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 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 (Muma, et al., 2007;Singh, et al., 2007). In the current 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 signaling is accompanied by increases in RGS7 and activation of JAK2. Treatment with the selective 5-HT2A receptor antagonist MDL100907 also increased RGS7 protein levels and JAK2 activation. Using a JAK2 inhibitor AG490, we found that clozapine and MDL100907-induced increases in RGS7 are dependent on activation of the JAK-STAT pathway. Olanzapine, clozapine, and MDL100907 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 signaling by terminating the activated Gαq/11 proteins more rapidly. Overall, our data suggest that the complete desensitization of 5-HT2A receptor-stimulated PLC activity by olanzapine, clozapine and MDL100,907 requires activation of the JAK-STAT pathway, which in turn increases RGS7 expression likely by direct transcriptional activity of STAT3.

Interleukin-6 Attenuates Serotonin 2A Receptor Signaling by Activating the JAK-STAT Pathway

“…Interestingly, in these systems, JAK-STAT activation was shown to mediate 5-HT 2A receptor desensitization (Singh et al, 2007(Singh et al, , 2009(Singh et al, , 2010. These previous observations coincide with our demonstration that directly activating the JAK/STAT pathway, through the IL-6 receptor system, attenuates DOI-induced 5-HT 2A receptor-mediated IP accumulation, substantiating the possibility of crosstalk between these receptor systems.…”

“…, have also been shown to activate the JAK2-STAT3 pathway in both the neuronally derived A1A1 cell line (Singh et al, 2007(Singh et al, , 2009 and in the frontal cortex (Singh et al, 2010). Interestingly, in these systems, JAK-STAT activation was shown to mediate 5-HT 2A receptor desensitization (Singh et al, 2007(Singh et al, , 2009(Singh et al, , 2010.…”

“…These observations also imply that long-term activation of the JAK-STAT pathway, which occurs under chronic inflammatory conditions, such as obesity and cardiovascular disease, may have different or more permanent effects on the 5-HT 2A receptor system. There is evidence to suggest that STAT proteins can influence expression of the 5-HT 2A receptor itself (Singh et al, 2009). However, it is also possible that STAT proteins may affect the transcription of other components of this signaling cascade.…”

“…However, it is also possible that STAT proteins may affect the transcription of other components of this signaling cascade. For example, longterm treatment with olanzapine, which caused prolonged activation of the JAK-STAT pathway, increased expression of regulator of G-protein signaling proteins, which have been shown to desensitize multiple G-protein-coupled receptor systems (Singh et al, 2007(Singh et al, , 2009(Singh et al, , 2010. Therefore, long-term interactions between the IL-6 and 5-HT 2A receptor systems may have lasting effects through STAT-dependent changes in gene transcription that may influence behavior and mental health.…”

RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer

“…Similarly, GWAS studies have also indicated that another SNP in RGS6 (rs2332700) is significantly associated with schizophrenia (25). The possible significance of RGS6's role in schizophrenia is further supported by preliminary studies which also suggest that RGS7 and RGS9 may be differentially expressed in patients with schizophrenia (86,87) and may modulate brain responses to psychostimulants and antipsychotics (49,(88)(89)(90)(91)(92)(93). Finally, not only is there substantial evidence detailing the critical role of various R7 family members in proper vision (94-97) but a splice acceptor variant of RGS6 (c.1369-1G>C) has also been positively associated with the familial inheritance of congenital cataracts (26).…”