This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Riddle, E. L. Articles by Insel, P. A. Search for Related Content PubMed PubMed Citation Articles by Riddle, E. L. Articles by Insel, P. A. Related Collections Cardiovascular Pharmacology Cell signalling/signal transduction Heart failure - basic studies Hypertension - basic studies Receptor pharmacology

(Circulation Research. 2005;96:401.)
© 2005 American Heart Association, Inc.

Review

Multi-Tasking RGS Proteins in the Heart

The Next Therapeutic Target?

Evan L. Riddle, Raúl A. Schwartzman, Meredith Bond, Paul A. Insel

From the Department of Pharmacology (E.L.R., P.A.I.), University of California San Diego, La Jolla; the Department of Physiology (R.A.S., M.B.), University of Maryland School of Medicine, Baltimore; and the Department of Molecular Cardiology (M.B.), Lerner Research Institute, The Cleveland Clinic Foundation, Ohio.

Correspondence to Meredith Bond, PhD, Department of Physiology, University of Maryland, 655 W Baltimore St, Baltimore, MD 21201. E-mail mbond001{at}umaryland.edu

This Review is part of a thematic series on Heterodimerization of Signaling Molecules, which includes the following articles:

Regulation of G Protein–Coupled Receptor Signaling By Scaffold Proteins

G Protein–Coupled Receptor Oligomerization: Implications for G Protein Activation and Cell Signaling

Multi-Tasking RGS Proteins in the Heart: The Next Therapeutic Target?
Gerda Breitwieser Editor

	Abstract

Top Abstract Introduction RGS Protein Structure Regulation of RGS Proteins RGS and G-Protein Selectivity RGS Proteins and the... RGS Proteins as Drug... References

 
Regulator of G-protein–signaling (RGS) proteins play a key role in the regulation of G-protein–coupled receptor (GPCR) signaling. The characteristic hallmark of RGS proteins is a conserved 120-aa RGS region that confers on these proteins the ability to serve as GTPase-activating proteins (GAPs) for G proteins. Most RGS proteins can serve as GAPs for multiple isoforms of G and therefore have the potential to influence many cellular signaling pathways. However, RGS proteins can be highly regulated and can demonstrate extreme specificity for a particular signaling pathway. RGS proteins can be regulated by altering their GAP activity or subcellular localization; such regulation is achieved by phosphorylation, palmitoylation, and interaction with protein and lipid-binding partners. Many RGS proteins have GAP-independent functions that influence GPCR and non-GPCR–mediated signaling, such as effector regulation or action as an effector. Hence, RGS proteins should be considered multifunctional signaling regulators. GPCR-mediated signaling is critical for normal function in the cardiovascular system and is currently the primary target for the pharmacological treatment of disease. Alterations in RGS protein levels, in particular RGS2 and RGS4, produce cardiovascular phenotypes. Thus, because of the importance of GPCR-signaling pathways and the profound influence of RGS proteins on these pathways, RGS proteins are regulators of cardiovascular physiology and potentially novel drug targets as well.

Key Words: RGS protein • regulator of G-protein signaling • GPCRheart

	Introduction

Top Abstract Introduction RGS Protein Structure Regulation of RGS Proteins RGS and G-Protein Selectivity RGS Proteins and the... RGS Proteins as Drug... References

 
G-Protein–coupled receptors (GPCRs) are found ubiquitously through the body and are involved in virtually every physiological process. Cardiovascular cells possess >100 different GPCRs.¹ GPCRs bind a heterotrimeric G-protein complex of -, ß-, and -subunits. G-Proteins are divided into four families (eg, G_s, G_i, G_q, and G₁₂) based on similarity of -subunits among individual family members;² at least 20 -subunits are found in mammalian cells.³ Agonist binding of GPCRs promotes G-protein activation. This activation is achieved by catalyzing GDP–GTP exchange on the -subunit. A conformational change in the GTP-bound -subunit leads to a dissociation of G from the ß-subunits. GTP-bound G-subunits and dissociated ß-dimers regulate downstream effectors. These signaling events are terminated as a consequence of intrinsic GTPase activity of the G-subunit, which hydrolyzes bound GTP to GDP, resulting in a reassociation of the G-protein heterotrimer. The intrinsic GTPase activity of -subunits is generally insufficient to correlate with physiological rates of G-protein inactivation, but this activity can be accelerated by the presence of GTPase-activating proteins (GAPs), such as regulator of G-protein–signaling (RGS) proteins.

The discovery of RGS proteins suggested the possibility of a specific RGS protein for each G subtype. However, this idea was discarded when it was discovered that the number of RGS proteins (now >30) was greater than that of G-subunits, along with the recognition that individual RGS proteins could act as GAPs for multiple families of G. However, as understanding of RGS function increases, evidence has emerged for G specificity of certain RGS proteins, especially in the in vivo setting, as well as their modulation of distinct GPCR-mediated signaling pathways. Although a substantial amount is known regarding identity and expression of RGS proteins, much remains to be elucidated regarding their function, localization, and regulation. Their GAP activity is a primary characteristic, but RGS proteins use a variety of mechanisms to regulate signaling. Several excellent reviews have provided insight on the structure and function of RGS proteins.^4–7 However, numerous recent developments related to RGS proteins have important implications, especially for cardiovascular physiology and pathophysiology. In this review, we first provide an overview of RGS structure, emphasizing non-RGS domains. Second, we discuss mechanisms for the regulation of RGS proteins. Finally, we bring the reader up to date on current knowledge of the importance of these "multitasking" RGS proteins in the cardiovascular system.

	RGS Protein Structure

Top Abstract Introduction RGS Protein Structure Regulation of RGS Proteins RGS and G-Protein Selectivity RGS Proteins and the... RGS Proteins as Drug... References

 
Figure 1 summarizes key features of RGS genes and proteins. Many RGS genes produce different isoforms (eg, rgs6 encodes 36 distinct transcripts⁸). A description of each isoform is beyond the scope of this review. RGS proteins are diverse, ranging in size from 152 (RGS21) to 1376 (RGS12) amino acids. Many, indeed most, RGS proteins identified to date exhibit GAP activity toward the G_i and G_q families of G-proteins. However, it is important to note that even though an RGS protein may be able to serve as a GAP for a particular G-subunit, particular GPCR signaling pathways involving the identical G-subunit can show receptor-selective regulation by RGS proteins.⁹

View larger version (37K): [in this window] [in a new window]   Figure 1. Summary of RGS protein family members, structure, and cardiac expression. The RGS families are listed with their subfamily classification (R4, R7, R12, RZ, and RL) and the G-protein family/families in which they exert their GAP activity (although they may not interact with all subtypes of the G-protein subfamily). Gene expression reflects reports that identify mRNA transcripts in the mammalian heart. Human, mouse, and rat proteins are compared by their amino acid length and percent identity compared with human. A general schematic is provided to show the common protein domains of each RGS protein (although variance may exist between isoforms or splice variants).

On the basis of sequence similarity of the RGS domain, RGS proteins can be classified into one of five subfamilies: R4, R7, R12, RZ, and RL (Figure 1). Although some RGS proteins consist almost exclusively of the RGS domain, a conserved 120-aa region, others contain additional domains. The RGS domain is necessary and sufficient to confer GAP activity;¹⁰ however, other domains, to be discussed subsequently, can increase specificity, determine cellular localization, and provide additional activities.

PSD-95 Disk-Large ZO-1 Domain
PSD-95 disk-large ZO-1 (PDZ) domains, 90-aa regions with a highly conserved four-residue GLGF sequence, are involved in the clustering of multiprotein signaling complexes.¹¹ RGS12 and a variant of RGS3, PDZ-RGS3, contain PDZ domains. The PDZ domain of PDZ-RGS3 binds the non-GPCR B-ephrin receptor, thereby providing a possible link between GPCR signaling and B-ephrin signaling.¹² In addition, PDZ-RGS3 could be important for B-ephrin–regulated cardiovascular development.¹³

The PDZ domain of RGS12 binds selectively to the interleukin-8 receptor B (CXCR2), a G_i-coupled GPCR.¹⁴ Although RGS12 has GAP activity toward G_i, it remains to be determined whether RGS12 alters CXCR2-mediated G-protein signaling. The interaction of RGS12 with CXCR2 has the potential to influence myocardial viability during ischemia reperfusion.¹⁵

G-Protein Subunit–Like Domain
RGS6, RGS7, RGS9, and RGS11 contain G-protein subunit–like (GGL) domains, a 64-aa region with a high level of similarity to the G-subunit, can form dimers with particular G-protein subunits (ie, Gß5) but not others (eg, Gß1 to Gß3).¹⁶ This RGS/Gß5 interaction appears to influence RGS and Gß5 protein stability,^17,18 GAP activity of RGS proteins,^16,19 and subcellular localization of RGS and Gß5.^8,20

GoLoco Domain
RGS12 and RGS14 contain GoLoco domains, a 19-aa G_i binding motif that acts as a guanine nucleotide dissociation inhibitor (GDI) by binding and stabilizing GDP-bound G_i, inhibiting the rate of exchange of GDP for GTP in a GAP-independent manner.²¹ The RGS and GoLoco domains of RGS14 can independently inhibit G_i signaling, but both domains are necessary for maximal inhibition.²² The GoLoco domain of RGS14 exhibits GDI activity toward G_i1 and G_i3 but not G_i2 or G_o even though the GAP activity is not G-protein subtype selective.²³

PX Domain
RGS-PX1, the only RGS protein thus far identified with GAP activity for G_s, contains a PX domain, an 120-aa phosphoinositide-binding domain involved in membrane targeting.^24,25 RGS-PX1 delays lysosomal degradation of the EGF receptor, most likely as a result of the sorting nexin function of the PX domain.²⁴ The relationship between RGS-PX1 and the EGF receptor suggests a possible role for RGS-PX1 in angiotensin II (Ang II)–induced cardiac hypertrophy.²⁶

Disheveled EGL-10 Pleckstrin Domain
The 70-aa disheveled EGL-10 pleckstrin (DEP) domains are present in various signaling proteins, including RGS6, RGS7, RGS9, and RGS11, but little is known about their function. The DEP domain of RGS9 appears to be critical for interaction with R9AP (RGS9 anchoring protein) and subcellular targeting of RGS9 to the rod outer segment.²⁷ The DEP domain of RGS7 can bind snapin, a protein that interacts with synaptosomal-associated protein of 25 kDa, a component of the soluble N-ethylmaleimide–sensitive factor attachment protein receptor complex, suggesting a role for RGS7 in synaptic vesicle exocytosis.²⁸ Interestingly, snapin was discovered recently to bind adenylyl cyclase type 6 (AC6),²⁹ a highly expressed isoform of adenylyl cyclase in the heart,³⁰ providing a possible link for RGS7 in the regulation of cAMP levels.

	Regulation of RGS Proteins

Top Abstract Introduction RGS Protein Structure Regulation of RGS Proteins RGS and G-Protein Selectivity RGS Proteins and the... RGS Proteins as Drug... References

 
RGS proteins have the potential to decrease or stop GPCR-mediated signaling. This important action implies that activity and expression of RGS proteins must be regulated. Indeed, RGS proteins are highly regulated through various mechanisms such as alterations in expression levels, subcellular localization, post-translational modifications, and binding partners. In addition to direct regulation of RGS proteins, the effects of RGS proteins can be regulated by post-translational modification of the G-protein -subunit.

Regulation of RGS Expression
Increases or decreases in cellular levels of RGS proteins have the potential to be critical for RGS-induced regulation of G-protein signaling. Increasing evidence demonstrates that RGS protein and mRNA levels are dynamically altered by various drugs, second messengers, and disease states. Although numerous RGS proteins show dynamic expression, RGS2 provides an excellent example of a highly regulated RGS protein. Dopamine D1 receptor agonists increase RGS2 mRNA, whereas a decrease in RGS2 mRNA occurs with agonism of the dopamine D2 receptor.³¹ Increases in cAMP levels by forskolin appear to increase RGS2 protein levels.³² Alterations in RGS2 levels show pathophysiological relevance because an overabundance of RGS2 protein is seen in individuals with Bartter’s/Gitelman’s Syndrome,³³ and RGS2 knockout mice exhibit a severe cardiovascular phenotype,³⁴ as is discussed subsequently. Chronic pharmacological therapy, as commonly used in the treatment of cardiovascular disease, likely alters RGS expression. The impact of such alterations on signal transduction has not been well studied but could lead to a myriad of effects, including sensitization or desensitization of signaling pathways, side effects, tolerance, dependence, etc.

Subcellular Localization
In order for an RGS protein to actively serve as a GAP, it must be localized in a region in the cell where it can bind its target G-subunit. Localization of RGS proteins in a particular subcellular compartment could increase the specificity of an RGS protein for particular G-proteins and GPCRs or pathway even though the GAP activity of an RGS protein may have multiple potential G targets.

On G-protein activation, RGS3 is translocated from the cytosol to the plasma membrane.³⁵ In addition, the phosphorylation of RGS10 promotes its translocation from the plasma membrane and cytosol to the nucleus.³⁶ The subcellular localization of RGS2 and RGS4 are dependent on specific G-proteins and GPCRs.³⁷ In human embryonic kidney 293 cells, transfected RGS2 and RGS4 localize to the nucleus and cytosol, respectively. Whereas RGS2 translocates to the plasma membrane when cotransfected with G_q or G_s but not G_i2 RGS4 translocates to the plasma membrane when cotransfected with G_i2 but not G_q or G_s. A similar translocation profile is observed when GPCRs have been expressed that preferentially interact with specific G-protein family members. For example, the Ang II receptor (G_q-coupled) and ß₂-adrenergic receptor (G_s-coupled) promoted plasmalemmal translocation of RGS2, whereas RGS4 was only translocated by expression of the M₂ muscarinic cholinergic receptor (mAChR; G_i-coupled). Unlike RGS3, the translocation of RGS2 and RGS4 does not appear to depend on G-protein activation.

Colocalization of proteins in a signaling pathway may be critical for signaling. Membrane microdomains, such as lipid rafts and caveolae, allow for the clustering and compartmentation of signaling molecules and are likely important for integrating GPCR-mediated signaling pathways.³⁸ Many GPCRs move into or out of lipid rafts on agonist stimulation,^39,40 an effect that could move the GPCR closer to or away from an RGS protein. Little work has been performed to determine whether RGS proteins are found in membrane microdomains. However, RGS16 localizes to lipid rafts on palmitoylation,^41,42 which may be important for it to exert GAP activity for a particular signaling pathway.

Phosphorylation and Palmitoylation
Phosphorylation and palmitoylation, which reportedly can occur for multiple RGS proteins, produce a variety of effects, including alterations in subcellular localization, protein stability, and alterations in GAP activity. However, the physiological importance of these modifications remains to be determined. Tables 1 and 2 provide a summary of RGS proteins known to be influenced by phosphorylation and palmitoylation, respectively. It is likely that most, if not all, RGS proteins are regulated by phosphorylation or palmitoylation; however, much work needs to be done in this area.⁴³ Phosphorylation and palmitoylation of G-subunits can affect RGS GAP activity, in particular, decreasing such activity.^44–46

View this table: [in this window] [in a new window]   Table 1. Phosphorylation of RGS Proteins

View this table: [in this window] [in a new window]   Table 2. Palmitoylation of RGS Proteins

Protein and Lipid-Binding Partners
Several RGS protein-binding partners have been identified. Of particular interest are 14-3-3 proteins, which bind target proteins at phosphorylated residues.⁴⁷ 14-3-3 binds RGS7 on phosphoserine 434 within the RGS domain, thereby decreasing RGS7 GAP activity;⁴⁸ this binding is inhibited by tumor necrosis factor-, which can decrease serine 434 phosphorylation.⁴⁹ In contrast, 14-3-3 binds RGS3 at phosphoserine 264 in a region outside the RGS domain but still reduces the potency of RGS3 in the inhibition of G-protein signaling.⁵⁰ Only RGS3 and RGS7 have thus far been reported to bind 14-3-3, although other RGS proteins possess putative binding sites.^48,50

The GAP activity of many RGS proteins is inhibited by phosphatidylinositol-3,4,5,-trisphosphate (PIP₃), phosphatidic acid (PA), and lysophosphatidic acid, effects reversed by Ca²⁺/calmodulin.^51–55 PIP₃ and PA can bind RGS4 and additively inhibit GAP activity, which suggests multiple binding sites. The binding of Ca²⁺/calmodulin can occur on two sites of RGS4 to reverse PA- and PIP₃-mediated GAP inhibition without affecting GAP activity alone.⁵⁵ The physiological significance for PIP₃-mediated inhibition of RGS proteins includes regulation of G-protein–gated K⁺ channels in cardiac myocytes, as is discussed subsequently.

Receptor Selectivity
As noted above, some RGS proteins can be very "promiscuous" in that they have GAP activity in vitro for many subtypes of G-subunits. However, it has become apparent that RGS proteins are highly regulated and can be extremely specific in modulating distinct signal transduction pathways. In addition to the various methods of RGS regulation discussed above, RGS proteins may selectively alter GPCR signaling in a receptor-specific manner, as summarized in Table 3.

View this table: [in this window] [in a new window]   Table 3. GPCR Selectivity of RGS Proteins

Many of the methods used to determine receptor selectivity involve overexpression of GPCRs or RGS proteins. Overexpression can lead to artifactual results by producing "un-natural" protein levels. Alternatively, specific knockdown of proteins with ribozymes, antisense oligonucleotides, RNA interference, etc, avoids this problem, albeit introducing reagents with other potential sets of actions. Even so, one imagines that "knockdown strategies" can facilitate study of RGS/GPCR interactions in a setting with less potential for nonspecific perturbation than overexpression. Wang et al⁵⁶ have demonstrated that knockdown of RGS3 and RGS5 alters G_q signaling in a receptor-specific manner (ie, of muscarinic M₃ and Ang II type 1 [AT₁] receptor signaling, respectively).⁵⁶

It is clear that the ability of a RGS protein to show GAP activity for a specific G-subunit in vitro does not allow for the prediction of the precise signaling pathways that the RGS protein regulates in vivo. Because there are many factors that influence RGS activity or subcellular localization, it is not unreasonable to imagine cell-specific effects where a particular GPCR expressed in different cell types is differentially regulated by RGS proteins.

In addition to RGS selectivity for receptor signaling, Bernstein et al⁵⁷ have recently demonstrated differential physical binding of RGS proteins to mAChRs. RGS1, RGS2, RGS4, and RGS16 were tested for interaction with the third intracellular loops of each of the five mAChR subtypes. RGS2, but not RGS1 or RGS16, bound the M₁ mAChR, whereas none bound the M₂ mAChR. Moreover, RGS2, but not RGS16, colocalized with the M₁ mAChR at the plasma membrane and inhibited M₁ mAChR-induced phosphoinositide hydrolysis.

	RGS and G-Protein Selectivity

Top Abstract Introduction RGS Protein Structure Regulation of RGS Proteins RGS and G-Protein Selectivity RGS Proteins and the... RGS Proteins as Drug... References

 
As shown in Figure 1, most RGS proteins are GAPs for the G_i and G_q families of G-proteins. However, many RGS proteins show G subtype-selective activity, as demonstrated by the following. (1) RGS19 interacts with G_i1, G_i3, and G₀ but not G_i2;^58,59 (2) RGS4 shows selectivity for G_i2 and G_o1 over G_i1 and G_i3;⁶⁰ (3) GPCR kinase 2 (GRK2) binds G_q, G₁₁, and G₁₄ but not G₁₆;⁶¹ (4) RGS14 inhibits guanine nucleotide exchange on G_i1 and G_i3 but not G_i2;²³ and (5) A splice variant of RGS20, RGSZ1, is 100-fold selective for G_Z over G_i.⁴⁵

Only one RGS protein, RGS-PX1, has thus far been found to exhibit GAP activity for the G_s family.²⁴ Even though other RGS proteins do not regulate G_s-mediated signaling pathways via GAP activity, GAP-independent regulation occurs. Initial evidence demonstrated that RGS2 and a truncated form of RGS3, RGS3T, inhibited cAMP production.^62,63 Later, Sinnarajah et al⁶⁴ showed that RGS1, RGS2, and RGS3, but not RGS4 or RGS5, decreased odorant-induced cAMP production in olfactory membranes. Those workers also demonstrated that RGS2 inhibits cAMP production from AC3, AC5, and AC6, but not AC1 or AC2. This inhibition is achieved by the N terminal of RGS2 directly binding the C(1) domain of AC5.^64,65

p115Rho–guanine nucleotide exchange factor (GEF) is an RGS protein that shows selective GAP activity for members of the G₁₂ family of G-proteins, G₁₂ and G₁₃, but also has an additional functional role.⁶⁶ Activated G₁₃ stimulates p115Rho-GEF and enhances its GEF activity for the monomeric G-protein Rho.⁶⁷ Rho is involved in a variety of cellular responses, such as actin stress fiber formation, gene transcription and transformation. Of particular importance to the cardiovascular system, Rho induces hypertrophic responses in isolated cardiac myocytes,⁶⁸ and cardiac overexpression of Rho in mice results in the development of ventricular failure.⁶⁹ Because p115Rho-GEF activates (via GEF activity on Rho) and prevents activation (via GAP activity on G₁₃) of Rho, it has a unique dual role in Rho signaling that may be critical for cardiovascular function. Although no other RGS proteins have been reported to be GAPs for G₁₃, RGS16 is involved in the inhibition of G₁₃ signaling via a GAP-independent mechanism. RGS16 binds G₁₃ and translocates it to detergent-resistant membranes, presumably lipid rafts, preventing effector interaction and therefore inhibiting G₁₃ signaling.⁷⁰

	RGS Proteins and the Cardiovascular System

Top Abstract Introduction RGS Protein Structure Regulation of RGS Proteins RGS and G-Protein Selectivity RGS Proteins and the... RGS Proteins as Drug... References

 
GPCRs, and in turn, RGS proteins, are important regulators of cardiovascular signaling. Figure 1 demonstrates that the gene expression of virtually all known RGS proteins has been detected in the mammalian heart. Emerging evidence demonstrates that RGS proteins are needed for normal cardiovascular function and are altered in various cardiovascular disease states.

RGS2
Many GPCRs in the cardiovascular system responsible for vasoconstriction are coupled to G_q. More than half of the currently known RGS proteins exhibit GAP activity toward G_q and therefore have the potential to influence vascular tone. RGS2 shows some selectivity toward G_q and may be its most potent GAP.^34,71 RGS2 has emerged as a potentially critical regulator of cardiovascular function because its GAP activity for G_q antagonizes G_q-mediated vasoconstriction. Although RGS2 can regulate G_i and G_s signaling (through GAP and non-GAP mechanisms), its potent regulation of G_q^71,72 signaling appears to produce the most significant physiological effects.

Ang II is a vasoconstrictor, the effects of which are predominantly mediated through AT₁, a GPCR coupled to G_q. In cultured vascular smooth muscle cells, Ang II stimulates the gene expression of RGS2,⁷³ a response that may serve as negative feedback regulation, because RGS2 could inactivate this pathway via its GAP activity on G_q. In mice deficient for the RGS2 gene, a strong hypertensive phenotype is observed.³⁴ In anesthetized mice, this phenotype appears to be attributable exclusively to the Ang II signaling pathway because it can be reversed with an AT₁ antagonist or blockade of Ang II production with an angiotensin-converting enzyme inhibitor. Interestingly, rgs2+/– and rgs2–/– mice exhibit a similar hypertensive phenotype, demonstrating that both copies of the gene are essential for normal cardiovascular function.

RGS2 is also regulated through a GPCR-independent pathway. NO is a potent vasodilator that induces the activation of cyclic GMP–dependent protein kinases (PKGs). PKGs promote vascular relaxation through a variety of mechanisms including activation of RGS2.⁷⁴ In particular, cGMP-dependent protein kinase I- binds directly to and phosphorylates RGS2, which increases its GAP activity on G_q and results in vasodilation. In RGS2 knockout mice, this pathway is disrupted. Aortas from RGS2-deficient mice show increased vasoconstriction in vitro in response to G_q-coupled agonists and decreased relaxation in response to cyclic GMP.³⁴

RGS4
RGS4 is a key regulator of the G-protein–gated K⁺ (K_G) channels. Although it was discovered >80 years ago that acetylcholine (ACh) released from stimulation of the vagus nerve causes bradycardia,⁷⁵ it was not until the recent discovery and characterization of RGS proteins that the kinetic mechanisms behind ACh-induced heart deceleration could be explained more fully (Figure 2). K_G channels found in sino-atrial node cells decrease heart rate when activated by Gß. At a resting diastolic state (with low intracellular Ca²⁺) in the cardiac myocyte, PIP₃ binds RGS4 within its RGS domain, preventing GAP activity.^51–54 Because GAP activity is prevented, an ACh-bound M₂ mAChR causes the heterotrimeric G-protein complex to dissociate, allowing the Gß-subunit to bind and activate K_G channels, which leads to K⁺ efflux and cellular hyperpolarization.⁷⁶ On depolarization and subsequent Ca²⁺ influx, the Ca²⁺/calmodulin complex binds RGS4, relieving the PIP₃ inhibition. This allows RGS4 to accelerate the GTPase activity of the -subunit, promoting reassociation of the heterotrimeric complex and inactivation of the K_G channel. Because intracellular Ca²⁺ decreases, Ca²⁺/calmodulin dissociates from RGS4, allowing PIP₃ to again bind and inhibit RGS4. RGS proteins thus appear to speed the activation and deactivation of K_G channels.⁷⁷

View larger version (24K): [in this window] [in a new window]   Figure 2. Schematic of the role of RGS4 in KG channel activity. A, The muscarinic M2 GPCR (M2) is activated by the binding of ACh, which activates the associated G-proteins by catalyzing the exchange of GDP for GTP on the -subunit. This causes the dissociation of the ß-dimer, which binds and activates the KG channel. RGS4 is inhibited by PIP3.3,4,5 B, As calcium (Ca2+) levels rise in the cell after depolarization, the Ca2+/calmodulin complex binds RGS4 to relieve the PIP3-mediated inhibition. This allows RGS4 to exert its GAP activity on the -subunit, resulting in the hydrolysis of GTP. C, The GDP-bound -subunit promotes the reassociation of the heterotrimeric G-protein complex, leading to an inactivation of the KG channel. As intracellular Ca2+ levels decrease, Ca2+/calmodulin dissociates from RGS4, allowing PIP3 to bind and inhibit the GAP activity of RGS4.

In order for the kinetics of K_G channel activation and deactivation to approximate native conditions, RGS proteins must be present; however, it is still a subject of controversy whether physiological appropriate rates can be obtained,⁷⁸ perhaps as a consequence of assembly of different tetrameric K_G channels. Increased deactivation can be explained by RGS GAP activity promoting reassociation of the heterotrimeric G-protein complex. RGS-induced increases in channel activation are more difficult to explain with no conclusive data available thus far.

Muslin et al^79–81 have characterized an additional role for RGS4 in influencing cardiac hypertrophy. Reversible exercise-induced cardiac hypertrophy is not detrimental, whereas chronic hypertrophy is associated with cardiac arrhythmias, congestive heart failure, and death.^82–84 Initially, the overexpression of RGS4 in neonatal cardiac myocytes was observed to inhibit phenylephrine- and endothelin-1–induced hypertrophy.⁸⁰ A second study used transgenic mice overexpressing RGS4 in ventricular tissue to study cardiac physiology.⁷⁹ Overexpression of RGS4 did not affect basal cardiac function but significantly reduced the ability of the heart to adapt to an increase in cardiac afterload induced by transverse aortic constriction. Compared with littermate controls, the transgenic mice exhibited reduced ventricular hypertrophy, left ventricular dilation, depressed systolic function, and increased mortality in response to transverse aortic constriction. Thus, ventricular RGS4 overexpression appears to block beneficial compensatory hypertrophic mechanisms of the heart in response to an acute increase in cardiac afterload. Such results possibly suggest that increased cardiac RGS4 expression/activity would be unfavorable. However, a third study demonstrated favorable effects of RGS4 overexpression in mice that co-overexpress G_q.⁷⁹ Transgenic mice overexpressing G_q in the heart exhibit a phenotype similar to human cardiac hypertrophy,^85,86 but co-overexpression of RGS4 and G_q delays the G_q-mediated onset of cardiac hypertrophy.⁷⁹

GRK2
GRKs decrease ß-adrenergic receptor signaling via phosphorylation of the activated receptor and by antagonizing G-protein signaling. In addition to its kinase activity, GRK2 (also known as ßARK1) is an RGS protein that shows weak GAP activity for G_q.⁸⁷ However, GRK2-mediated inhibition of G signaling is likely attributable to its binding and sequestration of activated G instead of the weak GAP activity.⁸⁷ GRK2 activity and expression are increased in human hypertension and heart disease, including heart failure.^88–91 GRK2 inhibition can help prevent and blunt heart failure in animal models.^92,93 In addition, the RGS domain of a kinase-inactivated mutant of GRK2 decreases endothelin-1 and Ang II signaling.⁹⁴ Such data suggest that GRK2 has a dual role, perhaps in serving as a negative RGS (via its GAP activity and its sequestration of G) and in addition, as a receptor-desensitizing kinase for GPCRs. The ability of GRK2 to interact with caveolin may also contribute to its localization and actions, including its RGS activity.⁹⁵

Human Heart Failure
Although variable results have been obtained, the expression profile of RGS2, RGS3, and RGS4 are altered in failing human hearts. Mittmann et al⁹⁶ observed an increase in RGS4 mRNA but no change in RGS2 or RGS3 in such hearts, whereas Owen et al⁹⁷ found an apparent upregulation of RGS3 and RGS4 protein and mRNA in human heart failure, and Takeishi et al⁹⁸ identified an apparent decrease in RGS2 protein. These alterations in RGS expression have the potential to significantly alter cardiac physiology, as demonstrated in animal studies that show cardiovascular abnormalities in mice overexpressing RGS4⁷⁹ or deficient for RGS2.³⁴

	RGS Proteins as Drug Targets

Top Abstract Introduction RGS Protein Structure Regulation of RGS Proteins RGS and G-Protein Selectivity RGS Proteins and the... RGS Proteins as Drug... References

 
Approximately 50% of all drugs target GPCRs,^99,100 a fact that underscores the importance of GPCR signaling in the treatment of disease. However, there are many cases in which the current drugs targeted to GPCRs are inadequate. A good example is targeting of ß-adrenergic receptors. ß₂-Adrenergic receptor agonists are widely used for the treatment of bronchospasm, but these drugs can stimulate cardiac ß-adrenergic receptors as well. ß-Adrenergic receptor antagonists are commonly used for the treatment of various cardiovascular disorders. Difficulties can arise when an individual requires a ß-agonist for bronchospasm but has associated cardiovascular disease.¹⁰¹ Conversely, nonselective ß-blockers can be contraindicated in asthma and chronic obstructive pulmonary disease because of induced bronchoconstriction, and even ß₁-selective antagonists can cause problems in some patients.¹⁰² At higher doses, the selectivity of the "cardioselective" ß-blockers is lost and an increase in pulmonary side effects are seen. In the treatment of asthma, the use of ß₂-agonists leads to an increase in heart rate and is associated with an increased risk of adverse cardiovascular events.¹⁰¹ Thus, although ß-adrenergic receptors are important targets for the treatment of bronchospasm and cardiovascular disorders, treatment of one disease can precipitate dangerous side effects in the other organ system, thereby complicating therapy directed to the GPCR. RGS proteins, as potent regulators of GPCR signaling, potentially provide a new target for the regulation of GPCR signaling in such settings. A possible target could be RGS1, which shows strong mRNA expression in the lung but not the heart.¹⁰³ In addition, RGS4 is found at moderate levels in the heart but low levels in the lung.^103,104

In some reconstituted and in vitro systems, RGS proteins can exhibit GAP activity toward a variety of G-subunits. However, data in more physiological systems suggest that RGS proteins act with much more specificity. As the unique specificity profile of each RGS protein is determined, in particular in the in vivo setting, pharmacological manipulation of RGS proteins seem likely to become more enticing. Pharmacological regulation of RGS proteins could: (1) potentiate or attenuate the actions of an endogenous agonist; (2) complement a GPCR pharmacological agonist or antagonist, thereby reducing the dose needed; or 3) combat the drug-induced side effects produced by GPCR agonism or antagonism.

The mechanistic effects of pharmacological manipulation of RGS proteins can be grouped into two categories: (1) alteration of RGS activity; and 2) addition or removal of an RGS protein from a particular pathway, perhaps by altering subcellular localization. Drugs developed to alter RGS activity may be preferred to drugs that alter localization because drugs with the latter action have the potential to promote RGS protein interaction with other signaling pathways.

RGS proteins of the R4 subfamily are the most studied because of their "simple" structure. However, these "simple" proteins exert profound physiological effects and, perhaps as a consequence, are highly regulated via a variety of mechanisms. For example, RGS4 is regulated by phosphorylation, palmitoylation, PIP₃, Ca²⁺/calmodulin, G-proteins, and GPCRs. Other RGS proteins with a more complex structure would presumably be subject to an even larger number of regulatory factors. The complexity of RGS protein structure or regulation may present problems in developing drugs that selectively alter a specific pathway without influencing other pathways. However, from another perspective, the numerous methods of regulation could provide additional drug targets for the manipulation of RGS activity.

One could argue that every physiological process uses a unique subset of signaling events. The challenge in developing drugs to treat disease is in finding unique targets within a specific signaling pathway that would yield efficacy without toxicity. Drugs targeted to GPCRs have proven to be extremely important for the treatment of many diseases, in part as a consequence of unique patterns of tissue expression and accessibility on the cell surface. RGS proteins appear to offer an alternative target to alter GPCR and G-protein–mediated signaling. With a tissue distribution different from that of GPCRs, RGS proteins may prove to be useful targets. Work is already under way to develop agents that alter RGS function. Mosberg et al¹⁰⁵ have begun developing RGS4 inhibitors that could be useful in treatment of cardiovascular disorders.⁷⁹ However, RGS proteins may not prove immune to specificity problems, and accessibility of drugs to key sites on the proteins will need to be achieved. In the case of RGS4, it would be important that RGS4 activity in the brain is not altered because it may lead to schizophrenic symptoms.¹⁰⁶

The "gaps" in current understanding of the unique mechanisms by which each RGS protein alters signaling make it challenging to predict the impact that drugs targeted to RGS proteins would have on human cardiovascular physiology. However, in our view, the significance of RGS proteins in the regulation of cell signaling warrants drug discovery efforts.

	Acknowledgments

 
This work was supported by National Institutes of Health (NIH) grants HL007261 (to E.L.R.), and NIH AG16613 and NIH HL56256 (to M.B.), American Heart Association postdoctoral fellowship (to R.S.), and NIH grants NIH HL69758, HL66941, HL58120, and HL53773 (to P.A.I.).

	Footnotes

 
Original received May 23, 2003; resubmission received October 22, 2004; revised resubmission received January 13, 2005; accepted January 21, 2005.

	References

Top Abstract Introduction RGS Protein Structure Regulation of RGS Proteins RGS and G-Protein Selectivity RGS Proteins and the... RGS Proteins as Drug... References

 
1. Tang CM, Insel PA. GPCR expression in the heart; "new" receptors in myocytes and fibroblasts. Trends Cardiovasc Med. 2004; 14: 94–99.[CrossRef][Medline] [Order article via Infotrieve]

2. Cabrera-Vera TM, Vanhauwe J, Thomas TO, Medkova M, Preininger A, Mazzoni MR, Hamm HE. Insights into G-protein structure, function, and regulation. Endocr Rev. 2003; 24: 765–781.[Abstract/Free Full Text]

3. Downes GB, Gautam N. The G-protein subunit gene families. Genomics. 1999; 62: 544–552.[CrossRef][Medline] [Order article via Infotrieve]

4. Ross EM, Wilkie TM. GTPase-activating proteins for heterotrimeric G-proteins: regulators of G-protein signaling (RGS) and RGS-like proteins. Annu Rev Biochem. 2000; 69: 795–827.[CrossRef][Medline] [Order article via Infotrieve]

5. Hollinger S, Hepler JR. Cellular regulation of RGS proteins: modulators and integrators of G-protein signaling. Pharmacol Rev. 2002; 54: 527–559.[Abstract/Free Full Text]

6. Wieland T, Mittmann C. Regulators of G-protein signaling: multifunctional proteins with impact on signaling in the cardiovascular system. Pharmacol Ther. 2003; 97: 95–115.[CrossRef][Medline] [Order article via Infotrieve]

7. Liebmann C. G-protein-coupled receptors and their signaling pathways: classical therapeutical targets susceptible to novel therapeutic concepts. Curr Pharm Des. 2004; 10: 1937–1958.[CrossRef][Medline] [Order article via Infotrieve]

8. Chatterjee TK, Liu Z, Fisher RA. Human RGS6 gene structure, complex alternative splicing and role of N terminus and G-protein -subunit-like (GGL) domain in subcellular localization of RGS6 splice variants. J Biol Chem. 2003; 278: 30261–30271.[Abstract/Free Full Text]

9. Cho H, Harrison K, Schwartz O, Kehrl JH. The aorta and heart differentially express RGS (regulators of G-protein signaling) proteins that selectively regulate sphingosine 1-phosphate, angiotensin II and endothelin-1 signaling. Biochem J. 2003; 371: 973–980.[CrossRef][Medline] [Order article via Infotrieve]

10. Popov S, Yu K, Kozasa T, Wilkie TM. The regulators of G-protein signaling (RGS) domains of RGS4, RGS10, and GAIP retain GTPase activating protein activity in vitro. Proc Natl Acad Sci U S A. 1997; 94: 7216–7220.[Abstract/Free Full Text]

11. Zhang M, Wang W. Organization of signaling complexes by PDZ-domain scaffold proteins. Acc Chem Res. 2003; 36: 530–538.[CrossRef][Medline] [Order article via Infotrieve]

12. Lu Q, Sun EE, Klein RS, Flanagan JG. Eprin-B reverse signaling is mediated by a novel PDZ-RGS protein and selectively inhibits G-protein-coupled chemoattraction. Cell. 2001; 105: 69–79.[CrossRef][Medline] [Order article via Infotrieve]

13. Adams RH, Wilkinson GA, Weiss C, Diella F, Gale NW, Deutsch U, Risau W, Klein R. Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev. 1999; 13: 295–306.[Abstract/Free Full Text]

14. Snow BE, Hall RA, Krumins AM, Brothers GM, Bouchard D, Brothers CA, Chung S, Mangion J, Gilman AG, Lefkowitz RJ, Siderovski DP. GTPase activating specificity of RGS12 and binding specificity of an alternatively spliced PDZ (PSD-95/Dlg/ZO-1) domain. J Biol Chem. 1998; 273: 17749–17755.[Abstract/Free Full Text]

15. Tarzami ST, Miao W, Mani K, Lopez L, Factor SM, Berman JW, Kitsis RN. Opposing effects mediated by the chemokine receptor CXCR2 on myocardial ischemia-reperfusion injury: recruitment of potentially damaging neutrophils and direct myocardial protection. Circulation. 2003; 108: 2387–2392.[Abstract/Free Full Text]

16. Snow BE, Krumins AM, Brothers GM, Lee SF, Wall M, Chung S, Mangion J, Arya A, Gilman AG, Siderovski. A G-protein subunit-like domain shared between RGS11 and other RGS proteins specifies binding to Gß₅ subunits. Proc Natl Acad Sci U S A. 1998; 95: 13307–13312.[Abstract/Free Full Text]

17. Chen CK, Burns ME, He W, Wensel TG, Baylor DA, Simon MI. Slowed recovery of rod photoresponse in mice lacking the GTPase accelerating protein RGS9–1. Nature. 2000; 403: 557–560.[CrossRef][Medline] [Order article via Infotrieve]

18. Chen CK, Eversole-Cire P, Haikun Z, Mancino V, Chen YJ, He W, Wensel WG, Simon MI. Instability of GGL domain-containing RGS proteins in mice lacking the G-protein ß-subunit Gß5. Proc Natl Acad Sci U S A. 2003; 100: 6604–6609.[Abstract/Free Full Text]

19. Levay K, Cabrera JL, Satpaev DK, Slepak VZ. Gß5 prevents the RGS7-Go interaction through binding to a distinct G-like domain found in RGS7 and other RGS proteins. Proc Natl Acad Sci U S A. 1999; 96: 2503–2507.[Abstract/Free Full Text]

20. Zhang JH, Barr VA, Mo Y, Rojkova AM, Liu S, Simonds WF. Nuclear localization of G-protein beta 5 and regulator of G-protein signaling 7 in neurons and brain. J Biol Chem. 2001; 276: 10284–10289.[Abstract/Free Full Text]

21. De Vries L, Fischer T, Tronchere H, Brothers GM, Strockbine B, Siderovski DP, Farquhar MG. Activator of G-protein signaling 3 is a guanine dissociation inhibitor for Galpha I subunits. Proc Natl Acad Sci U S A. 2000; 97: 14364–14369.[Abstract/Free Full Text]

22. Traver S, Splingard A, Guadriault G, De Gunzberg J. The RGS (regulator of G-protein signaling) and GoLoco domains of RGS14 cooperate to regulate Gi-mediated signaling. Biochem J. 2004; 379: 627–632.[CrossRef][Medline] [Order article via Infotrieve]

23. Mittal V, Linder ME. The RGS14 GoLoco domain discriminates among G_i isoforms. J Biol Chem. 2004; 279: 46772–46778.[Abstract/Free Full Text]

24. Zheng B, Ma Y, Ostrom RS, Lavoie C, Gill GN, Insel PA, Huang X, Farquhar MG. RGS-PX1, a GAP for G_s and sorting nexin in vesicular trafficking. Science. 2001; 294: 1939–1942.[Abstract/Free Full Text]

25. Cheever ML, Sato TK, de Beer T, Kutateladze TG, Emr SD, Overduin M. Phox domain interaction with PtdIns(3)P targets the Vam7 t-SNARE to vacuole membranes. Nat Cell Biol. 2001; 3: 613–618.[CrossRef][Medline] [Order article via Infotrieve]

26. Shah BH, Catt KJ. A central role of EGF receptor transactivation in angiotensin II-induced cardiac hypertrophy. Trends Pharmacol Sci. 2003; 24: 239–244.[Medline] [Order article via Infotrieve]

27. Martemyanov KA, Lishko PV, Calero N, Keresztes G, Sokolov M, Strissel KJ, Leskov IB, Hopp JA, Kolesnikov AV, Chen CK, Lem J, Heller S, Burns ME, Arshavsky VY. The DEP domain determines subcellular targeting of the GTPase activating protein RGS9 in vivo. J Neurosci. 2003; 23: 10175–10181.[Abstract/Free Full Text]

28. Hunt RA, Edris W, Chanda PK, Niewenhuijsen B, Young KH. Snapin interacts with the N-terminus of regulator of G-protein signaling 7. Biochem Biophys Res Commun. 2003; 303: 594–599.[CrossRef][Medline] [Order article via Infotrieve]

29. Chou JL, Huang CL, Lai HL, Hung AC, Chien CL, Kao YY, Chern Y. Regulation of type VI adenylyl cyclase by Snapin, a SNAP25-binding protein. J Biol Chem. 2004; 279: 46271–46279.[Abstract/Free Full Text]

30. Ostrom RS, Violin JD, Coleman S, Insel PA. Selective enhancement of ß-adrenergic receptor signaling by overexpression of adenylyl cyclase type 6: colocalization of receptor and adenylyl cyclase in caveolae of cardiac myocytes. Mol Pharmacol. 2000; 57: 1075–1079.[Abstract/Free Full Text]

31. Taymans JM, Leysen JE, Langlois X. Striatal gene expression of RGS2 and RGS4 is specifically mediated by dopamine D1 and D2 receptors: clues for RGS2 and RGS4 functions. J Neurochem. 2003; 84: 1118–1127.[CrossRef][Medline] [Order article via Infotrieve]

32. Zmijewski JW, Song L, Harkins L, Cobbs CS, Jope RS. Second messengers regulate RGS2 expression which is targeted to the nucleus. Biochim Biophys Acta. 2001; 1541: 201–211.[Medline] [Order article via Infotrieve]

33. Calo LA, Pagnin E, Davis PA, Sartori M, Ceolotto G, Pessina AC, Semplicini A. Increased expression of regulator of G-protein signaling-2 (RGS-2) in Bartter’s/Gitelman’s syndrome. A role in the control of vascular tone and implication for hypertension. J Clin Endocrinol Metab. 2004; 89: 4153–4157.[Abstract/Free Full Text]

34. Heximer SP, Knutsen RH, Sun X, Kaltenbronn KM, Rhee MH, Peng N, Olivera-dos-Santos A, Penninger JM, Muslin AJ, Steinberg RH, Wyss JM, Mecham RP, Blumer KJ. Hypertension and prolonged vasoconstrictor signaling in RGS2-deficient mice. J Clin Invest. 2003; 111: 445–452.[CrossRef][Medline] [Order article via Infotrieve]

35. Dulin NO, Sorokin A, Reed E, Elliott S, Kehrl JH, Dunn MJ. RGS3 inhibits G-protein-mediated signaling via translocation to the membrane and binding to Galpha11. Mol Cell Biol. 1999; 19: 714–723.[Abstract/Free Full Text]

36. Burgon PG, Lee WL, Nixon AB, Peralta EG, Casey PJ. Phosphorylation and nuclear translocation of a regulator of protein signaling (RGS10). J Biol Chem. 2001; 276: 32828–32834.[Abstract/Free Full Text]

37. Roy AA, Lemberg KE, Chidiac P. Recruitment of RGS2 and RGS4 to the plasma membrane by G-proteins and receptors reflects functional interactions. Mol Pharmacol. 2003; 64: 587–593.[Abstract/Free Full Text]

38. Steinberg SF, Brunton LL. Compartmentation of G-protein-coupled signaling pathways in cardiac myocytes. Annu Rev Pharmacol Toxicol. 2001; 41: 751–773.[CrossRef][Medline] [Order article via Infotrieve]

39. Pike LJ. Lipid rafts: bringing order to chaos. J Lipid Res. 2003; 44: 655–667.[Abstract/Free Full Text]

40. Ostrom RS, Insel PA. The evolving role of lipid rafts and caveolae in G-protein-coupled receptor signaling: implications for molecular pharmacology. Br J Pharmacol. 2004; 143: 235–245.[CrossRef][Medline] [Order article via Infotrieve]

41. Hiol A, Davey PC, Osterhout JL, Waheed AA, Fischer ER, Chen CK, Milligan G, Druey KM, Jones TLZ. Palmitoylation regulates regulators of G-protein signaling (RGS) 16 function. I. Mutation of amino-terminal cysteine residue on RGS16 prevents its targeting to lipid rafts and palmitoylation of an internal cysteine residue. J Biol Chem. 2003; 278: 19301–19308.[Abstract/Free Full Text]

42. Osterhout JL, Waheed AA, Hiol A, Ward RJ, Davey PC, Nini L, Wang J, Milligan G, Jones TLZ, Druey KM. Palmitoylation regulates regulator of G-protein signaling (RGS) 16 function. II. Palmitoylatoin of a cysteine residure in the RGS box is critical for RGS16 GTPase acceleration activity and regulation of Gi-coupled signaling. J Biol Chem. 2003; 278: 19309–19316.[Abstract/Free Full Text]

43. Jones TLZ. Role of palmitoylation in RGS protein function. Methods Enzymol. 2004; 389: 33–55.[CrossRef][Medline] [Order article via Infotrieve]

44. Tu Y, Wang J, Ross EM. Inhibition of brain Gz RAP and other RGS proteins by palmitoylation of G-protein subunits. Science. 1997; 278: 1132–1135.[Abstract/Free Full Text]

45. Wang J, Ducret A, Tu Y, Kozasa T, Aebersold R, Ross EM. RGSZ1, a Gz-selective RGS protein in brain. J Biol Chem. 1998; 273: 26104–26025.

46. Glick JL, Meigs TE, Mron A, Casey PJ. RGSZ1, a Gz-selective regulator of G-protein signaling whose action is sensitive to the phosphorylation state of Gzalpha. J Biol Chem. 1998; 273: 26008–26013.[Abstract/Free Full Text]

47. Yaffe MB. How do 14–3-3 proteins work? Gatekeeper phosphorylation and the molecular anvil hypothesis. FEBS Lett. 2002; 513: 53–57.[CrossRef][Medline] [Order article via Infotrieve]

48. Benzing T, Yaffe MB, Arnould T, Sellin L, Schermer B, Schilling B, Schreiber R, Kunzelmann K, Leparc GG, Kim E, Walz G. 14–3-3 interacts with regulator of G-protein signaling proteins and modulates their activity. J Biol Chem. 2000; 275: 28167–28172.[Abstract/Free Full Text]

49. Benzing T, Kottgen M, Johnson M, Schermer B, Zentgraf H, Walz G, Kim E. Interaction of 14–3-3 protein with regulator of G-protein signaling 7 is dynamically regulated by tumor necrosis factor-alpha. J Biol Chem. 2002; 277: 32954–32962.[Abstract/Free Full Text]

50. Niu J, Scheschonka A, Druey KM, Davis A, Reed E, Kolenko V, Bodnar R, Voyno-Yasenetskaya T, Du X, Kehrl J, Dulin NO. RGS3 interacts with 14–3-3 via the N-terminal region distinct from the RGS (regulator of G-protein signaling) domain. Biochem J. 2002; 365: 677–684.[Medline] [Order article via Infotrieve]

51. Popov SG, Murali Krishna U, Falck JR, Wilkie TM. Ca2+/Calmodulin reverses phosphatidylinositol 3,4,5-triphosphate-dependent inhibition of regulators of G-protein-signaling GTPase-activating protein activity. J Biol Chem. 2000; 275: 18962–18968.[Abstract/Free Full Text]

52. Ishii M, Inanobe A, Kurachi Y. PIP3 inhibition of RGS protein and its reversal by Ca2+/calmodulin mediate voltage-dependent control or the G-protein cycle in cardiac K+ channel. Proc Natl Acad Sci U S A. 2002; 99: 4325–4330.[Abstract/Free Full Text]

53. Ishii M, Fujita S, Yamada M, Hosaka Y, Kurachi Y. Phosphatidylinositol 3,4,5-trisphosphate and Ca2+/calmodulin competitively bind to the regulators of G-protein-signaling (RGS) domain of RGS4 and reciprocally regulate its action. Biochem J. 2005; 385: 65–73.[CrossRef][Medline] [Order article via Infotrieve]

54. Ishii M, Kurachi Y. Assays of RGS protein modulation by phosphatidyinositides and calmodulin. Methods Enzymol. 2004; 389: 105–118.[Medline] [Order article via Infotrieve]

55. Tu Y, Wilkie TM. Allosteric regulation of GAP activity by phospholipids in regulators of G-protein signaling. Methods Enzymol. 2004; 389: 89–105.[Medline] [Order article via Infotrieve]

56. Wang Q, Liu M, Mullah B, Siderovski DP, Neubig RR. Receptor-selective effects of endogenous RGS3 and RGS5 to regulate mitogen-activated protein kinase activation in rat vascular smooth muscle cells. J Biol Chem. 2002; 277: 24949–24958.[Abstract/Free Full Text]

57. Bernstein LS, Ramineni S, Hague C, Cladman W, Chidiac P, Levey AI, Hepler JR. RGS2 binds directly and selectively to the M1 muscarinic acetylcholine receptor third intracellular loop to modulate Gq/11alpha signaling. J Biol Chem. 2004; 279: 21248–21256.[Abstract/Free Full Text]

58. De Vries L, Mousli M, Wurmser A, Farquhar MG. GAIP, a protein that specifically interacts with the trimeric G-protein G alpha i3, is a member of a protein family with a highly conserved core domain. Proc Natl Acad Sci U S A. 1995; 92: 11916–11920.[Abstract/Free Full Text]

59. Woulfe DS, Stadel JM. Structural basis for the selectivity of the RGS protein, GAIP, for Galphai family members. Identification of a single amino acid determinant for selective interaction of Galphai subunits with GAIP. J Biol Chem. 1999; 274: 17718–17724.[Abstract/Free Full Text]

60. Cavalli A, Druey KM, Milligan G. The regulator of G-protein signaling RGS4 selectively enhances _2A-adrenoceptor stimulation of the GTPase activity of G_o1 and G_i2a. J Biol Chem. 2000; 275: 23693–23699.[Abstract/Free Full Text]

61. Day PW, Carman CV, Sterne-Marr R, Benovic JL, Wedegaertner PB. Differential interaction of GRK2 with members of the G_q family. Biochemistry. 2003; 42: 9176–9184.[CrossRef][Medline] [Order article via Infotrieve]

62. Chatterjee RK, Eapen AK, Fisher RA. A truncated form of RGS3 negatively regulates G-protein-coupled receptor stimulation of adenylyl cyclase and phosphoinositide phospholipase C. J Biol Chem. 1997; 272: 15481–15487.[Abstract/Free Full Text]

63. Tseng CC, Zhang XY. Role of regulator of G-proteins signaling in desensitization of the glucose-dependent insulinotropic peptide receptor. Endocrinology. 1998; 139: 4470–4475.[Abstract/Free Full Text]

64. Sinnarajah S, Dessauer CW, Srikumar D, Chen J, Yuen J, Yilma S, Dennis JC, Morrison EE, Vodyanoy V, Kehrl JH. RGS2 regulates signal transduction in olfactory neurons by attenuating activation of adenylyl cyclase III. Nature. 2001; 409: 1051–1055.[CrossRef][Medline] [Order article via Infotrieve]

65. Salim S, Sinnarajah S, Kehrl JH, Dessauer CW. Identification of RGS2 and type V adenylyl cyclase interaction sites. J Biol Chem. 2003; 278: 15842–15849.[Abstract/Free Full Text]

66. Kozasa T, Jiang X, Hart MJ, Sternweis PM, Singer WD, Gilman AG, Bollag G, Sternweis PC. p115 RhoGEF, a GTPase activating protein for Galpha12 and Galpha13. Science. 1998; 280: 2109–2111.[Abstract/Free Full Text]

67. Hart MJ, Jiang X, Tohru K, Roscoe W, Singer WD, Gilman AG, Sternweis PC, Bollag G. Direct stimulation of the guanine nucleotide exchange activity of p115 RhoGEF by G₁₃. Science. 1998; 280: 2112–2114.[Abstract/Free Full Text]

68. Hoshijima M, Sah VP, Wang Y, Chien KR, Brown JH. The low molecular weight GTPase Rho regulates myofibril formation and organization in neonatal rat ventricular myocytes. J Biol Chem. 1998; 273: 7725–7730.[Abstract/Free Full Text]

69. Sah VO, Minamisawa S, Tam SP, Wu TH, Dorn GW II. Ross J Jr, Chien KR, Brown JH. Cardiac-specific overexpression of RhoA results in sinus and atriobentricular nodal dysfunction and contractile failure. J Clin Invest. 1999; 103: 1627–1634.[Medline] [Order article via Infotrieve]

70. Johnson EN, Seasholtz TM, Waheed AA, Kreutz B, Suzuki N, Kozasa T, Jones TLZ, Brown JH, Druey KM. RGS16 inhibits signaling through the G₁₃-Rho axis. Nat Cell Biol. 2003; 5: 1095–1103.[CrossRef][Medline] [Order article via Infotrieve]

71. Heximer SP, Srinivasa SP, Bernstein LS, Bernard JL, Linder ME, Helper JR, and Blumer KJ. G-protein selectivity is a determinant of RGS2 function. J Biol Chem. 1999; 274: 34253–34259.[Abstract/Free Full Text]

72. Heximer SP, Watson N, Linder ME, Blumer KJ, Helper JR. RGS2/GOS8 is a selective inhibitor of Gqalpha function. Proc Natl Acad Sci U S A. 1997; 94: 14389–14393.[Abstract/Free Full Text]

73. Grant SL, Lassegue B, Griendling KK, Ushio-Fukai M, Lyons PR, Alexander RW. Specific regulation of RGS2 messenger RNA by angiotensin II in cultured vascular smooth muscle cells. Mol Pharmacol. 2000; 57: 460–467.[Abstract/Free Full Text]

74. Tang MK, Wang GR, Lu P, Karas RH, Aronovitz M, Heximer SP, Kaltenbronn KM, Blumer KJ, Siderovski DP, Zhu Y, Mendelsohn ME. Regulator of G-protein signaling-2 mediates vascular smooth muscle relaxation and blood pressure. Nat Med. 2003; 9: 1506–1512.[CrossRef][Medline] [Order article via Infotrieve]

75. Loewi O. Über humorale Übertragbarkeit der Herznervenwirking. Pflügers Arch. 1921; 189: 239–242.[CrossRef]

76. Logothetis DE, Kurachi Y, Galper J, Neer EJ, Clapham DE. The ß subunit of GTP-binding proteins activate the muscarinic K⁺ channel in heart. Nature. 1987; 325: 321–326.[CrossRef][Medline] [Order article via Infotrieve]

77. Doupnik CA, Davidson N, Lester LA, Kofuji P. RGS proteins reconstitute the rapid gating kinetics of Gß-activated inwardly rectifying K⁺ channels. Proc Natl Acad Sci U S A. 1997; 94: 10461–10466.[Abstract/Free Full Text]

78. Kurachi Y, Ishii M. Cell signal control of the G-protein-gated potassium channel and its subcellular localization. J Physiol. 2004; 554: 285–294.[Abstract/Free Full Text]

79. Rogers JH, Tamirisa P, Kovacs A, Weinheimer C, Courtois M, Blumer KJ, Kelly DP, Muslin AJ. RGS4 causes increased mortality and reduced cardiac hypertrophy in response to pressure overload. J Clin Invest. 1999; 104: 567–576.[Medline] [Order article via Infotrieve]

80. Tamirisa P, Blumer KJ, Muslin AJ. RGS4 inhibits G-protein signaling in cardiomyocytes. Circulation. 1999; 99: 441–447.[Abstract/Free Full Text]

81. Rogers JH, Tsirka A, Kovacs A, Blumer KJ, Dorn GW II, Muslin AJ. RGS4 reduces contractile dysfunction and hypertrophic gene induction in G_q overexpressing mice. J Mol Cell Cardiol. 2001; 33: 209–218.[CrossRef][Medline] [Order article via Infotrieve]

82. Messerli FH, Soria F. Ventricular dysrhythmias, left ventricular hypertrophy, and sudden death. Cardiovasc Drugs Ther. 1994; Suppl3: 557–563.

83. Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP. Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med. 1990; 322: 1561–1566.[Abstract]

84. Shephard RJ. The athlete’s heart: is big beautiful. Br J Sports Med. 1996; 30: 5–10.[Abstract/Free Full Text]

85. D’Angelo DD, Sakata Y, Lorenz JN, Boivin GP, Walsh RA, Liggett SB, Dorn GW II. Transgenic Galphaq overexpression induces cardiac contractile failure in mice. Proc Natl Acad Sci U S A. 1997; 94: 8121–8126.[Abstract/Free Full Text]

86. Adams JW, Sakata Y, Davis MG, Sah VP, Wang Y, Liggett SB, Chien KR, Brown JH, Dorn GW II. Enhanced Galphaq signaling: a common pathway mediates cardiac hypertrophy and apoptotic heart failure. Proc Natl Acad Sci U S A. 1998; 95: 10140–10145.[Abstract/Free Full Text]

87. Carman CV, Parent JL, Day PW, Pronin AN, Sternweis PM, Wedegaertner PB, Gilman AG, Benovic JL, Kozasa T. Selective regulation of Galpha(q/11) by an RGS domain in the G-protein-coupled receptor kinase, GRK2. J Biol Chem. 1999; 274: 34483–34492.[Abstract/Free Full Text]

88. Gros R, Benovic JL, Tan M, Feldman RD. G-protein-coupled receptor kinase activity is increased in hypertension. J Clin Invest. 1997; 99: 2087–2093.[Medline] [Order article via Infotrieve]

89. Ungerer M, Bohm M, Elce JS, Erdmann E, Lohse ML. Altered expression of ß-adrenergic receptor kinase and the ß₁-adrenergic receptors in the failing heart. Circulation. 1993; 87: 454–463.[Abstract/Free Full Text]

90. Ungerer M, Parruti G, Bohm M, Puzicha M, DeBlasi A, Erdmann E, Lohse MJ. Expression of ß-arrestins and ß-adrenergic receptor kinases in the failing heart. Circ Res. 1994; 74: 206–213.[Abstract/Free Full Text]

91. Dzimiri N, Muiya P, Andres E, Al-Halees Z. Differential functional expression of human myocardial G-protein receptor kinases in left ventricular cardiac diseases. Eur J Pharmacol. 2004; 489: 167–177.[CrossRef][Medline] [Order article via Infotrieve]

92. Harding V, Jones L, Lefkowitz RJ, Koch WJ, Rockman HA. Cardiac ßARK1 inhibition prolongs survival and augments ß blocker therapy in a mouse model of severe heart failure. Proc Natl Acad Sci U S A. 2001; 98: 5809–5814.[Abstract/Free Full Text]

93. Rockman HA, Chien KR, Choi D-J, Iaccarino G, Hunter JJ, Ross J Jr, Lefkowitz RJ, Koch WJ. Expression of a ß-adrenergic receptor kinase 1 inhibitor prevents the development of heart failure in gene targeted mice. Proc Natl Acad Sci U S A. 1998; 95: 7000–7005.[Abstract/Free Full Text]

94. Usui H, Nishiyama M, Moroi K, Shibasaki T, Zhou J, Ishida J, Fukamizu A, Haga T, Sekiya S, Kimura S. RGS domain in the amino-terminus of G-protein-coupled receptor kinase 2 inhibits Gq mediated signaling. Int J Mol Med. 2000; 5: 335–340.[Medline] [Order article via Infotrieve]

95. Carman CV, Lisanti MP, Benovic JL. Regulation of G-protein-coupled receptor kinases by caveolin. J Biol Chem. 1999; 274: 8858–8864.[Abstract/Free Full Text]

96. Mittmann C, Chung CH, Hoppner G, Michalek C, Nose M, Schuler C, Schuh A, Eschenhagen T, Weil J, Pieske B, Hirt S, Weiland T. Expression of ten RGS proteins in human myocardium: functional characterization of an upregulation of RGS4 in heart failure. Cardiovasc Res. 2002; 55: 778–786.[Abstract/Free Full Text]

97. Owen VJ, Burton PBJ. Mullen AJ, Birks EJ, Barton P, Yacoub MH. Expression of RGS3, RGS4 and Gi alpha 2 in acutely failing donor hearts and end-stage heart failure. Eur Heart J. 2001; 22: 1015–1020.[Abstract/Free Full Text]

98. Takeishi Y, Jalili T, Hoit BD, Kirkpatrick DL, Wagoner LE, Abraham WT, Walsh RA. Alterations in Ca²⁺ cycling proteins and Gq signaling after left ventricular assist device support in failing human hearts. Cardiovasc Res. 2000; 45: 883–888.[Abstract/Free Full Text]

99. Gudermann T, Nurnberg B, Schultz G. Receptors and G-proteins as primary components of transmembrane signal transduction. Part 1. G-protein-coupled receptors: structure and function. J Mol Med. 1995; 73: 51–63.[CrossRef][Medline] [Order article via Infotrieve]

100. Johnson JA, Lima JJ. Drug receptor/effector polymorphisms and pharmacogenetics: current status and challenges. Pharmacogenetics. 2003; 13: 525–534.[CrossRef][Medline] [Order article via Infotrieve]

101. Salpeter SR. Cardiovascular safety of ß2-adrenoceptor agonist use in patients with obstructive airway disease: a systematic review. Drugs Aging. 2004; 21: 405–414.[CrossRef][Medline] [Order article via Infotrieve]

102. Self T, Soberman JE, Bubla JM, Chafin CC. Cardioselective beta-blockers in patients with asthma and concomitant heart failure or history of myocardial infarction: when do benefits outweigh risks? J Asthma. 2003; 40: 839–845.[CrossRef][Medline] [Order article via Infotrieve]

103. Larminie C, Murdock P, Walhin JP, Duckworth M, Blumer KJ, Scheideler MA, Garnier M. Selective expression of regulators of G-protein signaling (RGS) in the human central nervous system. Brain Res Mol Brain Res. 2004; 122: 24–34.[Medline] [Order article via Infotrieve]

104. Nomoto S, Adachi K, Yang LX, Hirata Y, Muraguchi S, Kiuchi K. Distribution of RGS4 mRNA in mouse brain shown by in situ hybridization. Biochem Biophys Res Commun. 1997; 241: 281–287.[CrossRef][Medline] [Order article via Infotrieve]

105. Jin Y, Zhong H, Omnaas JR, Neubig RR, Mosberg HI. Structure-based design, synthesis, and pharmacologic evaluation of peptide RGS4 inhibitors. J Pept Res. 2004; 63: 141–146.[CrossRef][Medline] [Order article via Infotrieve]

106. Mirnics K, Middleton FA, Stanwood GD, Lewis DA, Levitt P. Disease-specific changes in regulator of G-protein signaling 4 (RGS4) expression in schizophrenia. Mol Psychiatry. 2001; 6: 293–301.[CrossRef][Medline] [Order article via Infotrieve]

107. Cunningham ML, Waldo GL, Hollinger S, Helper JR, Harden TK. Protein kinase C phosphorylates RGS2 and modulates its capacity for negative regulation of Galpha 11 signaling. J Biol Chem. 2001; 276: 5438–5444.[Abstract/Free Full Text]

108. Pedram A, Razandi M, Kehrl J, Levin ER. Natriuretic peptides inhibit G-protein activation. Mediation through cross-talk between cyclic GMP-dependent protein kinase and regulators of G-protein-signaling proteins. J Biol Chem. 2000; 275: 7365–7372.[Abstract/Free Full Text]

109. Balasubramanian N, Levay K, Keren-Raifman T, Faurobert E, Slepak VZ. Phosphorylation of regulator of G-protein signaling RGS9–1 by protein kinase A is a potential mechanism of light- and Ca2+-mediated regulation of G-protein function in photoreceptors. Biochemistry. 2001; 40: 12619–12627.[CrossRef][Medline] [Order article via Infotrieve]

110. Sokal I, Hu G, Liang Y, Mao M, Wensel TG, Palczewski. Identification of protein kinase C isozymes responsible for the phosphorylation of photoreceptor-specific RGS9–1 at Ser475. J Biol Chem. 2003; 278: 8316–8325.[Abstract/Free Full Text]

111. Hollinger S, Ramineni S, Helper JR. Phosphorylation of RGS14 by protein kinase A potentiates its activity toward Gi. Biochemistry. 2003; 42: 811–819.[CrossRef][Medline] [Order article via Infotrieve]

112. Derrien A, Zheng B, Osterhout JL, Ma YC, Milligan G, Farquhar MG, Druey KM. Src-mediated RGS16 tyrosine phosphorylation promotes RGS16 stability. J Biol Chem. 2003; 278: 16107–16116.[Abstract/Free Full Text]

113. Chen C, Wang H, Fong CW, Lin SC. Multiple phosphorylation sites in RGS16 differentially modulate its GAP activity. FEBS Lett. 2001; 504: 16–22.[CrossRef][Medline] [Order article via Infotrieve]

114. Derrien A, Druey KM. RGS16 function is regulated by epidermal growth factor receptor-mediated tyrosine phosphorylation. J Biol Chem. 2001; 276: 48532–48538.[Abstract/Free Full Text]

115. Garcia A, Prabhakar S, Hughan S, Anderson TW, Brock CJ, Pearce AC, Dwek RA, Watson SP, Hebestreit HF, Zitzmann N. Differential proteome analysis of TRAP-activated platelets: involvement of DOK-2 and phosphorylation of RGS proteins. Blood. 2004; 103: 2088–2095.[Abstract/Free Full Text]

116. Ogier-Denis E, Pattingre S, El Benna J, Codogno P. Erk1/2-dependent phosphorylation of Galpha-interacting protein stimulates its GTPase accelerating activity and autophagy in human colon cancer cells. J Biol Chem. 2000; 275: 39090–39095.[Abstract/Free Full Text]

117. Castro-Fernandez C, Janovick JA, Brothers SP, Fisher RA, Ji TH, Conn PM. Regulation of RGS3 and RGS10 palmitoylation by GnRH. Endocrinology. 2002; 143: 1310–1317.[Abstract/Free Full Text]

118. Srinivasa SP, Bernstein LS, Blumer KJ, Linder ME. Plasma membrane localization is required for RGS4 function in Saccharomyces cerevisiae. Proc Natl Acad Sci U S A. 1998; 95: 5584–5589.[Abstract/Free Full Text]

119. Tu Y, Popov S, Slaughter C, Ross EM. Palmitoylation of a conserved cysteine in the regulator of G-protein signaling (RGS) domain modulates the GTPase-activating activity of RGS4 and RGS10. J Biol Chem. 1999; 274: 38260–38267.[Abstract/Free Full Text]

120. Rose JJ, Taylor JB, Shi J, Cockett MI, Jones JG, Hepler JR. RGS7 is palmitoylated and exists as biochemically distinct forms. J Neurochem. 2000; 75: 2103–2122.[CrossRef][Medline] [Order article via Infotrieve]

121. Takida S, Fischer CC, Wedegaertner PB. Palmitoylation and plasma membrane targeting of RGS7 are promoted by alpha o. Mol Pharmacol. 2005; 67: 132–139.[Abstract/Free Full Text]

122. Druey KM, Ugur O, Caron JM, Chen CK, Backlund PS, Jones TLZ. Amino-terminal cysteine residues of RGS16 are required for palmitoylation and modulation of G_i- and G_q-mediated signaling. J Biol Chem. 1999; 274: 18836–18842.[Abstract/Free Full Text]

123. De Vries L, Elenko E, Hubler L, Jones TLZ, Farquhar MG. GAIP is membrane-anchored by palmitoylation and interacts with the activated (GTP-bound) form of G_I subunits. Proc Natl Acad Sci U S A. 1996; 93: 15203–15208.[Abstract/Free Full Text]

124. Neill JD, Duck LW, Sellers JC, Musgrove LC, Scheschonka A, Druey KM, Kehrl JH. Potential role for a regulator of G-protein signaling (RGS3) in gonadotropin-releasing hormone (GnRH) stimulated desensitization. Endocrinology. 1997; 138: 843–846.[Abstract/Free Full Text]

125. Xu X, Zeng W, Popov S, Berman DM, Davignon I, Yu K, Yowe D, Offermanns S, Muallem S, Wilkie TM. RGS proteins determine signaling spedificity of G_q-coupled receptors. J Biol Chem. 1999; 274: 3549–3556.[Abstract/Free Full Text]

This article has been cited by other articles:

				L. K. K. Pacey, S. P. Heximer, and D. R. Hampson Increased GABAB Receptor-Mediated Signaling Reduces the Susceptibility of Fragile X Knockout Mice to Audiogenic Seizures Mol. Pharmacol., July 1, 2009; 76(1): 18 - 24. [Abstract] [Full Text] [PDF]

				W. Hu, F. Li, S. Mahavadi, and K. S. Murthy Upregulation of RGS4 expression by IL-1{beta} in colonic smooth muscle is enhanced by ERK1/2 and p38 MAPK and inhibited by the PI3K/Akt/GSK3{beta} pathway Am J Physiol Cell Physiol, June 1, 2009; 296(6): C1310 - C1320. [Abstract] [Full Text] [PDF]

				M. Lelonek, T. Pietrucha, M. Matyjaszczyk, and J. H. Goch A novel approach to syncopal patients: association analysis of polymorphisms in G-protein genes and tilt outcome Europace, January 1, 2009; 11(1): 89 - 93. [Abstract] [Full Text] [PDF]

				I. Iankova, C. Chavey, C. Clape, C. Colomer, N. C. Guerineau, N. Grillet, J.-F. Brunet, J.-S. Annicotte, and L. Fajas Regulator of G Protein Signaling-4 Controls Fatty Acid and Glucose Homeostasis Endocrinology, November 1, 2008; 149(11): 5706 - 5712. [Abstract] [Full Text] [PDF]

				T. Tokudome, I. Kishimoto, T. Horio, Y. Arai, D. O. Schwenke, J. Hino, I. Okano, Y. Kawano, M. Kohno, M. Miyazato, et al. Regulator of G-Protein Signaling Subtype 4 Mediates Antihypertrophic Effect of Locally Secreted Natriuretic Peptides in the Heart Circulation, May 6, 2008; 117(18): 2329 - 2339. [Abstract] [Full Text] [PDF]

				K. V. Chowdari, M. Bamne, J. Wood, M. E. Talkowski, K. Mirnics, P. Levitt, D. A. Lewis, and V. L. Nimgaonkar Linkage Disequilibrium Patterns and Functional Analysis of RGS4 Polymorphisms in Relation to Schizophrenia Schizophr Bull, January 1, 2008; 34(1): 118 - 126. [Abstract] [Full Text] [PDF]

				X. Huang, R. A. Charbeneau, Y. Fu, K. Kaur, I. Gerin, O. A. MacDougald, and R. R. Neubig Resistance to Diet-Induced Obesity and Improved Insulin Sensitivity in Mice With a Regulator of G Protein Signaling Insensitive G184S Gnai2 Allele Diabetes, January 1, 2008; 57(1): 77 - 85. [Abstract] [Full Text] [PDF]

				N. Makita, J. Sato, P. Rondard, H. Fukamachi, Y. Yuasa, M. A. Aldred, M. Hashimoto, T. Fujita, and T. Iiri Human Gs{alpha} mutant causes pseudohypoparathyroidism type Ia/neonatal diarrhea, a potential cell-specific role of the palmitoylation cycle PNAS, October 30, 2007; 104(44): 17424 - 17429. [Abstract] [Full Text] [PDF]

				D. G Romero, M. Y. Zhou, L. L Yanes, M. W Plonczynski, T. R Washington, C. E Gomez-Sanchez, and E. P Gomez-Sanchez Regulators of G-protein signaling 4 in adrenal gland: localization, regulation, and role in aldosterone secretion J. Endocrinol., August 1, 2007; 194(2): 429 - 440. [Abstract] [Full Text] [PDF]

				S. Engelhardt and F. Rochais G Proteins: More Than Transducers of Receptor-Generated Signals? Circ. Res., April 27, 2007; 100(8): 1109 - 1111. [Full Text] [PDF]

				G. Fejes-Toth and A. Naray-Fejes-Toth Early Aldosterone-Regulated Genes in Cardiomyocytes: Clues to Cardiac Remodeling? Endocrinology, April 1, 2007; 148(4): 1502 - 1510. [Abstract] [Full Text] [PDF]

				D. L. Roman, J. N. Talbot, R. A. Roof, R. K. Sunahara, J. R. Traynor, and R. R. Neubig Identification of Small-Molecule Inhibitors of RGS4 Using a High-Throughput Flow Cytometry Protein Interaction Assay Mol. Pharmacol., January 1, 2007; 71(1): 169 - 175. [Abstract] [Full Text] [PDF]

				Y. Wang and H. G. Dohlman Regulation of G Protein and Mitogen-Activated Protein Kinase Signaling by Ubiquitination: Insights From Model Organisms Circ. Res., December 8, 2006; 99(12): 1305 - 1314. [Abstract] [Full Text] [PDF]

				M. E Talkowski, K. Chowdari, D. A Lewis, and V. L Nimgaonkar Can RGS4 Polymorphisms Be Viewed as Credible Risk Factors for Schizophrenia? A Critical Review of the Evidence Schizophr Bull, April 1, 2006; 32(2): 203 - 208. [Abstract] [Full Text] [PDF]

				T. Wieland and S. Herzig Specificity and Diversity in Gi/o-Mediated Signaling: How the Heart Operates the RGS Brake Pedal Circ. Res., March 17, 2006; 98(5): 585 - 586. [Full Text] [PDF]

				Y. Fu, X. Huang, H. Zhong, R. M. Mortensen, L. G. D'Alecy, and R. R. Neubig Endogenous RGS Proteins and G{alpha} Subtypes Differentially Control Muscarinic and Adenosine-Mediated Chronotropic Effects Circ. Res., March 17, 2006; 98(5): 659 - 666. [Abstract] [Full Text] [PDF]

				W. Zhang, T. Anger, J. Su, J. Hao, X. Xu, M. Zhu, A. Gach, L. Cui, R. Liao, and U. Mende Selective Loss of Fine Tuning of Gq/11 Signaling by RGS2 Protein Exacerbates Cardiomyocyte Hypertrophy J. Biol. Chem., March 3, 2006; 281(9): 5811 - 5820. [Abstract] [Full Text] [PDF]

				E. L. Riddle, B. K. Rana, K. K. Murthy, F. Rao, E. Eskin, D. T. O'Connor, and P. A. Insel Polymorphisms and Haplotypes of the Regulator of G Protein Signaling-2 Gene in Normotensives and Hypertensives Hypertension, March 1, 2006; 47(3): 415 - 420. [Abstract] [Full Text] [PDF]

				R. J. Ward and G. Milligan A Key Serine for the GTPase-Activating Protein Function of Regulator of G Protein Signaling Proteins Is Not a General Target for 14-3-3 Interactions Mol. Pharmacol., December 1, 2005; 68(6): 1821 - 1830. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Riddle, E. L. Articles by Insel, P. A. Search for Related Content PubMed PubMed Citation Articles by Riddle, E. L. Articles by Insel, P. A. Related Collections Cardiovascular Pharmacology Cell signalling/signal transduction Heart failure - basic studies Hypertension - basic studies Receptor pharmacology