title: Activation of the JAK-STAT pathway is necessary for desensitization of 5-HT2A receptor-stimulated phospholipase C signalling by olanzapine, clozapine and MDL 100907.
abstract: We have previously demonstrated that olanzapine-induced desensitization of 5-HT2A receptor-stimulated phospholipase C (PLC) activity is associated with increases in RGS7 protein levels both in vivo and in cells in culture, and the increase in RGS7 is dependent on activation of the JAK-STAT pathway in cells in culture. In the present study, we found that desensitization of 5-HT2A receptor-stimulated PLC activity induced by olanzapine is dependent on activation of the JAK-STAT pathway. Similar to olanzapine, clozapine-induced desensitization of 5-HT2A receptor signalling is accompanied by increases in RGS7 and activation of JAK2. Treatment with the selective 5-HT2A receptor antagonist MDL 100907 also increased RGS7 protein levels and JAK2 activation. Using a JAK2 inhibitor AG490, we found that clozapine and MDL 100907-induced increases in RGS7 are dependent on activation of the JAK-STAT pathway. Olanzapine, clozapine, and MDL 100907 treatment increased mRNA levels of RGS7. Using a chromatin immunoprecipitation assay we found STAT3 binding to the putative RGS7 promoter region. Taken together, olanzapine-induced activation of the JAK-STAT pathway, and STAT3 binding to the RGS7 gene could underlie the increase in RGS7 mRNA which could subsequently increase protein expression. Furthermore, the increase in RGS7 protein could play a role in the desensitization of 5-HT2A receptor signalling by terminating the activated Galphaq/11 proteins more rapidly. Overall, our data suggest that the complete desensitization of 5-HT2A receptor-stimulated PLC activity by olanzapine, clozapine and MDL 100907 requires activation of the JAK-STAT pathway, which in turn increases RGS7 expression probably by direct transcriptional activity of STAT3.
authors.affiliation: Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, Lawrence, KS 66045, USA.
authors.forename: Rakesh K
authors.initials: RK
authors.lastname: Singh
authors.forename: Ying
authors.initials: Y
authors.lastname: Dai
authors.forename: Jeff L
authors.initials: JL
authors.lastname: Staudinger
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Muma
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D002460:Cell Line; D003024:Clozapine / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D005464:Fluorobenzenes / Q000494:pharmacology*; D053612:Janus Kinases / Q000502:physiology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D000077152:Olanzapine; D010880:Piperidines / Q000494:pharmacology*; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000502:physiology*; D058830:Serotonin 5-HT2 Receptor Antagonists; D010738:Type C Phospholipases / Q000502:physiology*
chemical_list: D005464:Fluorobenzenes; D010880:Piperidines; D044402:Receptor, Serotonin, 5-HT2A; D050796:STAT3 Transcription Factor; D058830:Serotonin 5-HT2 Receptor Antagonists; D001569:Benzodiazepines; D053612:Janus Kinases; D010738:Type C Phospholipases; C079049:volinanserin; D003024:Clozapine; D000077152:Olanzapine