Abstract
Regulator of G protein signaling 4 (RGS4) is a critical modulator of G protein-coupled receptor (GPCR)-mediated signaling and plays important roles in many neural process and diseases. Particularly, drug-induced alteration in RGS4 protein levels is associated with acute and chronic effects of drugs of abuse. However, the precise mechanism underlying the regulation of RGS4 expression is largely unknown. Here, we demonstrated that the expression of RGS4 gene was subject to regulation by alternative splicing of the exon 6. Transformer-2β (Tra2β), an important splicing factor, bound to RGS4 mRNA and increased the relative level of RGS4-1 mRNA isoform by enhancing the inclusion of exon 6. Meanwhile, Tra2β increased the expression of full-length RGS4 protein. In rat brain, Tra2β was co-localized with RGS4 in multiple opioid action-related brain regions. In addition, the acute and chronic morphine treatment induced alteration in the expression level of Tra2β in rat locus coerulus (LC) in parallel to that of RGS4 proteins. It suggests that induction of this splicing factor may contribute to the change of RGS4 level elicited by morphine. Taken together, the results provide the evidence demonstrating the function of Tra2β as a new mediator in opioid-induced signaling pathway via regulating RGS4 expression.
Highlights
Regulators of G protein signaling (RGS) proteins are critical modulators of G protein-coupled receptor (GPCR)-mediated signal transduction [1]
At day 14, naloxone-precipitated withdrawal resulted in marked decreases in both Tra2b and Regulator of G protein signaling 4 (RGS4) protein levels 1 hour following injection of naloxone. These results indicated that the expression of Tra2b and RGS4 in the locus coeruleus (LC) were regulated by chronic morphine treatment and naloxone withdrawal (Fig. 6E–F)
RGS4 is an important component of opioid signaling, the mechanisms regulating expression of RGS4 gene have not been well elucidated
Summary
Regulators of G protein signaling (RGS) proteins are critical modulators of G protein-coupled receptor (GPCR)-mediated signal transduction [1]. These proteins act as GTPase-activating proteins (GAPs) for heterotrimeric Ga subunits, accelerating the shut-off mechanism for G protein signaling [2]. Microarray and genomic analyses showed decreased levels of RGS4 in the prefrontal cortex in patients with schizophrenia [5]. Polymorphisms of the RGS4 gene have been identified in schizophrenia patients [6]. Genetic studies indicate RGS4 as a vulnerability factor for schizophrenia [5,7]. RGS4 plays important roles for dopaminergic control of striatal long-term depression and susceptibility to Parkinson’s disease [8] as well as in neural plasticity [9]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
