Multi-Tasking RGS Proteins in the Heart

Riddle, Evan L.; Schwartzman, R.; Bond, Meredith; Insel, Paul A.

doi:10.1161/01.res.0000158287.49872.4e

Cited by 112 publications

(94 citation statements)

References 128 publications

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“…The interesting question of whether depalmitoylation may possibly be another example of a signal-desensitization mechanism working at the G protein level remains to be addressed. However, if this notion proves to be correct, the palmitoylation cycle itself would become a desirable target for the development of novel treatments against human diseases resulting from abnormal signal desensitization, including chronic heart failure (40,41) and hypertension (1,42,43).…”

Section: Discussionmentioning

confidence: 99%

Human G _sα mutant causes pseudohypoparathyroidism type Ia/neonatal diarrhea, a potential cell-specific role of the palmitoylation cycle

Makita

Sato

Rondard

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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Pseudohypoparathyroidism type Ia (PHP-Ia) results from the loss of one allele of G s␣, causing resistance to parathyroid hormone and other hormones that transduce signals via G s. Most Gs␣mutations cause the complete loss of protein expression, but some cause loss of function only, and these have provided valuable insights into the normal function of G proteins. Here we have analyzed a mutant G s␣ (␣s-AVDT) harboring AVDT amino acid repeats within its GDP/GTP binding site, which was identified in unique patients with PHP-Ia accompanied by neonatal diarrhea. Biochemical and intact cell analyses showed that ␣s-AVDT is unstable but constitutively active as a result of rapid GDP release and reduced GTP hydrolysis. This instability underlies the PHP-Ia phenotype. ␣s-AVDT is predominantly localized in the cytosol, but in rat and mouse small intestine epithelial cells (IEC-6 and DIF-12 cells) ␣s-AVDT was found to be localized predominantly in the membrane where adenylyl cyclase is present and constitutive increases in cAMP accumulation occur in parallel. The likely cause of this membrane localization is the inhibition of an activation-dependent decrease in ␣s palmitoylation. Upon the overexpression of acyl-protein thioesterase 1, however, ␣s-AVDT translocates from the membrane to the cytosol, and the constitutive accumulation of cAMP becomes attenuated. These results suggest that PHP-Ia results from the instability of ␣s-AVDT and that the accompanying neonatal diarrhea may result from its enhanced constitutive activity in the intestine. Hence, palmitoylation may control the activity and localization of G s␣ in a cell-specific manner.disease ͉ G protein ͉ lipid modification ͉ localization ͉ activity G protein diseases have revealed key pathways underlying physiologic regulation and the molecular mechanisms involved. Pseudohypoparathyroidism type Ia (PHP-Ia) is a classic example of such a disease and results from the heterozygous loss of function of G s␣ (1-4). In most cases, the loss of G s␣ function results from a loss of protein expression due to insertions, deletions, frameshift deletions, nonsense mutations, and splice junction mutations. In some cases, however, PHP-Ia occurs in the presence of G s␣ protein expression, and analyses of the corresponding mutations have greatly furthered our understanding of how G proteins function normally (5).The activity of G s␣ is cyclically regulated via two unidirectional steps, a GDP/GTP exchange and the hydrolysis of GTP (5-8). The agonist-occupied receptor accelerates GDP release from the ␣␤␥ trimer, which allows GTP to bind to the empty guanine nucleotide pocket of G ␣ and thus induce a conformational change that enables its dissociation from the receptor and ␤␥ subunit. The GTP-bound G ␣ and ␤␥ dimer transmit a signal until GTP is hydrolyzed, which then allows the GDP-bound G ␣ to bind and inactivate G ␤␥ .The defects resulting from G s␣ mutations that do not prevent protein expression but nevertheless result in the onset of PHP-Ia have now been elucidated at the molecular l...

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Section: Discussionmentioning

confidence: 99%

Human G _sα mutant causes pseudohypoparathyroidism type Ia/neonatal diarrhea, a potential cell-specific role of the palmitoylation cycle

Makita

Sato

Rondard

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

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“…In the past two decades, RGS proteins have received increasing interest as potential drug targets in numerous therapeutic areas, including cardiovascular disease, multiple CNS disorders and several types of cancer (Mittmann et al, 2002;Riddle et al, 2005;Hurst and Hooks, 2009;Sjögren et al, 2010). While GPCR signalling has been a major focus in drug development, traditional GPCR agonists and antagonists are often associated with side effects due to widespread expression of many receptors and lack of receptor selectivity of drugs.…”

Section: Why Target Rgs Proteins In Drug Discovery?mentioning

confidence: 99%

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

Sjögren

2017

British J Pharmacology

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Regulators of G protein signalling (RGS) proteins are celebrating the 20th anniversary of their discovery. The unveiling of this new family of negative regulators of G protein signalling in the mid-1990s solved a persistent conundrum in the G protein signalling field, in which the rate of deactivation of signalling cascades in vivo could not be replicated in exogenous systems. Since then, there has been tremendous advancement in the knowledge of RGS protein structure, function, regulation and their role as novel drug targets. RGS proteins play an important modulatory role through their GTPase-activating protein (GAP) activity at active, GTP-bound Gα subunits of heterotrimeric G proteins. They also possess many non-canonical functions not related to G protein signalling. Here, an update on the status of RGS proteins as drug targets is provided, highlighting advances that have led to the inclusion of RGS proteins in the IUPHAR/BPS Guide to PHARMACOLOGY database of drug targets.Abbreviations DEP, Disheveled Egl-10 Pleckstrin; GAP, GTPase-activating protein; GGL, G protein γ-like; PPI, protein-protein interaction; RGS, regulator of G protein signalling; R7BP, R7 binding protein; R9AP, RGS9 associated protein IntroductionG protein-mediated signalling pathways have played a pivotal role in drug discovery and development for many decades. The large family of GPCRs or their downstream effectors are the target of 40% of clinically used drugs and thus represent a multi-billion-dollar industry (Wise et al., 2002). Interestingly, of the more than 300 non-olfactory GPCRs known, only a fraction of them are targeted by drugs. Thus, there is a large untapped area of drug development still available. Moreover, many GPCR drugs are associated with low efficacy and/or side effects. More targeted therapies are therefore required, and as we learn more about the structure and function of GPCRs and their regulators, these goals will be achievable.All biological signals are tightly regulated and for every on-switch there is usually an off-switch. GPCRs are activated by ligands, transmitting signalling information to Gα subunits of heterotrimeric G proteins by enhancing the exchange of GDP for GTP in the Gα nucleotide binding site, which results in the dissociation of Gα from Gβγ dimers and activation of both G protein components. Deactivation of G proteins does not occur by simple reversal of nucleotide exchange, but rather by an independently regulated GTPase activity, hydrolyzing GTP to GDP. Although Gα proteins possess an intrinsic ability to hydrolyze GTP, this process is very slow and cannot account for the transient nature of intracellular signalling cascades in vivo. Hence, additional kinetic mechanisms are required for the physiological timing of signals. One of the most critical of these kinetic mechanisms is mediated through regulator of G protein signalling (RGS) proteins, which have received increasing interest as novel drug targets in the past two decades. As a result, RGS proteins have now been added as the most recent ad...

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“…RGS proteins also act as effecter antagonists by physically blocking the binding of G protein subunits to their protein targets and interfering with downstream signaling proteins (4). RGS2-RGS5 are thought to be important in the heart (5,6), although their precise roles remain unclear. Human heart failure is associated with increased RGS4 expression, whereas expression of RGS2 is unchanged (7).…”

Section: Introductionmentioning

confidence: 99%

Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice

Takimoto¹,

Koitabashi²,

Hsu³

et al. 2009

J. Clin. Invest.

140

174

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The heart initially compensates for hypertension-mediated pressure overload by enhancing its contractile force and developing hypertrophy without dilation. G q protein-coupled receptor pathways become activated and can depress function, leading to cardiac failure. Initial adaptation mechanisms to reduce cardiac damage during such stimulation remain largely unknown. Here we have shown that this initial adaptation requires regulator of G protein signaling 2 (RGS2). Mice lacking RGS2 had a normal basal cardiac phenotype, yet responded rapidly to pressure overload, with increased myocardial G q signaling, marked cardiac hypertrophy and failure, and early mortality. Swimming exercise, which is not accompanied by G q activation, induced a normal cardiac response, while Rgs2 deletion in G αq -overexpressing hearts exacerbated hypertrophy and dilation. In vascular smooth muscle, RGS2 is activated by cGMP-dependent protein kinase (PKG), suppressing G q -stimulated vascular contraction. In normal mice, but not Rgs2 -/-mice, PKG activation by the chronic inhibition of cGMP-selective phosphodiesterase 5 (PDE5) suppressed maladaptive cardiac hypertrophy, inhibiting G q -coupled stimuli. Importantly, PKG was similarly activated by PDE5 inhibition in myocardium from both genotypes, but PKG plasma membrane translocation was more transient in Rgs2 -/-myocytes than in controls and was unaffected by PDE5 inhibition. Thus, RGS2 is required for early myocardial compensation to pressure overload and mediates the initial antihypertrophic and cardioprotective effects of PDE5 inhibitors.

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Multi-Tasking RGS Proteins in the Heart

Cited by 112 publications

References 128 publications

Human G _sα mutant causes pseudohypoparathyroidism type Ia/neonatal diarrhea, a potential cell-specific role of the palmitoylation cycle

Human G _sα mutant causes pseudohypoparathyroidism type Ia/neonatal diarrhea, a potential cell-specific role of the palmitoylation cycle

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice

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Multi-Tasking RGS Proteins in the Heart

Cited by 112 publications

References 128 publications

Human G sα mutant causes pseudohypoparathyroidism type Ia/neonatal diarrhea, a potential cell-specific role of the palmitoylation cycle

Human G sα mutant causes pseudohypoparathyroidism type Ia/neonatal diarrhea, a potential cell-specific role of the palmitoylation cycle

The evolution of regulators of G protein signalling proteins as drug targets – 20 years in the making: IUPHAR Review 21

Regulator of G protein signaling 2 mediates cardiac compensation to pressure overload and antihypertrophic effects of PDE5 inhibition in mice

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Human G _sα mutant causes pseudohypoparathyroidism type Ia/neonatal diarrhea, a potential cell-specific role of the palmitoylation cycle

Human G _sα mutant causes pseudohypoparathyroidism type Ia/neonatal diarrhea, a potential cell-specific role of the palmitoylation cycle