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NEUROPHARMACOLOGY

Olanzapine Increases RGS7 Protein Expression via Stimulation of the Janus Tyrosine Kinase-Signal Transducer and Activator of Transcription Signaling Cascade

Department of Pharmacology and Experimental Therapeutics, Loyola University Chicago, Stritch School of Medicine, Maywood, Illinois

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 [-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 G_q protein and accelerates GTP hydrolysis.

Address correspondence to: Dr. Nancy A. Muma, Department of Pharmacology and Toxicology, School of Pharmacy, University of Kansas, 1251 Wescoe Hall Drive, 5064 Malott Hall, Lawrence, KS 66045. E-mail: nmuma{at}ku.edu

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