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

Takimoto, Eiki; Koitabashi, Norimichi; Hsu, Steven; Ketner, Elizabeth; Zhang, Manling; Nagayama, Takahiro; Bedja, Djahida; Gabrielson, Kathleen L.; Blanton, Robert M.; Siderovski, David P.; Mendelsohn, Michael E.; Kass, David A.

doi:10.1172/jci35620

Cited by 140 publications

(191 citation statements)

References 57 publications

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“…As discussed above, RGS2 is one of several RGS proteins that is rapidly degraded through the ubiquitin-proteasomal pathway. Low RGS2 protein levels are associated with hypertension and other cardiovascular pathologies (Heximer et al, 2003;Takimoto et al, 2009;Tsang et al, 2010) and could also be involved in the progression of prostate and breast cancer (Cao et al, 2006;Lyu et al, 2015). In our initial screen, we identified digoxin and other cardiotonic steroids as selective stabilizers of RGS2 protein levels (Sjögren et al, 2012).…”

Section: Advances In Rgs Protein Drug Discovery -From Biochemical Actmentioning

confidence: 96%

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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Section: Advances In Rgs Protein Drug Discovery -From Biochemical Actmentioning

confidence: 96%

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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“…Knockdown of RGS2 and RGS4 Does Not Affect the Effect of PDE5-IIt has been recently reported that PKG-dependent phosphorylation of RGS2 and RGS4 mediates the anti-hypertrophic effects in mouse hearts (32,40,41). Thus, we next examined the involvement of RGS proteins in the inhibition of agonistinduced Ca 2ϩ responses by PDE5 inhibition, using siRNAs for RGS2 and RGS4.…”

Section: Suppression Of Mechanical Stretch-induced Ca 2ϩmentioning

confidence: 96%

“…In fact, chronic treatment with sildenafil, a PDE5 inhibitor, exhibits the anti-hypertrophic effects in mice (29,30) and in patients with systolic heart failure (31). It has been reported that RGS2 mediates cardiac compensation to pressure overload and anti-hypertrophic effects of PDE5 inhibition in mice (32). Because PKG-dependent phosphorylation of RGS2 enhances GTPase activity of the ␣-subunit of G q protein (G␣ q ), this may explain the cGMP-dependent disruption of intracellular Ca 2ϩ signaling induced by G q -coupled receptor stimulation.…”

mentioning

confidence: 99%

Phosphorylation of TRPC6 Channels at Thr69 Is Required for Anti-hypertrophic Effects of Phosphodiesterase 5 Inhibition

Nishida

Watanabe

Sato

et al. 2010

Journal of Biological Chemistry

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Activation of Ca2؉ signaling induced by receptor stimulation and mechanical stress plays a critical role in the development of cardiac hypertrophy. A canonical transient receptor potential protein subfamily member, TRPC6, which is activated by diacylglycerol and mechanical stretch, works as an upstream regulator of the Ca 2؉ signaling pathway. Although activation of protein kinase G (PKG) inhibits TRPC6 channel activity and cardiac hypertrophy, respectively, it is unclear whether PKG suppresses cardiac hypertrophy through inhibition of TRPC6. Here, we show that inhibition of cGMP-selective PDE5 (phosphodiesterase 5) suppresses endothelin-1-, diacylglycerol analog-, and mechanical stretch-induced hypertrophy through inhibition of Ca 2؉ influx in rat neonatal cardiomyocytes. influx. Substitution of Ala for Thr 69 in TRPC6 abolished the anti-hypertrophic effects of PDE5 inhibition. In addition, chronic PDE5 inhibition by oral sildenafil treatment actually induced TRPC6 phosphorylation in mouse hearts. Knockdown of RGS2 (regulator of G protein signaling 2) and RGS4, both of which are activated by PKG to reduce G␣ q -mediated signaling, did not affect the suppression of receptor-activated Ca 2؉ influx by PDE5 inhibition. These results suggest that phosphorylation and functional suppression of TRPC6 underlie prevention of pathological hypertrophy by PDE5 inhibition.Pathological hypertrophy of the heart, induced by pressure overload, such as chronic hypertension and aortic stenosis, is a major risk factor for heart failure and cardiovascular mortality (1). Neurohumoral factors, such as norepinephrine, angiotensin II (Ang II), 2 and endothelin-1 (ET-1), and mechanical stress are believed to be prominent contributors for pressure overloadinduced cardiac hypertrophy (2, (9). A partial depolarization of plasma membrane by receptor stimulation is reported to increase the frequency of Ca 2ϩ oscillations, leading to activation of nuclear factor of activated T cells (NFAT), a transcription factor that is predominantly regulated by calcineurin (10). Recent reports have indicated that transient receptor potential canonical (TRPC) subfamily proteins play an essential role in agonistinduced membrane depolarization (11, 12). The relevance of TRPC channels to pathological hypertrophy is underscored by the observations that heart-targeted transgenic mice expressing TRPC channels caused hypertrophy (13,14) and that TRPC proteins were up-regulated in hypertrophied and failing hearts (14 -17). Among seven TRPC subfamilies, increased channel activities of TRPC1, TRPC3, and TRPC6 have been implicated in cardiac hypertrophy in vivo. TRPC1 is known to function not * This study was supported by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to M. Nishida, M. Nakaya, and H. Kurose), a grant-in-aid for scientific research on Innovative Areas (to M. Nishida), a grant-in-aid for scientific research on Priority Areas (H. Kurose), and grants from the Naito Foundation, the Nakatomi Foundation, the Sapporo ...

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“…Specifically, we examined the three cGMP-generating proteins GC-A, GC-B, and sGC; the NO-producing enzyme NOS3; the cGMP-degrading enzyme PDE5; and the cGMP target protein PRKG1. As the non-transmembrane proteins sGC, NOS3, PDE5, and PRKG1 may have either soluble (cytosolic) or particulate (membrane) cellular locations, and considering that the relative amount in particulate fractions is indicative of membrane-localized signaling microdomains (Takimoto et al 2009, Mü ller et al 2010a) the concentrations of these proteins were monitored in both cytosolic (C) and membrane (M) fractions.…”

Section: Pronounced Tissue-specific Expression Patterns Of Cgmp Pathwmentioning

confidence: 99%

Cyclic GMP signaling in rat urinary bladder, prostate, and epididymis: tissue-specific changes with aging and in response to Leydig cell depletion

Müller

Mukhopadhyay²,

Davidoff³

et al. 2011

Reproduction

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Aging of the male reproductive system leads to changes in endocrine signaling and is frequently associated with the emergence of prostate hyperplasia and bladder dysfunctions. Recent reports highlight prostate and bladder as promising targets for therapeutic interventions with inhibitors of the cyclic GMP (cGMP)-degrading phosphodiesterase 5 (PDE5). However, the cGMP signaling system in these organs is as yet poorly characterized, and the possibility of age-related alterations has not been addressed. This study investigates key proteins of cGMP pathways in bladder, prostate, and epididymis of young (3 months) and old (23-24 months) Wistar rats. Local differences in the abundance of PDE5, soluble guanylyl cyclase (sGC) and particulate guanylyl cyclases (GC-A, GC-B), endothelial nitric oxide synthase, and cGMP-dependent protein kinase I (PRKG1 (cGKI)) revealed pronounced tissue-specific peculiarities. Although cGMP-generating enzymes were not affected by age in all organs, we recognized age-related decreases of PDE5 expression in bladder and a selective diminishment of membrane-associated PRKG1 in epididymis. In disagreement with published data, all cGMP pathway proteins including PDE5 are poorly expressed in prostate. However, prostatic PRKG1 expression increases with aging. Androgen withdrawal during temporary Leydig cell elimination induced a massive (O12-fold) upregulation of PRKG1 in prostate but not in other (penis and epididymis) androgen-dependent organs. These findings identify PRKG1 as a key androgen-sensitive signaling protein in prostate of possible importance for growth regulation. The elucidated effects may have significance for age-associated pathologies in the male lower-urinary tract.

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

Cited by 140 publications

References 57 publications

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

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

Phosphorylation of TRPC6 Channels at Thr69 Is Required for Anti-hypertrophic Effects of Phosphodiesterase 5 Inhibition

Cyclic GMP signaling in rat urinary bladder, prostate, and epididymis: tissue-specific changes with aging and in response to Leydig cell depletion

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