Disease relevance of Rgs4

• These observations suggest that RGS4-dependent attenuation of interneuronal autoreceptor signaling is a major factor in the elevation of striatal acetylcholine release in Parkinson disease [1].
• RGS4 causes increased mortality and reduced cardiac hypertrophy in response to pressure overload [2].
• We recently reported that transgenic mice with cardiac-specific expression of RGS4, a Galpha q and Galpha i GTPase activator, exhibit decreased left ventricular hypertrophy and ANF induction in response to pressure overload [3].

High impact information on Rgs4

• This adaptation was attributable to the upregulation of RGS4-an autoreceptor-associated, GTPase-accelerating protein [1].
• RGS4-dependent attenuation of M4 autoreceptor function in striatal cholinergic interneurons following dopamine depletion [1].
• Moreover, Homer 2 preferentially bound to PLCbeta in pancreatic acini and brain extracts and stimulated GAP activity of RGS4 and of PLCbeta in an in vitro reconstitution system, with minimal effect on PLCbeta-mediated PIP2 hydrolysis [4].
• We propose a model in which the sequential modifications of RGS4, RGS5, and RGS16 (N-terminal exposure of their Cys-2, its oxidation, and subsequent arginylation) act as a licensing mechanism in response to extracellular and intracellular signals before the targeting for proteolysis by UBR1 and UBR2 [5].
• Here, we describe a mouse line deficient for Rgs4, a gene normally expressed early on in discrete populations of differentiating neurons and later on at multiple sites of the central nervous system, the cortex in particular, where it is one of the most highly transcribed Rgs genes [6].

Biological context of Rgs4

• Generation of compound transgenic mice demonstrated that cardiac RGS4 overexpression ameliorated the cardiomyopathic phenotype that occurred as a result of PPAR-alpha overexpression without affecting the metabolic abnormalities seen in these hearts [7].
• We therefore propose RGS4 as a novel antagonist of epithelial and endothelial cell tubulogenesis that selectively antagonizes intracellular signaling by G proteins and VEGF, thereby inhibiting cell proliferation, migration, and invasion, and VEGF and KDR expression [8].

Anatomical context of Rgs4

• Similarly, RGS4 overexpression abrogated endothelial cell angiogenic sprouting by inhibiting their synthesis of DNA and invasion through synthetic basement membranes [8].
• The tubulogenic defects imparted by RGS4 in epithelial cells, including its reduction in VEGF expression, were rescued by overexpression of constitutively active MKK6, an activator of p38 MAPK [8].
• Morphine treatment recruited RGS4 to the PAG membranes, and 30 min and 3 h after the opioid challenge its association with mu receptors had increased [9].
• Northern blot analysis of various mouse tissues revealed that RGS4 is expressed at high levels in brain, moderately low levels in heart, and very low levels in lung, liver, and skeletal muscle [10].
• In situ hybridization of mouse brain showed RGS4 mRNA mainly in the cerebral cortex, hippocampus, anterior olfactory nucleus, piriform cortex, olfactory tubercle, caudate-putamen, nucleus accumbens, islands of Calleja, substantia nigra, amygdala, the granular layer of cerebellum, middle cerebellar peduncle, and perifacial zone [10].

Associations of Rgs4 with chemical compounds

• RGS4 transgenic mice were resistant to STZ-induced cardiac fetal gene induction [7].
• RGS4 inhibits signaling by group I metabotropic glutamate receptors [11].
• In Xenopus oocytes, purified RGS4 virtually abolishes the mGluR1a- and mGluR5a-mediated but not the inositol trisphospate-mediated activation of a calcium-dependent chloride current [11].
• Radiochemical sequencing indicated that the N-terminal methionine of the lysate-produced RGS4 was replaced with arginine [12].
• Since N-terminal arginine is a destabilizing residue not encoded by RGS4 mRNA, we conclude that the degron of RGS4 is generated through the removal of N-terminal methionine and enzymatic arginylation of the resulting N-terminal cysteine [12].

Regulatory relationships of Rgs4

• Accordingly, RGS4 overexpression delayed and altered lung epithelial cell tubulation by selectively inhibiting G protein-mediated p38 MAPK activation, and, consequently, by reducing epithelial cell proliferation, migration, and expression of vascular endothelial growth factor (VEGF) [8].

Other interactions of Rgs4

• Rgs4 mRNA expression is decreased in the brain of Fmr1 knockout mouse [13].
• RGS4 and RGS5 are in vivo substrates of the N-end rule pathway [5].
• The same pattern of receptor-selective inhibition by RGS4 was observed in acinar cells from wild type and several single and double Gq class knockout mice [14].
• Finally, we found that RGS4 reduced endothelial cell response to VEGF by decreasing VEGF receptor-2 (KDR) expression [8].
• Consistent with a required role for GTP-bound G(q)/G(11), expression of the regulators of G protein signaling (RGS4 and RGS16) also attenuated insulin-stimulated GLUT4-EGFP translocation [15].

Analytical, diagnostic and therapeutic context of Rgs4

• We performed microarray analysis to further our understanding of tubulogenesis and observed a robust induction of regulator of G protein signaling 4 (RGS4) mRNA expression solely in tubulating cells, thereby implicating RGS4 as a potential regulator of tubulogenesis [8].
• Distribution of RGS4 mRNA in mouse brain shown by in situ hybridization [10].
• Overexpression of RGS4 in postnatal ventricular tissue did not affect cardiac morphology or basal cardiac function, but markedly compromised the ability of the heart to adapt to transverse aortic constriction (TAC) [2].

References