Motor coordination deficits in mice lacking RGS9

Blundell, Jacqueline; Hoang, C.; Potts, Bryan W.; Gold, Stephen J.; Powell, Craig M.

doi:10.1016/j.brainres.2007.11.017

Cited by 48 publications

(45 citation statements)

References 55 publications

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“…The Rota-Rod is commonly used to test coordination and motor performance in rodents at a gross level. To test motor performance, mice are run on a Rota-Rod for shorter durations (1-5 min) and at higher maximal speeds (up to 45 rpms) (7,10,35) than that used in the current study. Furthermore, in human subjects, fatigue affects coordination resulting in changes in firing patterns of muscles; however, there are no apparent gender differences in abilities to perform the exercise-related tasks (12,17).…”

Section: Fatigue Tasksmentioning

confidence: 99%

Enhanced muscle fatigue occurs in male but not female ASIC3−/− mice

Burnes¹,

Kolker²,

Danielson³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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Burnes LA, Kolker SJ, Danielson JF, Walder RY, Sluka KA. Enhanced muscle fatigue occurs in male but not female ASIC3Ϫ/Ϫ mice. Am J Physiol Regul Integr Comp Physiol 294: R1347-R1355, 2008. First published February 27, 2008 doi:10.1152/ajpregu.00687.2007.-Muscle fatigue is associated with a number of clinical diseases, including chronic pain conditions. Decreases in extracellular pH activates acid-sensing ion channel 3 (ASIC3), depolarizes muscle, protects against fatigue, and produces pain. We examined whether ASIC3Ϫ/Ϫ mice were more fatigable than ASIC3ϩ/ϩ mice in a task-dependent manner. We developed two exercise protocols to measure exercise-induced muscle fatigue: ( fatigue task 1, three 1-h runs; fatigue task 2, three 30-min runs). In fatigue task 1, male ASIC3ϩ/ϩ mice muscle showed less fatigue than male ASIC3Ϫ/Ϫ mice and female ASIC3ϩ/ϩ mice. No differences in fatigue were observed in fatigue task 2. We then tested whether the development of muscle fatigue was dependent on sex and modulated by testosterone. Female ASIC3ϩ/ϩ mice that were ovariectomized and administered testosterone developed less muscle fatigue than female ASIC3ϩ/ϩ mice and behaved similarly to male ASIC3ϩ/ϩ mice. However, testosterone was unable to rescue the muscle fatigue responses in ovariectomized ASIC3Ϫ/Ϫ mice. Plasma levels of testosterone from male ASIC3Ϫ/Ϫ mice were significantly lower than in male ASIC3ϩ/ϩ mice and were similar to female ASIC3ϩ/ϩ mice. Muscle fiber types, measured by counting ATPase-stained whole muscle sections, were similar in calf muscles from male and female ASIC3ϩ/ϩ mice. These data suggest that both ASIC3 and testosterone are necessary to protect against muscle fatigue in a task-dependent manner. Also, differences in expression of ASIC3 and the development of exercise-induced fatigue could explain the female predominance in clinical syndromes of pain that include muscle fatigue.

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Section: Fatigue Tasksmentioning

confidence: 99%

Enhanced muscle fatigue occurs in male but not female ASIC3−/− mice

Burnes¹,

Kolker²,

Danielson³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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“…They also represent novel potential drug targets in numerous diseases, including hypertension, heart failure, Parkinson's disease, and schizophrenia (Chowdari et al, 2002;Heximer et al, 2003;Blundell et al, 2008;Blazer and Neubig, 2009). Modulation of RGS proteins might alter GPCR signaling in a pathway-and tissue-specific manner (Blazer and Neubig, 2009).…”

Section: Introductionmentioning

confidence: 99%

Cardiotonic Steroids Stabilize Regulator of G Protein Signaling 2 Protein Levels

et al. 2012

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Regulator of G protein signaling 2 (RGS2), a G q -specific GTPase-activating protein, is strongly implicated in cardiovascular function. RGS2(Ϫ/Ϫ) mice are hypertensive and prone to heart failure, and several rare human mutations that accelerate RGS2 degradation have been identified among patients with hypertension. Therefore, pharmacological up-regulation of RGS2 protein levels might be beneficial. We used a ␤-galactosidase complementation method to screen several thousand compounds with known pharmacological functions for those that increased RGS2 protein levels. Several cardiotonic steroids (CTSs), including ouabain and digoxin, increased RGS2 but not RGS4 protein levels. CTSs increased RGS2 protein levels through a post-transcriptional mechanism, by slowing protein degradation. RGS2 mRNA levels in primary vascular smooth muscle cells were unaffected by CTS treatment, whereas protein levels were increased 2-to 3-fold. Na ϩ /K ϩ -ATPase was required for the increase in RGS2 protein levels, because the effect was lost in Na ϩ /K ϩ -ATPase-knockdown cells. Furthermore, we demonstrated that CTS-induced increases in RGS2 levels were functional and reduced receptor-stimulated, G qdependent, extracellular signal-regulated kinase phosphorylation. Finally, we showed that in vivo treatment with digoxin led to increased RGS2 protein levels in heart and kidney. CTSinduced increases in RGS2 protein levels and function might modify several deleterious mechanisms in hypertension and heart failure. This novel CTS mechanism might contribute to the beneficial actions of low-dose digoxin treatment in heart failure. Our results support the concept of small-molecule modulation of RGS2 protein levels as a new strategy for cardiovascular therapy.

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“…One example is RGS9-2, which is specifically enriched in striatum (Mancuso et al, 2009) [an alternative isoform, RGS9-1, is exclusively expressed in photoreceptor cells in the retina (He et al, 1998)]. This selective distribution matches the critical site of L-DOPA-induced dyskinesia, and the Gα i/o -protein selectivity of RGS9 GAP activity corresponds to the Gα i/o coupling of the dopamine D 2 receptor, which is critical in mediating L-DOPA effects in the striatum (Gold et al, 2007;Blundell et al, 2008). The broad distribution of D 2 receptor expression limits the use of D 2 receptor targeted approaches to regulate striatal signalling pathways.…”

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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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Motor coordination deficits in mice lacking RGS9

Cited by 48 publications

References 55 publications

Enhanced muscle fatigue occurs in male but not female ASIC3−/− mice

Enhanced muscle fatigue occurs in male but not female ASIC3−/− mice

Cardiotonic Steroids Stabilize Regulator of G Protein Signaling 2 Protein Levels

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

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