Dynamic Regulation of RGS2 Suggests a Novel Mechanism in G-Protein Signaling and Neuronal Plasticity

Ingi, Tatsuya; Krumins, Andrejs M.; Chidiac, Peter; Brothers, Greg M.; Chung, Shinjae; Snow, Bryan E.; Barnes, Carol A.; Lanahan, Anthony A.; Siderovski, David P.; Ross, Elliott M.; Gilman, Alfred G.; Worley, Paul F.

doi:10.1523/jneurosci.18-18-07178.1998

Cited by 279 publications

(309 citation statements)

References 66 publications

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“…Thus, it seems reasonable that RGS2 would not be recruited by receptors that activate G i/o pathways. However, RGS4 is an efficient GAP in vitro for both G q ␣ and G i ␣ (6) and has been shown to modulate M2-mediated signaling in many cases (25,34,36), yet we did not detect RGS4 binding to the M2i3 or M4i3 loop. One explanation for this discrepancy is that the relative expression levels of receptor, RGS and G␣␤␥ in these assay systems may allow the RGS-G␣ coupling to predominate such that RGS can inhibit G␣ despite a lack of RGS-M2 interaction.…”

Section: Differential Binding Profiles Of Various Rgs Proteins With Tcontrasting

confidence: 53%

“…M1 mAChR is functionally linked to G q/11 ␣, and we have shown previously that RGS2 selectively interacts with G q ␣ (31,33,34). Initially our studies did not distinguish whether the RGS-G␣ interaction could occur while RGS2 is bound to M1i3, or whether the RGS protein was released prior to it actions on G␣.…”

Section: Differential Binding Profiles Of Various Rgs Proteins With Tmentioning

confidence: 80%

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RGS2 Binds Directly and Selectively to the M1 Muscarinic Acetylcholine Receptor Third Intracellular Loop to Modulate Gq/11α Signaling

Bernstein

Ramineni

Hague

et al. 2004

Journal of Biological Chemistry

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RGS proteins serve as GTPase-activating proteins and/or effector antagonists to modulate G␣ signaling events. In live cells, members of the B/R4 subfamily of RGS proteins selectively modulate G protein signaling depending on the associated receptor (GPCR). Here we examine whether GPCRs selectively recruit RGS proteins to modulate linked G protein signaling. We report the novel finding that RGS2 binds directly to the third intracellular (i3) loop of the G q/11 -coupled M1 muscarinic cholinergic receptor (M1 mAChR; M1i3). This interaction is selective because closely related RGS16 does not bind M1i3, and neither RGS2 nor RGS16 binds to the G i/o -coupled M2i3 loop. When expressed in cells, RGS2 and M1 mAChR co-localize to the plasma membrane whereas RGS16 does not. The N-terminal region of RGS2 is both necessary and sufficient for binding to M1i3, and RGS2 forms a stable heterotrimeric complex with both activated G q ␣ and M1i3. RGS2 potently inhibits M1 mAChR-mediated phosphoinositide hydrolysis in cell membranes by acting as an effector antagonist. Deletion of the N terminus abolishes this effector antagonist activity of RGS2 but not its GTPase-activating protein activity toward G 11 ␣ in membranes. These findings predict a model where the i3 loops of GPCRs selectively recruit specific RGS protein(s) via their N termini to regulate the linked G protein. Consistent with this model, we find that the i3 loops of the mAChR subtypes (M1-M5) exhibit differential profiles for binding distinct B/R4 RGS family members, indicating that this novel mechanism for GPCR modulation of RGS signaling may generally extend to other receptors and RGS proteins.Cells rely upon G protein-coupled receptors (GPCRs) 1 to convey signals from extracellular hormones and neurotransmitters to intracellular effectors and linked signaling pathways. Agonist occupancy of the GPCR activates a heterotrimeric G protein (G␣␤␥) by catalyzing the exchange of GDP for GTP on the G␣ subunit (1). This initiates dissociation of the trimer into free G␣ and G␤␥, which independently or in coordinated fashion activate downstream effectors and linked signaling pathways. Members of the regulators of G protein signaling (RGS) family of proteins are direct modulators of G protein activity. RGS proteins are best understood as GTPaseactivating proteins (GAPs), which bind to the activated form of G␣ and accelerate its GTPase activity thereby promoting the termination of G protein signaling (2-5). By virtue of their interactions with activated G␣, RGS proteins also serve as effector antagonists to block activation of downstream effector molecules (6, 7).All RGS proteins share a conserved RGS core domain of ϳ130 amino acids that contains binding sites for G␣ and is responsible for their GAP activity (5,8,9). Outside of the RGS domain, however, the more than 30 family members are widely divergent. Some RGS proteins are quite complex and contain multiple domains for binding a variety of signaling proteins. Other RGS proteins are simple, with relatively short, featureless N...

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Section: Differential Binding Profiles Of Various Rgs Proteins With Tcontrasting

confidence: 53%

Section: Differential Binding Profiles Of Various Rgs Proteins With Tmentioning

confidence: 80%

RGS2 Binds Directly and Selectively to the M1 Muscarinic Acetylcholine Receptor Third Intracellular Loop to Modulate Gq/11α Signaling

Bernstein

Ramineni

Hague

et al. 2004

Journal of Biological Chemistry

Self Cite

209

205

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“…Similarly, an increase only in the present associative learning group A was seen for the membrane interacting protein of RGS16, involved in lipid metabolism and G-protein signaling (Zheng et al 2000). While there is some indication for an involvement of another regulator of G-protein signaling (RGS2) in synaptic plasticity and emotional behavior (Ingi et al 1998;Oliveira-Dos-Santos et al 2000), our finding is the first evidence of a role for RGS16 in these processes. On the other hand, a great body of…”

Section: Expression Of Signal Transduction and Structural Reorganizatmentioning

confidence: 41%

Identification of Genes Expressed in the Amygdala During the Formation of Fear Memory

Stork

Stork²,

Pape³

et al. 2001

Learn. Mem.

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In this study we describe changes of gene expression that occur in the basolateral complex of the mouse amygdala (BLA) during the formation of fear memory. Through the combination of a behavioral training scheme with polymerase chain reaction-based expression analysis (subtractive hybridization and virtual Northern analysis) we were able to identify various gene products that are increased in expression after Pavlovian fear conditioning and are of potential significance for neural plasticity and information storage in the amygdala. In particular, a key enzyme of monoamine metabolism, aldehyde reductase, and the protein sorting and ubiquitination factor Praja1, showed pronounced and learning-specific induction six hours after fear conditioning training. Aldehyde reductase and Praja1, including a novel alternatively spliced isoform termed Praja1a, were induced in the BLA depending on the emotional stimulus presented and showed different expression levels in response to associative conditioning, training stress, and experience of conditioned fear. Stress and fear were further found to induce various signal transduction factors (transthyretin, phosphodiesterase1, protein kinase inhibitor-␣) and structural reorganization factors (e.g., E2-ubiquitin conjugating enzyme, neuroligin1, actin, UDP-galactose transporter) during training. Our results show that the formation of Pavlovian fear memory is associated with changes of gene expression in the BLA, which may contribute to neural plasticity and the processing of information about both conditioned and unconditioned fear stimuli.[The Praja1a sequence has been deposited in GenBank data base under accession no. AF335250.]

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“…While RGS2 can act as a GAP protein for Gα i and Gα S proteins (Ingi et al 1998;Sinnarajah et al 2001), it is the most potent RGS for Gαq, the Gα subunit pivotal for the signalling of most vasoconstrictors, including noradrenaline, AngII, endothelin-1, thromboxane, vasopressin and thrombin (Heximer et al 1997). RGS2 will not only attenuate Gαq-mediated vasoconstrictor signals, vasoconstrictors such as AngII can also stimulate RGS2 transcript expression, which will ultimately result in a further feedback inhibition of Gαq-mediated signals (Grant et al 2000).…”

Section: Genetic Variants Of the Regulator Of G Protein Signalling (Rmentioning

confidence: 99%

Genetics of arterial hypertension and hypotension

Rosskopf

Schürks

Rimmbach

et al. 2007

Naunyn-Schmied Arch Pharmacol

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Human hypertension affects affects more than 20% of the adult population in industrialized countries, and it is implicated in millions of deaths worldwide each year from stroke, heart failure and ischemic heart disease. Available evidence suggests a major genetic impact on blood pressure regulation. Studies in monogenic hypertension revealed that renal salt and volume regulation systems are predominantly involved in the genesis of these disorders. Mutations here affect the synthesis of mineralocorticoids, the function of the mineralocorticoid receptor, epithelial sodium channels and their regulation by a new class of kinases, termed WNK kinases. It has been learned from monogenic hypotension that almost all ion transporters involved in the renal uptake of Na + have a major impact on blood pressure regulation. For essential hypertension as a complex disease, many candidate genes have been analysed. These include components of the reninangiotensin-aldosterone system, adducin, β-adrenoceptors, G protein subunits, regulators of G protein signalling (RGS) proteins, Rho kinases and G protein receptor kinases. At present, the individual impact of common polymorphisms in these genes on the observed blood pressure variation, on risk for stroke and as predictors of antihypertensive responses remains small and clinically irrelevant. Nevertheless, these studies have greatly augmented our knowledge on the regulation of renal functions, cellular signal transduction and the integration of both. Together, this provides the basis for the identification of novel drug targets and, hopefully, innovative antihypertensive drugs.

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Dynamic Regulation of RGS2 Suggests a Novel Mechanism in G-Protein Signaling and Neuronal Plasticity

Cited by 279 publications

References 66 publications

RGS2 Binds Directly and Selectively to the M1 Muscarinic Acetylcholine Receptor Third Intracellular Loop to Modulate Gq/11α Signaling

RGS2 Binds Directly and Selectively to the M1 Muscarinic Acetylcholine Receptor Third Intracellular Loop to Modulate Gq/11α Signaling

Identification of Genes Expressed in the Amygdala During the Formation of Fear Memory

Genetics of arterial hypertension and hypotension

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