| Literature DB >> 30670597 |
Joseph M Schrader1, Craig M Irving1, J Christopher Octeau1, Joseph A Christian1, Timothy J Aballo1, Dean J Kareemo1, Joseph Conti2, Jodi L Camberg2, J Robert Lane3,4, Jonathan A Javitch5,6, Abraham Kovoor7.
Abstract
Most clinically available antipsychotic drugs (APDs) bind dopamine D2 receptors (D2R) at therapeutic concentrations, and it is thought that they suppress psychotic symptoms by serving as competitive antagonists of dopamine at D2R. Here, we present data that demonstrate that APDs act independently of dopamine at an intracellular pool of D2R to enhance transport of D2R to the cell surface and suggest that APDs can act as pharmacological chaperones at D2R. Among the first- and second-generation APDs that we tested, clozapine exhibited the lowest efficacy for translocating D2R to the cell surface. Thus, our observations could provide a cellular explanation for some of the distinct therapeutic characteristics of clozapine in schizophrenia. They also suggest that differential intracellular actions of APDs at their common G protein-coupled receptor (GPCR) target, D2R, could contribute to differences in their clinical profiles.Entities:
Keywords: D2 dopamine receptor; G protein-coupled receptor (GPCR); antipsychotic drug; clozapine; pharmacological chaperone; pharmacoperone; protein misfolding; receptor supersensitivity; receptor trafficking; receptor up-regulation; schizophrenia
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Year: 2019 PMID： 30670597 PMCID： PMC6462534 DOI： 10.1074/jbc.RA118.004682
Source DB: PubMed Journal: J Biol Chem ISSN： 0021-9258 Impact factor: 5.157