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SKF83959 selectively regulates phosphatidylinositol‐linked D 1 dopamine receptors in rat brain
Author(s) -
Jin LiQing,
Goswami Satindra,
Cai Guoping,
Zhen Xuechu,
Friedman Eitan
Publication year - 2003
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.1471-4159.2003.01698.x
Subject(s) - agonist , phosphatidylinositol , g protein , receptor , guanosine , phospholipase c , microbiology and biotechnology , dopamine , biology , endocrinology , pertussis toxin , medicine , stimulation , chemistry , biochemistry , signal transduction
Previously a distinct D 1 ‐like dopamine receptor (DAR) that selectively couples to phospholipase C/phosphatidylinositol (PLC/PI) was proposed. However, lack of a selective agonist has limited efforts aimed at characterizing this receptor. We characterized the in vitro and in vivo effects of SKF83959 in regulating PI metabolism. SKF83959 stimulates (EC 50 , 8 µm) phosphatidylinositol 4,5‐biphosphate hydrolysis in membranes of frontal cortex (FC) but not in membranes from PC12 cells expressing classical D 1A DARs. Stimulation of FC PI metabolism was attenuated by the D 1 antagonist, SCH23390, indicating that SKF83959 activates a D 1 ‐like DAR. The PI‐linked DAR is located in hippocampus, cerebellum, striatum and FC. Most significantly, administration of SKF83959 induced accumulations of IP 3 in striatum and hippocampus. In contrast to other D 1 DAR agonists, SKF83959 did not increase cAMP production in brain or in D 1A DAR‐expressing PC12 cell membranes. However, SKF83959 inhibited cAMP elevation elicited by the D 1A DAR agonist, SKF81297, indicating that the compound is an antagonist of the classical D 1A DAR. Lastly, we demonstrated that SKF83959 enhances [ 35 S]guanosine 5′‐ O ‐(3‐thiotriphosphate) binding to membrane Gαq and Gαi proteins, suggesting that PI stimulation is mediated by activation of these guanine nucleotide‐binding regulatory proteins. Results indicate that SKF83959 is a selective agonist for the PI‐linked D 1 ‐like DAR, providing a unique tool for investigating the functions of this brain D 1 DAR subtype.