Cannabinoid receptor agonist efficacy for stimulating [35S]GTPgammaS binding to rat cerebellar membranes correlates with agonist-induced decreases in GDP affinity.

The Journal of Biological Chemistry
C S BreivogelS R Childers

Abstract

The relationship between GDP and cannabinoid-stimulated [35S]guanosine-5'-O-(3-thiotriphosphate) ([35S]GTPgammaS) binding was investigated in rat cerebellar membranes. Kinetic analyses showed that [35S]GTPgammaS binding reached steady-state levels and that the association rate was increased by the agonist WIN 55212-2 proportional to the concentration of GDP. Dissociation of [35S]GTPgammaS occurred with two rates (t1/2 = 7 and 170 min), and WIN 55212-2 increased the proportion of sites exhibiting the faster rate. Without GDP, [35S]GTPgammaS bound to membranes with high and low affinity, and WIN 55212-2 had no effect. With 30 microM GDP, [35S]GTPgammaS bound to low and intermediate affinity sites, and WIN 55212-2 induced high affinity [35S]GTPgammaS binding without affecting low affinity sites. GDP competed for high affinity [35S]GTPgammaS binding with high and intermediate affinity in the absence of WIN 55212-2 and with high and low affinity in the presence of WIN 55212-2. Cannabinoid ligands displayed differential abilities to maximally stimulate [35S]GTPgammaS binding in the presence of GDP. Efficacy differences among ligands increased with increasing GDP concentrations. GDP competition curves revealed that agonists induced lo...Continue Reading

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