'-O-(2-thiodiphosphate) (GDP.beta.S) were inhibitory on basal activity, yet promoted limited but significant stimulation by PGE1. In turkey erythrocytes, stimulation by isoproterenol could not be elicited with GDP or GDP.beta.S. Although less effective than GTP in promoting hormonal stimulation of several AC systems, GDP was clearly not inactive. Concentration effect curves for active hormone in the presence of GDP had higher apparent Ka values than in the presence of GTP. In spite of differences between the effects of GTP and GDP on hormonal stimulation of AC activities, GTP and GDP affected equally well isoproterenol binding, regardless of whether or not its receptor could be shown to stimulate AC in the presence of GDP. Determination of transphosphorylation of GDP to GTP showed that, at saturating concentrations, the proportion of GDP converted to GTP is negligible and unaffected by hormonal stimulation. Concentrations giving 50% inhibition were determined for GTP- and GDP-mediated inhibition of guanyl-5'-yl imidodiphosphate stimulation in the absence and presence of stimulatory hormones. In all 4 systems studied, GTP and GDP interacted with about equal potency and hormonal stimulation was not accompanied by a selective decrease in affinity for GDP. One way to explain the results obtained is to view hormonally sensitive AC systems as 2-state enzymes: the activities are regulated by GTP and GDP through an allosteric site related to the catalytic moiety, and receptors are entities that are inactive and, hence, unable to couple unless occupied by hormones and activated by any guanine nucleotide through a distinct receptor-related process.

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