RGS4 Modulates Serotonin Signaling in Prefrontal Cortex and Links to Serotonin Dysfunction in a Rat Model of Schizophrenia

Abstract

Regulator of G protein signaling 4 (RGS4) has recently been identified as one of the genes linked to the susceptibility of schizophrenia. However, the functional roles of RGS4 and how it may be involved in the pathophysiology of schizophrenia remain largely unknown. In this study, we investigated the possible impact of RGS4 on the function of serotonin and dopamine receptors, two main targets for schizophrenia treatment. Activation of serotonin 5-HT 1A receptors or dopamine D 4 receptors down-regulates the function of NMDA receptor (NMDAR) channel, a key player controlling cognition and emotion, in pyramidal neurons of prefrontal cortex (PFC). Blocking RGS4 function significantly potentiated the 5-HT 1A regulation of NMDAR current; conversely, overexpression of RGS4 attenuated the 5-HT 1A effect. In contrast, the D 4 regulation of NMDAR current was not altered by RGS4 manipulation. Moreover, the 5-HT 1A regulation of NMDA receptors was significantly enhanced in a subset of PFC pyramidal neurons from rats treated with subchronic phencyclidine, an animal model of schizophrenia, which was found to be associated with specifically decreased RGS4 expression in these cells. Thus, our study has revealed an important coupling of RGS4 to serotonin signaling in cortical neurons and provided a molecular and cellular mechanism underlying the potential involvement of RGS4 in the pathophysiology of schizophrenia.

Regulator of G protein signaling 4 is a crucial modulator of antidepressant drug action in depression and neuropathic pain models

“…This effect was mediated at least in part via the PFC, because local knockdown of Rgs4 from this brain region replicated the potentiated behavioral responses to ketamine observed in constitutive knockouts. Several studies have demonstrated the ability of GPCRs to inhibit NMDA glutamate receptor currents in PFC (7,8). Specifically, Rgs4 in PFC negatively modulates α 1 -and α 2 -adrenergic receptor subtypes, but only Rgs4 modulation of α 1 receptors involves complexes with the scaffold protein, spinophilin (8).…”

“…Regulator of G protein signaling 4 (Rgs4) is a 28-kDa protein known to control postreceptor signaling cascades for numerous G protein-coupled receptors (GPCRs), including dopamine, serotonin, adrenergic, muscarinic, and mu and delta opioid receptors (2)(3)(4)(5)(6)(7)(8)(9). Rgs4 is generally thought to be a negative modulator of Gα subunits by promoting their hydrolysis of GTP and by antagonizing the regulation of their effectors, although the actions of Rgs proteins are more complex, because they can either inhibit or facilitate several actions of their associated receptors (10,11).…”

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

“…Genetic risk factors for schizophrenia are beginning to be identified and include RGS4 protein with RGS4 protein expression being reduced in the frontal cortex in schizophrenics (Gu et al, 2007). Like RGS7 protein, RGS4 regulates 5-HT 2A receptor signaling.…”

Repeated Cocaine Administration Decreases 5-HT2A Receptor-Mediated Serotonergic Enhancement of Synaptic Activity in Rat Medial Prefrontal Cortex

“…RGS4, a member of R4 subfamily, is enriched in the PFC (Erdely et al, 2004) and has been shown to regulate 5-HT signaling negatively in PFC pyramidal neurons in the rat phencyclidine model of schizophrenia (Gu et al, 2007). To explore the possible involvement of RGS4 in the impairment of the 5-HT 2A receptor responsiveness after repeated cocaine administration, we examined the change of RGS4 expression in rats withdrawn from repeated cocaine administration for 3 days.…”