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The role of beta‐arrestin2 in clozapine's actions at the serotonin 2A receptor
Author(s) -
Schmid Cullen L,
Streicher John,
Bohn Laura M
Publication year - 2012
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.26.1_supplement.lb573
Subject(s) - clozapine , internalization , serotonin , protein kinase b , 5 ht receptor , receptor , atypical antipsychotic , microbiology and biotechnology , pharmacology , chemistry , antipsychotic , phosphorylation , neuroscience , biology , medicine , schizophrenia (object oriented programming) , biochemistry , psychiatry
The G protein‐coupled serotonin 2A receptor (5‐HT2AR) is a prominent target of atypical antipsychotic drugs, including clozapine. Although clozapine has classically been defined as an antagonist at the 5‐HT2AR, it is unique in that it also induces 5‐HT2AR internalization and promotes phosphorylation of Akt downstream of the receptor. We have previously demonstrated that serotonin also induces such signaling events in a manner that requires interactions between the receptor and the intracellular regulatory and scaffolding protein, barrestin2. Here, we demonstrate that unlike serotonin, clozapine mediates receptor internalization and induces Akt phosphorylation independent of barrestin2, in mouse embryonic fibroblasts and primary cortical neurons. Moreover, we show that the in vivo effects of clozapine, as measured by its ability to block MK801‐induced hyperlocomotion in mice, are also independent of barrestin2 expression. Therefore while clozapine induces some similar receptor mediated events as serotonin, it utilizes a unique signaling mechanism to do so. Further elucidating of these mechanisms in vivo may allow for the development of more effective atypical antipsychotic drugs.