Olanzapine increases RGS7 protein expression via stimulation of the Janus tyrosine kinase-signal transducer and activator of transcription signaling cascade.
Atypical antipsychotics such as olanzapine have high affinity for multiple monoamine neurotransmitter receptors and are the mainstay of pharmacological therapy for treatment of schizophrenia. In addition to blocking monoamine receptors, these drugs also affect intracellular signaling cascades. We now report that 24-h treatment with 300 nM olanzapine causes desensitization of serotonin (5-HT)(2A) receptors in A1A1v cells, a rat cortical cell line, as indicated by a reduction in inositol phosphate accumulation following stimulation with a 5-HT(2A/2C) receptor agonist (-)-1-(2,5-dimethoxy-4-lodophenyl)-2-aminopropane HCl. Olanzapine treatment for 24 h increased the levels of 5-HT(2A) receptors in both cytosol (234 +/- 34% of control level) and membrane fractions (206 +/- 14% of control levels) and RGS7 proteins in both cytosol (193 +/- 32% of control levels) and membrane fractions (160 +/- 18% of control levels) as measured on Western blots. Increased phosphorylation of Janus tyrosine kinase (JAK) 2 and increased phosphorylation and nuclear translocation of signal transducer and activator of transcription (STAT) 3 with 24-h olanzapine treatment demonstrate activation of the JAK-STAT signaling cascade. Pretreatment with a JAK inhibitor, AG490 [alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide], prevented the olanzapine-induced increase in membrane RGS7 protein levels; AG490 alone had no effect on RGS7 protein levels. We verified that treatment with AG490 reduced phosphorylation of JAK2 and inhibited the nuclear localization of phospho-STAT3. Interestingly, treatment with the JAK inhibitor had no effect on 5-HT(2A) receptor protein levels. These data suggest that olanzapine-induced activation of the JAK-STAT signaling cascade causes increased expression of RGS7 protein, which in turn could mediate desensitization of 5-HT(2A) receptor signaling caused by olanzapine because RGS7 binds to Galpha(q) protein and accelerates GTP hydrolysis.
Singh
Rakesh K
RK
Department of Pharmacology and Experimental Therapeutics, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois, USA.
Shi
Ju
J
Zemaitaitis
Bozena W
BW
Muma
Nancy A
NA
D021581:Active Transport, Cell Nucleus; D000595:Amino Acid Sequence; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001569:Benzodiazepines / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D053612:Janus Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D008969:Molecular Sequence Data; D000077152:Olanzapine; D010766:Phosphorylation; D020710:RGS Proteins / Q000032:analysis* / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000032:analysis / Q000276:immunology; D050791:STAT Transcription Factors / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D020032:Tyrphostins / Q000494:pharmacology
D014150:Antipsychotic Agents; D007295:Inositol Phosphates; D020710:RGS Proteins; C087182:RGS2 protein, human; C492039:RGS7 protein, human; D012333:RNA, Messenger; D044402:Receptor, Serotonin, 5-HT2A; D050791:STAT Transcription Factors; D020032:Tyrphostins; C095512:alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamide; D001569:Benzodiazepines; D053612:Janus Kinases; D000077152:Olanzapine