Regulator of G Protein Signaling 6 (RGS6) Protein Ensures Coordination of Motor Movement by Modulating GABAB Receptor Signaling

Maity, Biswanath; Stewart, Adele; Yang, Jianqi; Loo, Lipin; Sheff, David; Shepherd, Andrew J.; Mohapatra, Durga P.; Fisher, Rory A.

doi:10.1074/jbc.m111.297218

Cited by 47 publications

(74 citation statements)

References 49 publications

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“…The following RGS proteins also have reported roles in modulating synaptic signaling; however, further work is necessary to determine their precise function in synaptic plasticity. One such protein is RGS6, another member of the R7 subfamily, which is highly expressed in cerebellar granule neurons (Maity et al, 2012). Similar to RGS7 and RGS9-2, RGS6 forms a stable signaling complex with Gb5 and is a selective GAP for Ga i/o family members (Posner et al, 1999;Hooks et al, 2003).…”

Section: Other Rgs Proteinsmentioning

confidence: 99%

“…Similar to RGS7 and RGS9-2, RGS6 forms a stable signaling complex with Gb5 and is a selective GAP for Ga i/o family members (Posner et al, 1999;Hooks et al, 2003). Studies indicate that RGS6 antagonizes GABA B R-mediated GIRK currents, as shown by ataxia and increased cerebellar granule neuron GIRK currents exhibited by RGS6-KO mice that can be rescued by administration of a GABA B R antagonist (Maity et al, 2012). Additionally, RGS6 is required for adult maintenance of dopaminergic neurons in the ventral substantia nigra (Bifsha et al, 2014) and a recent study has proposed a role for RGS6 as a key mediator of both reward-related behavioral and pathologic responses to alcohol (Stewart et al, 2015), although it is unclear whether these effects are due to changes in synaptic signaling or plasticity.…”

Section: Other Rgs Proteinsmentioning

confidence: 99%

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Roles for Regulator of G Protein Signaling Proteins in Synaptic Signaling and Plasticity

2015

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The regulator of G protein signaling (RGS) family of proteins serves critical roles in G protein-coupled receptor (GPCR) and heterotrimeric G protein signal transduction. RGS proteins are best understood as negative regulators of GPCR/G protein signaling. They achieve this by acting as GTPase activating proteins (GAPs) for Ga subunits and accelerating the turnoff of G protein signaling. Many RGS proteins also bind additional signaling partners that either regulate their functions or enable them to regulate other important signaling events. At neuronal synapses, GPCRs, G proteins, and RGS proteins work in coordination to regulate key aspects of neurotransmitter release, synaptic transmission, and synaptic plasticity, which are necessary for central nervous system physiology and behavior. Accumulating evidence has revealed key roles for specific RGS proteins in multiple signaling pathways at neuronal synapses, regulating both pre-and postsynaptic signaling events and synaptic plasticity. Here, we review and highlight the current knowledge of specific RGS proteins (RGS2, RGS4, RGS7, RGS9-2, and RGS14) that have been clearly demonstrated to serve critical roles in modulating synaptic signaling and plasticity throughout the brain, and we consider their potential as future therapeutic targets.

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Section: Other Rgs Proteinsmentioning

confidence: 99%

Section: Other Rgs Proteinsmentioning

confidence: 99%

Roles for Regulator of G Protein Signaling Proteins in Synaptic Signaling and Plasticity

2015

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“…In light of the fact that baclofen-mediated modulation of the GABA B R is a viable treatment for alcoholism, RGS6 also became a protein of interest, as previous research had demonstrated its ability to negatively regulate GABA B R signaling in the cerebellum (33). In addition, there was also evidence to suggest that RGS6 was capable of regulating the signaling of other GPCRs, such as 5-HT 1A Rs and μ-opioid receptors (22,46), which had already been identified as potential therapeutic targets in the treatment of alcoholism (40,42).…”

Section: Alcohol Use Disordersmentioning

confidence: 99%

“…The Fisher lab has also demonstrated using western blot that certain tissues express multiple distinct RGS6 protein isoforms natively. For example, the brain expresses at least two distinct RGS6 isoforms that are larger (∼61 and 69 kDa) than ubiquitously expressed smaller forms of the protein (21,33). Interestingly, western blot analysis of brain tissue lysates using the antibody against the N-terminal protein domain, common to all RGS6L proteins, reveals a broad band of RGS6 immunoreactivity which could be explained by the presence of multiple RGS6L Fig.…”

Section: Introductionmentioning

confidence: 99%

RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer

Ahlers

Chakravarti

Fisher

2016

AAPS J

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Abstract. Regulator of G protein signaling (RGS) proteins are gatekeepers regulating the cellular responses induced by G protein-coupled receptor (GPCR)-mediated activation of heterotrimeric G proteins. Specifically, RGS proteins determine the magnitude and duration of GPCR signaling by acting as a GTPase-activating protein for Gα subunits, an activity facilitated by their semiconserved RGS domain. The R7 subfamily of RGS proteins is distinguished by two unique domains, DEP/DHEX and GGL, which mediate membrane targeting and stability of these proteins. RGS6, a member of the R7 subfamily, has been shown to specifically modulate Gα i/o protein activity which is critically important in the central nervous system (CNS) for neuronal responses to a wide array of neurotransmitters. As such, RGS6 has been implicated in several CNS pathologies associated with altered neurotransmission, including the following: alcoholism, anxiety/depression, and Parkinson's disease. In addition, unlike other members of the R7 subfamily, RGS6 has been shown to regulate G protein-independent signaling mechanisms which appear to promote both apoptotic and growth-suppressive pathways that are important in its tumor suppressor function in breast and possibly other tissues. Further highlighting the importance of RGS6 as a target in cancer, RGS6 mediates the chemotherapeutic actions of doxorubicin and blocks reticular activating system (Ras)-induced cellular transformation by promoting degradation of DNA (cytosine-5)-methyltransferase 1 (DNMT1) to prevent its silencing of pro-apoptotic and tumor suppressor genes. Together, these findings demonstrate the critical role of RGS6 in regulating both G protein-dependent CNS pathology and G protein-independent cancer pathology implicating RGS6 as a novel therapeutic target.

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“…Genetic deletion of RGS2 leads to a higher GABA B -GIRK coupling efficiency, which was demonstrated by an enhanced sensitivity to baclofeninduced GIRK current in RGS2 knockout mice compared to wildtype controls. In addition to RGS2 involvement in GIRK regulation, other RGS proteins such as RGS4 [61], RGS6 [62], RGS7 [63], RGS8 [64] and RGS9 [36] have been shown to modulate the GPcR-GIRK interaction in heterologous expression systems and rodent brain slices as well. Future research should focus on understanding whether these interactions occur in vivo and what the physiological functions of these interactions are.…”

Section: Rgs Protein Functionality: Modulation Of Psychostimulant Resmentioning

confidence: 99%

Dysregulation of RGS Proteins by Psychostimulants

2014

J Addict & Prev

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Regulator of G protein signaling (RGS) proteins are a class of proteins that negatively modulate GPCR-mediated G protein signaling. The distribution of subtypes of RGS proteins is brain region specific. Several subtypes of RGS proteins are present in the mesolimbic dopaminergic pathway and are subjected to modulation by psychostimulants. Acute or chronic exposure to psychostimulants induces changes in mRNA levels of RGS in a subtype-, brain region-, and time-dependent manner. The dynamic changes in the abundance of RGS proteins by psychostimulant treatment may be associated with dopamine receptor sensitization or desensitization, a potential mechanism underlying drug sensitization or tolerance. Small molecule RGS inhibitors are useful tools for studying in vivo function of RGS proteins and are potential therapeutics for the treatment of psychostimulant addiction.

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Regulator of G Protein Signaling 6 (RGS6) Protein Ensures Coordination of Motor Movement by Modulating GABAB Receptor Signaling

Cited by 47 publications

References 49 publications

Roles for Regulator of G Protein Signaling Proteins in Synaptic Signaling and Plasticity

Roles for Regulator of G Protein Signaling Proteins in Synaptic Signaling and Plasticity

RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer

Dysregulation of RGS Proteins by Psychostimulants

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