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At least 19 recordsLinked to original sources
PubMed2005

R7BP: a surprising new link between G proteins, RGS proteins, and nuclear signaling in the brain.

The regulators of G protein signaling (RGS proteins) bind directly to G protein alpha (Galpha) subunits in brain and other tissues to determine the strength, duration, and fidelity of neurotransmitter receptor signaling. A recent study shows, quite unexpectedly, that one class of RGS proteins [the R7 subfamily bound to Gbeta(5) (R7-Gbeta(5))] shuttles between the plasma membrane and the nucleus with assistance from a novel shuttle protein, R7BP. R7BP binds directly to R7-Gbeta(5) and the protein complex is tethered to the plasma membrane by addition of a lipid, palmitate, on R7BP. Removal of palmitate results in the translocation of the R7BP-R7-Gbeta(5) complex to the nucleus, presumably for nontraditional signaling functions. These findings suggest an entirely novel mechanism for regulating neurotransmitter signaling. That is, R7BP transduces signals directly from receptors and G proteins at the plasma membrane to the nucleus, and this plasma membrane-nuclear shuttling is controlled by reversible palmitoylation of R7BP.

Animals↗
PubMed2003

Specificity of G protein-RGS protein recognition is regulated by affinity adapters.

RGS proteins regulate the duration of cell signaling by modulating the lifetime of activated G proteins. The specificity of RGS-G protein mutual recognition is critical for meeting unique timing requirements of numerous G protein-mediated pathways. Our study of two splice isoforms of RGS9 expressed in different types of neurons revealed a novel mechanism whereby this specificity is determined by specialized protein domains or subunits acting as affinity adapters. The long RGS9 isoform contains a C-terminal domain that provides high-affinity interaction with its target G protein. The lack of this domain in the short RGS9 isoform is compensated by the action of a G protein effector subunit that is structurally similar to this C-terminal domain. This allows the short isoform to specifically target the complex between the G protein and its effector. Thus, the specific timing needs of different signaling pathways can be accommodated by affinity adapters positioned at various pathway components.

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed2003

Physiological actions of regulators of G-protein signaling (RGS) proteins.

Regulators of G-protein signaling (RGS) proteins are a family of proteins, which accelerate GTPase-activity intrinsic to the alpha subunits of heterotrimeric G-proteins and play crucial roles in the physiological control of G-protein signaling. If RGS proteins were active unrestrictedly, they would completely suppress various G-protein-mediated cell signaling as has been shown in the over-expression experiments of various RGS proteins. Thus, physiologically the modes of RGS-action should be under some regulation. The regulation can be achieved through the control of either the protein function and/or the subcellular localization. Examples for the former are as follows: (i) Phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) inhibits RGS-action, which can be recovered by Ca(2+)/calmodulin. This underlies a voltage-dependent "relaxation" behavior of G-protein-gated K(+) channels. (ii) A modulatory protein, 14-3-3, binds to the RGS proteins phosphorylated by PKA and inhibits their actions. For the latter mechanism, additional regulatory modules, such as PDZ, PX, and G-protein gamma subunit-like (GGL) domains, identified in several RGS proteins may be responsible: (i) PDZ domain of RGS12 interacts with a G-protein-coupled chemokine receptor, CXCR2, and thus facilitates its GAP action on CXCR2-mediated G-protein signals. (ii) RGS9 forms a complex with a type of G-protein beta-subunit (Gbeta5) via its GGL domain, which facilitates the GAP function of RGS9. Both types of regulations synergistically control the mode of action of RGS proteins in the physiological conditions, which contributes to fine tunings of G-protein signalings.

Amino Acid Sequence↗
PubMed2003

Activity, regulation, and intracellular localization of RGS proteins.

RGS proteins attenuate the activities of heterotrimeric G proteins largely by promoting the hydrolysis of the activating nucleotide GTP. This review discusses the interactions of RGS proteins and G proteins and how those interactions are regulated by a variety of factors including auxiliary proteins and other cellular constituents, posttranslational modifications, and intracellular localization patterns. In addition, we discuss progress that has been made toward understanding the roles that RGS proteins play in vivo, and how they may serve to govern responses to G protein-coupled receptors upon acute and prolonged activation by agonists.

Cell Membrane↗
PubMed2003

Mild heat and proteotoxic stress promote unique subcellular trafficking and nucleolar accumulation of RGS6 and other RGS proteins. Role of the RGS domain in stress-induced trafficking of RGS proteins.

RGS proteins comprise a large family of proteins named for their ability to negatively regulate heterotrimeric G protein signaling. RGS6 is a member of the R7 subfamily of RGS proteins possessing DEP (disheveled/Egl-10/pleckstrin) homology and GGL (G protein gamma-subunit-like) domains in addition to the semiconserved RGS domain. Our previous study documented unusual complexity in splicing of the human RGS6 gene, and we demonstrated localization of various RGS6 splice forms at sites other than the plasma membrane, including the cytoplasm and nucleus, where G proteins are not localized (Chatterjee, T. K., Liu, Z., and Fisher, R. A. (2003) J. Biol. Chem. 278, 30261-30271). Here we provide new evidence that mild heat stress, proteasome-mediated proteotoxic stress, and HSF1 expression induces dramatic relocalization of RGS6 proteins from such sites to nucleoli. This response was observed in COS-7 cells expressing various splice forms of RGS6, was not elicited by other forms of cellular stress and was observed in cells treated with various protein kinase inhibitors or co-expressing a dominant-negative kinase inactive SAPK. The RGS domain of RGS6 was identified as a primary structural module providing support for its stress-induced nucleolar trafficking and various other RGS proteins or their isolated RGS domains similarly undergo nucleolar migration in response to heat or proteotoxic stress or during co-expression of HSF1. The atypical RGS domains of axin and AKAP10 also underwent stress-induced nucleolar trafficking while structural domains outside of the RGS domain of some RGS proteins can override nucleolar trafficking in response to stress. Inhibition of rDNA transcription also promoted nucleolar migration of RGS6, a response previously observed in a subset of nucleolar proteins. The DEP domain of RGS6, but not its RGS domain, conferred structural support for its transcription-linked nucleolar migration. RGS6 exhibited trafficking from subnuclear dots to nucleoli in response to heat-, proteotoxic- or transcription-linked stress. These results provide new evidence that mammalian RGS proteins undergo unique subcellular trafficking in response to specific forms of cellular stress and implicate the RGS family of proteins in cellular stress signaling pathways.

Alternative Splicing↗
PubMed2004

Differential effects of regulator of G protein signaling (RGS) proteins on serotonin 5-HT1A, 5-HT2A, and dopamine D2 receptor-mediated signaling and adenylyl cyclase activity.

Regulator of G protein signaling (RGS) proteins function as GTPase accelerating proteins (GAP) for Galpha subunits, attenuating G-protein-coupled receptor signal transduction. The present study tested the ability of members of different subfamilies of RGS proteins to modulate both G-protein-dependent and -independent signaling in mammalian cells. RGS4, RGS10, and RGSZ1 significantly attenuated Galphai-mediated signaling by 5-HT1A, but not by dopamine D2, receptor-expressing cells. Additionally, RGS4 and RGS10 significantly inhibited forskolin-stimulated cAMP production in both cell lines. In contrast, RGS2, RGS7, and RGSZ1 had no effect on forskolin-stimulated cAMP production in these cells. RGS2 and RGS7 significantly decreased Galphaq-mediated signaling by 5-HT2A receptors, confirming that the RGS4 and RGS10 effects on forskolin-stimulated cAMP production were specific, and not simply due to overexpression. Interestingly, similar expression levels of RGS4 protein resulted in greater inhibition of G-protein-independent cAMP production compared to G-protein-dependent GAP activity. Our results suggest specificity and selectivity of RGS proteins on G-protein-dependent and -independent signaling in mammalian cells.

Adenylyl Cyclases↗
PubMed1997

Regulators of G-protein signaling (RGS) proteins: region-specific expression of nine subtypes in rat brain.

The recently discovered regulators of G-protein signaling (RGS) proteins potently modulate the functioning of heterotrimeric G-proteins by stimulating the GTPase activity of G-protein alpha subunits. The mRNAs for numerous subtypes of putative RGS proteins have been identified in mammalian tissues, but little is known about their expression in brain. We performed a systematic survey of the localization of mRNAs encoding nine of these RGSs, RGS3-RGS11, in brain by in situ hybridization. Striking region-specific patterns of expression were observed. Five subtypes, RGS4, RGS7, RGS8, RGS9, and RGS10 mRNAs, are densely expressed in brain, whereas the other subtypes (RGS3, RGS5, RGS6, and RGS11) are expressed at lower density and in more restricted regions. RGS4 mRNA is notable for its dense expression in neocortex, piriform cortex, caudoputamen, and ventrobasal thalamus. RGS8 mRNA is highly expressed in the cerebellar Purkinje cell layer as well as in several midbrain nuclei. RGS9 mRNA is remarkable for its nearly exclusive enrichment in striatal regions. RGS10 mRNA is densely expressed in dentate gyrus granule cells, superficial layers of neocortex, and dorsal raphe. To assess whether the expression of RGS mRNAs can be regulated, we examined the effect of an acute seizure on levels of RGS7, RGS8, and RGS10 mRNAs in hippocampus. Of the three subtypes, changes in RGS10 levels were most pronounced, decreasing by approximately 40% in a time-dependent manner in response to a single seizure. These results, which document highly specific patterns of RGS mRNA expression in brain and their ability to be regulated in a dynamic manner, support the view that RGS proteins may play an important role in determining the intensity and specificity of signaling pathways in brain as well as their adaptations to synaptic activity.

Animals↗
PubMed2003

Established and emerging fluorescence-based assays for G-protein function: heterotrimeric G-protein alpha subunits and regulator of G-protein signaling (RGS) proteins.

Heterotrimeric G-proteins are molecular switches that couple serpentine receptors to intracellular effector pathways and the regulation of cell physiology. Ligand-bound receptors cause G-protein alpha subunits to bind guanosine 5'-triphosphate (GTP) and activate effector pathways. Signal termination is facilitated by the intrinsic GTPase activity of G-protein alpha subunits. Regulators of G-protein signaling (RGS) proteins accelerate the GTPase activity of the G-protein alpha subunit, and thus negatively regulate G-protein-mediated signal transduction. In vitro biochemical assays of heterotrimeric G-proteins commonly include measurements of nucleotide binding, GTPase activity, and interaction with RGS proteins. However, the conventional assays for most of these processes involve radiolabeled guanine nucleotide analogues and scintillation counting. In this article, we focus on fluorescence-based methodologies to study heterotrimeric G-protein alpha subunit regulation in vitro. Furthermore, we consider the potential of such techniques in high-throughput screening and drug discovery.

Animals↗
PubMed2002

Regulators of G protein signaling (RGS proteins): novel central nervous system drug targets.

Many drugs of abuse signal through receptors that couple to G proteins (GPCRs), so the factors that control GPCR signaling are likely to be important to the understanding of drug abuse. Contributions by the recently identified protein family, regulators of G protein signaling (RGS) to the control of GPCR function are just beginning to be understood. RGS proteins can accelerate the deactivation of G proteins by 1000-fold and in cell systems they profoundly inhibit signaling by many receptors, including mu-opioid receptors. Coupled with the known dynamic regulation of RGS protein expression and function, they are of obvious interest in understanding tolerance and dependence mechanisms. Furthermore, drugs that could inhibit their activity could be useful in preventing the development of or in treating drug dependence.

Animals↗
PubMed2001

Binding of regulator of G protein signaling (RGS) proteins to phospholipid bilayers. Contribution of location and/or orientation to Gtpase-activating protein activity.

Regulator of G protein signaling (RGS) proteins must bind membranes in an orientation that permits the protein-protein interactions necessary for regulatory activity. RGS4 binds to phospholipid surfaces in a slow, multistep process that leads to maximal GTPase-activating protein (GAP) activity. When RGS4 is added to phospholipid vesicles that contain m2 or m1 muscarinic receptor and G(i), G(z), or G(q), GAP activity increases approximately 3-fold over 4 h at 30 degrees C and more slowly at 20 degrees C. This increase in GAP activity is preceded by several other events that suggest that, after binding, optimal interaction with G protein and receptor requires reorientation of RGS4 on the membrane surface, a conformational change, or both. Binding of RGS4 is initially reversible but becomes irreversible within 5 min. Onset of irreversibility parallels initial quenching of tryptophan fluorescence (t(12) approximately 30 s). Further quenching occurs after binding has become irreversible (t(12) approximately 6 min) but is complete well before maximal GAP activity is attained. These processes all appear to be energetically driven by the amphipathic N-terminal domain of RGS4 and are accelerated by palmitoylation of cysteine residues in this region. The RGS4 N-terminal domain confers similar membrane binding behavior on the RGS domains of either RGS10 or RGSZ1.

Animals↗
PubMed2005

Effector antagonism by the regulators of G protein signalling (RGS) proteins causes desensitization of mu-opioid receptors in the CNS.

RATIONALE: In cell culture systems, agonists can promote the phosphorylation and internalization of receptors coupled to G proteins (GPCR), leading to their desensitization. However, in the CNS opioid agonists promote a profound desensitization of their analgesic effects without diminishing the presence of their receptors in the neuronal membrane. Recent studies have indicated that CNS proteins of the RGS family, specific regulators of G protein signalling, may be involved in mu-opioid receptor desensitization in vivo. OBJECTIVE: In this work we review the role played by RGS proteins in the intensity and duration of the effects of mu-opioid receptor agonists, and how they influence the delayed tolerance that develops in response to specific doses of opioids. RESULTS: RGS proteins are GTPase-activating proteins (GAP) that accelerate the hydrolysis of GalphaGTP to terminate signalling at effectors. The GAP activity of RGS-R4 and RGS-Rz proteins restricts the amplitude of opioid analgesia, and the efficient deactivation of GalphazGTP subunits by RGS-Rz proteins prevents mu receptor desensitization. However, RGS-R7 proteins antagonize effectors by binding to and sequestering mu receptor-activated Galphai/o/z subunits. Thus, they reduce the pool of receptor-regulated G proteins and hence, the effects of agonists. The delayed tolerance observed following morphine administration correlates with the transfer of Galpha subunits from mu receptors to RGS-R7 proteins and the subsequent stabilization of this association. CONCLUSION: In the CNS, the RGS proteins control the activity of mu opioid receptors through GAP-dependent (RGS-R4 and RGS-Rz) as well as by GAP-independent mechanisms (RGS-R7). As a result, they can both antagonize effectors and desensitize receptors under certain circumstances.

Analgesics, Opioid↗
PubMed1998

Regulators of G protein signaling (RGS) proteins constitutively activate Gbeta gamma-gated potassium channels.

Here we report novel effects of regulators of G protein signaling (RGS) on G protein-regulated ion channels. RGS3 and RGS4 induced a substantial increase in currents through the Gbeta gamma-regulated inwardly rectifying K+ channels, IK(ACh), in the absence of receptor activation. Concomitantly, the amount of current that could be activated by agonist was reduced. Pretreatment with pertussis toxin or a muscarinic receptor antagonist abolished agonist-induced currents but did not modify RGS effects. Cotransfection of cells with a Gbetagamma-binding protein significantly reduced the RGS4-induced basal IK(ACh) currents. The RGS proteins also modified the properties of another Gbeta gamma effector, the N-type Ca2+ channels. These observations strongly suggest that RGS proteins increase the availability of Gbeta gamma in addition to their previously described GTPase-activating function.

Calcium Channels↗
PubMed2006

Regulator of G-protein signaling (RGS) proteins differentially control chondrocyte differentiation.

Control of chondrocyte differentiation is attained, in part, through G-protein signaling, but the functions of the RGS family of genes, well known to control G-protein signaling at the Galpha subunit, have not been studied extensively in chondrogenesis. Recently, we have identified the Rgs2 gene as a regulator of chondrocyte differentiation. Here we extend these studies to additional Rgs genes. We demonstrate that the Rgs4, Rgs5, Rgs7, and Rgs10 genes are differentially regulated during chondrogenic differentiation in vitro and in vivo. To investigate the roles of RGS proteins during cartilage development, we overexpressed RGS4, RGS5, RGS7, and RGS10 in the chondrogenic cell line ATDC5. We found unique and overlapping effects of individual Rgs genes on numerous parameters of chondrocyte differentiation. In particular, RGS5, RGS7, and RGS10 promote and RGS4 inhibits chondrogenic differentiation. The identification of Rgs genes as novel regulators of chondrogenesis will contribute to a better understanding of both normal cartilage development and the etiology of chondrodysplasias and osteoarthritis.

Animals↗
PubMed2000

A regulator of G protein signalling (RGS) protein confers agonist-dependent relaxation gating to a G protein-gated K+ channel.

1. The effects of RGS4 on the voltage-dependent relaxation of G protein-gated K+ (KG) channels were examined by heterologous expression in Xenopus oocytes. 2. While the relaxation kinetics was unaffected by the acetylcholine concentration ([ACh]) in the absence of RGS4, it became dependent on [ACh] when RGS4 was co-expressed. 3. Kinetic analyses indicated that RGS4 confers to the KG channel a voltage-independent inhibitory gating mechanism, which was attenuated by ACh in a concentration-dependent fashion. 4. In vitro biochemical studies showed that RGS4 could bind to the protein complex containing KG channel subunits. 5. Since the native cardiac KG channel exhibited similar agonist-dependent relaxation kinetics to that mediated by RGS4, it is suggested that KG channel gating is a novel physiological target of RGS protein-mediated regulation.

Acetylcholine↗
PubMed1997

A new family of G-protein regulators - the RGS proteins.

Genetic experiments have recently been used to identify a family of 'regulator of G-protein signaling' (RGS) proteins, which downregulate signaling by heterotrimeric G proteins. The first biochemical studies of RGS proteins have shown that they accelerate the GTPase activities of G-protein alpha subunits, thus driving G proteins into their inactive GDP-bound forms. The physiological significance of the large number of different RGS proteins remains to be explored.

Animals↗
PubMed2001

Regulation of G protein-mediated signal transduction by RGS proteins.

RGS proteins form a new family of regulatory proteins of G protein signaling. They contain homologous core domains (RGS domains) of about 120 amino acids. RGS domains interact with activated Galpha subunits. Several RGS proteins have been shown biochemically to act as GTPase activating proteins (GAPs) for their interacting Galpha subunits. Other than RGS domains, RGS proteins differ significantly in size, amino acid sequences, and tissue distribution. In addition, many RGS proteins have other protein-protein interaction motifs involved in cell signaling. We have shown that p115RhoGEF, a newly identified GEF(guanine nucleotide exchange factor) for RhoGTPase, has a RGS domain at its N-terminal region and this domain acts as a specific GAP for Galpha12 and Galpha13. Furthermore, binding of activated Galpha13 to this RGS domain stimulated GEF activity of p115RhoGEF. Activated Galpha12 inhibited Galpha13-stimulated GEF activity. Thus p115RhoGEF is a direct link between heterotrimeric G protein and RhoGTPase and it functions as an effector for Galpha12 and Galpha13 in addition to acting as their GAP. We also found that RGS domain at N-terminal regions of G protein receptor kinase 2 (GRK2) specifically interacts with Galphaq/11 and inhibits Galphaq-mediated activation of PLC-beta, apparently through sequestration of activated Galphaq. However, unlike other RGS proteins, this RGS domain did not show significant GAP activity to Galphaq. These results indicate that RGS proteins have far more diverse functions than acting simply as GAPs and the characterization of function of each RGS protein is crucial to understand the G protein signaling network in cells.

Animals↗
PubMed2005

RGS proteins have a signalling complex: interactions between RGS proteins and GPCRs, effectors, and auxiliary proteins.

The intracellular regulator of G protein signalling (RGS) proteins were first identified as GTPase activating proteins (GAPs) for heterotrimeric G proteins, however, it was later found that they can also regulate G protein-effector interactions in other ways that are still not well understood. There is increasing evidence that some of the effects of RGS proteins occur due to their ability to interact with multiprotein signalling complexes. In this review, we will discuss recent evidence that supports the idea that RGS proteins can bind to proteins other than Galpha, such as G protein coupled receptors (GPCRs, e.g. muscarinic, dopaminergic, adrenergic, angiotensin, interleukin and opioid receptors) and effectors (e.g. adenylyl cyclase, GIRK channels, PDEgamma, PLC-beta and Ca(2+) channels). Furthermore, we will investigate novel RGS binding partners (e.g. GIPC, spinophilin, 14-3-3) that underlie the formation of signalling scaffolds or govern RGS protein availability and/or activity.

14-3-3 Proteins↗
PubMed2005

R7BP, a novel neuronal protein interacting with RGS proteins of the R7 family.

The R7 subfamily of the regulators of G protein signaling (RGS) proteins is represented by four members broadly expressed in the mammalian nervous system. Here we report that in the brain all four R7 proteins form tight complexes with a previously unidentified protein, which we call the R7-binding protein or R7BP. We initially identified R7BP as a protein co-precipitating with the R7 protein, RGS9, from extracts obtained from the striatal region of the brain. We further showed that R7BP forms a tight complex with RGS9 in vitro and that this binding occurs via the N-terminal DEP domain of RGS9. R7BP is expressed throughout the entire central nervous system but not in any of the tested non-neuronal tissues. All four R7 RGS proteins co-precipitate with R7BP from brain extracts and recombinant R7 proteins bind recombinant R7BP with high efficiency. The closest homolog of R7BP is R9AP which was previously found to interact with RGS9 in photoreceptors. Both R7BP and R9AP are related to the syntaxin subfamily of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins involved in vesicular trafficking and exocytosis. In photoreceptors R9AP regulates several critical properties of RGS9 including its intracellular targeting, stability and catalytic activity. This suggests that R7BP interactions with R7 proteins in the brain may also bear major functional significance.

Amino Acid Sequence↗