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Modulation of cannabinoid agonist binding by 5‐HT in the rat cerebellum
Author(s) -
Devlin Mark G.,
Christopoulos Arthur
Publication year - 2002
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.0022-3042.2002.00797.x
Subject(s) - agonist , cannabinoid , chemistry , cannabinoid receptor agonists , receptor , cannabinoid receptor , inverse agonist , serotonin agonist , competitive antagonist , endogenous agonist , gtp' , quipazine , medicine , endocrinology , serotonin , 5 ht receptor , biochemistry , biology , dopamine receptor d1 , enzyme
Cross‐talk between cannabinoid CB 1 and serotonin 5‐HT receptors in rat cerebellar membranes was investigated using radioligand binding. In competition against the CB 1 antagonist, [ 3 H]SR141716A, the agonist, WIN 55,212‐2 yielded a biphasic isotherm. The majority of binding was to a high‐affinity state that was significantly reduced by the GTP analogue, Gpp(NH)p. Interestingly, 5‐HT enhanced the high‐affinity binding constant of WIN 55,212‐2 while attenuating the proportion of high‐affinity binding. 5‐HT also significantly reduced the proportion of high‐affinity binding of the cannabinoid agonist, HU 210, but had no effect on the agonist, CP 55,940. The effect of 5‐HT on WIN 55,212‐2 binding was inhibited by the 5‐HT 2 receptor antagonist ritanserin as well as Gpp(NH)p, suggesting a dependence on the 5‐HT 2 receptor and on G protein‐receptor interactions, respectively. Subsequent [ 3 H]WIN 55,212‐2 dissociation kinetic experiments revealed that 5‐HT promoted a slower‐dissociating species of radiolabelled agonist‐receptor complex. Our findings support a membrane‐delimited cross‐talk between two G protein‐coupled receptors that are co‐localized in certain cells of the central nervous system. Intriguingly, the cannabinoid agonist dependence of the 5‐HT modulatory effect suggests that agonist‐specific conformations of the CB 1 receptor may also be important in determining the extent of this cross‐talk.