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Desensitization of the Dopamine D1‐D2 Receptor Heteromeric Complex in Primary Striatal Neurons and Bi‐functional Regulation by GRK2
Author(s) -
Verma Vaneeta,
Hasbi Ahmed,
O'Dowd Brian F.,
George Susan R.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.24.1_supplement.585.2
Subject(s) - dopamine receptor d2 , desensitization (medicine) , homologous desensitization , agonist , g protein coupled receptor kinase , chemistry , dopamine receptor d1 , enzyme linked receptor , beta adrenergic receptor kinase , receptor , 5 ht5a receptor , microbiology and biotechnology , pharmacology , g protein coupled receptor , biology , biochemistry
Co‐activation of a Gq‐linked heteromeric D1‐D2 dopamine receptor signaling complex results in phospholipase C‐dependent intracellular calcium release. We have specifically identified that the D1 agonist, SKF83959, selectively activates the D1‐D2 receptor heteromer, while SKF83822 only activates the D1 homooligomer. These agonists were used to evaluate agonist induced desensitization of the D1‐D2 receptor heteromer mediated calcium signal. Pre‐treatment with each agonist for 5 min led to rapid desensitization of the calcium signal both in cells and in primary striatal neurons. Desensitization was abolished by the D1 antagonist, but not by the D2 antagonist. Expression of G protein‐coupled receptor kinase 2 (GRK2) led to a decrease in the calcium signal. This was mediated by both the catalytic and RGS domains of GRK2. Our results indicate that desensitization of the D1‐D2 receptor heteromer mediated calcium signal occurs by D1 receptor occupancy with or without signal activation and is regulated by two distinct functions of GRK2. Intriguingly, occupancy of the D1 receptor binding pocket by SKF83822 that was unable to activate the D1‐D2 receptor complex still permitted desensitization of the calcium response, suggesting that activation of the receptor was not a prerequisite and occupancy of the receptor binding pocket with its associated conformational changes could lead to decreased signaling. This work is supported by the NIH National Institute on Drug Abuse.