Regulator of G‐protein signaling 6 (RGS6) promotes anxiety and depression by attenuating serotonin‐mediated activation of the 5‐HT
            <sub>1A</sub>
            receptor‐adenylyl cyclase axis

Stewart, Adele; Maity, Biswanath; Wunsch, Amanda M.; Meng, Fantao; Wu, Qi; Wemmie, John A.; Fisher, Rory A.

doi:10.1096/fj.13-235648

Cited by 47 publications

(63 citation statements)

References 40 publications

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“…Inhibition of RGS6 has also been implicated as a promising therapeutic strategy in depression and anxiety (Stewart et al, 2014). In contrast, RGS6 protects against dopaminergic neuron loss in the VTA, indicating that enhancing RGS6 could be beneficial in the treatment of PD (Bifsha et al, 2014).…”

Section: Regulation Of Function Localization and Expressionmentioning

confidence: 99%

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

Sjögren

2017

British J Pharmacology

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Regulators of G protein signalling (RGS) proteins are celebrating the 20th anniversary of their discovery. The unveiling of this new family of negative regulators of G protein signalling in the mid-1990s solved a persistent conundrum in the G protein signalling field, in which the rate of deactivation of signalling cascades in vivo could not be replicated in exogenous systems. Since then, there has been tremendous advancement in the knowledge of RGS protein structure, function, regulation and their role as novel drug targets. RGS proteins play an important modulatory role through their GTPase-activating protein (GAP) activity at active, GTP-bound Gα subunits of heterotrimeric G proteins. They also possess many non-canonical functions not related to G protein signalling. Here, an update on the status of RGS proteins as drug targets is provided, highlighting advances that have led to the inclusion of RGS proteins in the IUPHAR/BPS Guide to PHARMACOLOGY database of drug targets.Abbreviations DEP, Disheveled Egl-10 Pleckstrin; GAP, GTPase-activating protein; GGL, G protein γ-like; PPI, protein-protein interaction; RGS, regulator of G protein signalling; R7BP, R7 binding protein; R9AP, RGS9 associated protein IntroductionG protein-mediated signalling pathways have played a pivotal role in drug discovery and development for many decades. The large family of GPCRs or their downstream effectors are the target of 40% of clinically used drugs and thus represent a multi-billion-dollar industry (Wise et al., 2002). Interestingly, of the more than 300 non-olfactory GPCRs known, only a fraction of them are targeted by drugs. Thus, there is a large untapped area of drug development still available. Moreover, many GPCR drugs are associated with low efficacy and/or side effects. More targeted therapies are therefore required, and as we learn more about the structure and function of GPCRs and their regulators, these goals will be achievable.All biological signals are tightly regulated and for every on-switch there is usually an off-switch. GPCRs are activated by ligands, transmitting signalling information to Gα subunits of heterotrimeric G proteins by enhancing the exchange of GDP for GTP in the Gα nucleotide binding site, which results in the dissociation of Gα from Gβγ dimers and activation of both G protein components. Deactivation of G proteins does not occur by simple reversal of nucleotide exchange, but rather by an independently regulated GTPase activity, hydrolyzing GTP to GDP. Although Gα proteins possess an intrinsic ability to hydrolyze GTP, this process is very slow and cannot account for the transient nature of intracellular signalling cascades in vivo. Hence, additional kinetic mechanisms are required for the physiological timing of signals. One of the most critical of these kinetic mechanisms is mediated through regulator of G protein signalling (RGS) proteins, which have received increasing interest as novel drug targets in the past two decades. As a result, RGS proteins have now been added as the most recent ad...

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Section: Regulation Of Function Localization and Expressionmentioning

confidence: 99%

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

Sjögren

2017

British J Pharmacology

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“…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). Both immunohistochemical and western blot studies in wild type (RGS6+/+) mice subsequently demonstrated that RGS6 protein expression was upregulated in the ventral tegmental area (VTA) of the mesolimbic system following prolonged alcohol exposure.…”

Section: Alcohol Use Disordersmentioning

confidence: 99%

“…PFC prefrontal cortex, STR striatum, NAc nucleus accumbens, HP hippocampus, DOPAL 3,4-dihydroxyphenylacetaldehyde, DOPAC 3,4-dihydroxyphenylacetic acid. Image adapted from references (21)(22)(23) as a critical regulator of 5-HT 1A heteroreceptor signaling (22). Not only is RGS6 present in cortical and hippocampal neurons, as shown through immunohistochemistry and western blot, but RGS6−/− mice also display spontaneous antidepressant and anxiolytic behaviors which are reversed through i.p.…”

Section: Anxiety and Depressionmentioning

confidence: 99%

“…RGS6 α and β transcripts exist in two forms that arise from either the retention (α1 and β1) or removal (α2 and β2) of exon 18 (second pink square). Image adapted from reference (7) isoforms with different C-terminal domains and with or without complete GGL domains (22,34). The functions for these RGS6 variants and how they all arise (either through protein modification or additional RNA splicing) are unknown.…”

Section: Introductionmentioning

confidence: 99%

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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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“…74 La manipulación génica en el roedor de las proteínas que participan en la señalización del receptor 5-HT 1A también fundamenta su papel relevante en la conducta anti-(mayor función) o pro-depresiva (menor función). Por ejemplo, al prolongar la señalización de este receptor, ya sea por una mutación en la subunidad G αi2 que impide su interacción con las proteínas RGS, 76 o eliminando la expresión de RGS6, 77 el fenotipo obtenido son ratones con conducta antidepresiva y ansiolítica. Desde luego se requiere mayor conocimiento sobre cómo el receptor 5-HT 1A regula la comunicación entre las áreas corticales y con el sistema límbico (figura 2), para elaborar hipótesis más precisas sobre su papel en la conducta afectiva y cognitiva.…”

Section: -74unclassified

Neurobiología de la depresión mayor y de su tratamiento farmacológico

Hernández

Coronel

Aguilar

et al. 2016

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Regulator of G‐protein signaling 6 (RGS6) promotes anxiety and depression by attenuating serotonin‐mediated activation of the 5‐HT _1A receptor‐adenylyl cyclase axis

Cited by 47 publications

References 40 publications

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer

Neurobiología de la depresión mayor y de su tratamiento farmacológico

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Regulator of G‐protein signaling 6 (RGS6) promotes anxiety and depression by attenuating serotonin‐mediated activation of the 5‐HT 1A receptor‐adenylyl cyclase axis

Cited by 47 publications

References 40 publications

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

RGS6 as a Novel Therapeutic Target in CNS Diseases and Cancer

Neurobiología de la depresión mayor y de su tratamiento farmacológico

Contact Info

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Regulator of G‐protein signaling 6 (RGS6) promotes anxiety and depression by attenuating serotonin‐mediated activation of the 5‐HT _1A receptor‐adenylyl cyclase axis