Regulator of G-protein signalling 9, also known as RGS9, is a human gene, which codes for a protein involved in regulation of signal transduction inside cells. Members of the RGS family, such as RGS9, are signaling proteins that suppress the activity of G proteins by promoting their deactivation.[supplied by OMIM]
There are two splice isoforms of RGS9 with quite different properties and patterns of expression. RGS9-1 is mainly found in the eye and is involved in regulation of phototransduction in rod and cone cells of the retina, while RGS9-2 is found in the brain, and regulates dopamine and opioid signaling in the basal ganglia.
RGS9-2 is of particular interest as the most important RGS protein involved in terminating signalling by the mu opioid receptor (although RGS4 and RGS17 are also involved), and is thought to be important in the development of tolerance to opioid drugs. RGS9-deficient mice exhibit some motor and cognitive difficulties however, so inhibition of this protein is likely to cause similar side effects.
RGS9 is differentially regulated by Guanine nucleotide-binding protein subunit beta-5 (GNB5) via the DEP domain and DEP helical-extension domain in protein stability and membrane anchor association.
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^Sánchez-Blázquez P, Rodríguez-Muñoz M, Montero C, Garzón J (January 2005). "RGS-Rz and RGS9-2 proteins control mu-opioid receptor desensitisation in CNS: the role of activated Galphaz subunits". Neuropharmacology48 (1): 134–50. doi:10.1016/j.neuropharm.2004.08.016. PMID15617734.
^Garzón J, Rodríguez-Muñoz M, López-Fando A, Sánchez-Blázquez P (March 2005). "Activation of mu-opioid receptors transfers control of Galpha subunits to the regulator of G-protein signaling RGS9-2: role in receptor desensitization". The Journal of Biological Chemistry280 (10): 8951–60. doi:10.1074/jbc.M407005200. PMID15632124.
^Psifogeorgou K, Papakosta P, Russo SJ, Neve RL, Kardassis D, Gold SJ, Zachariou V (October 2007). "RGS9-2 is a negative modulator of mu-opioid receptor function". Journal of Neurochemistry103 (2): 617–25. doi:10.1111/j.1471-4159.2007.04812.x. PMID17725581.
^Traynor JR, Terzi D, Caldarone BJ, Zachariou V (March 2009). "RGS9-2: probing an intracellular modulator of behavior as a drug target". Trends in Pharmacological Sciences30 (3): 105–11. doi:10.1016/j.tips.2008.11.006. PMID19211160.
Granneman JG, Zhai Y, Zhu Z, et al. (1998). "Molecular characterization of human and rat RGS 9L, a novel splice variant enriched in dopamine target regions, and chromosomal localization of the RGS 9 gene". Mol. Pharmacol.54 (4): 687–94. PMID9765512.
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Nishiguchi KM, Sandberg MA, Kooijman AC, et al. (2004). "Defects in RGS9 or its anchor protein R9AP in patients with slow photoreceptor deactivation". Nature427 (6969): 75–8. doi:10.1038/nature02170. PMID14702087.
1fqj: CRYSTAL STRUCTURE OF THE HETEROTRIMERIC COMPLEX OF THE RGS DOMAIN OF RGS9, THE GAMMA SUBUNIT OF PHOSPHODIESTERASE AND THE GT/I1 CHIMERA ALPHA SUBUNIT [(RGS9)-(PDEGAMMA)-(GT/I1ALPHA)-(GDP)-(ALF4-)-(MG2+)]
1fqk: CRYSTAL STRUCTURE OF THE HETERODIMERIC COMPLEX OF THE RGS DOMAIN OF RGS9, AND THE GT/I1 CHIMERA ALPHA SUBUNIT [(RGS9)-(GT/I1ALPHA)-(GDP)-(ALF4-)-(MG2+)]