Disrupted nitric oxide signaling due to <i><scp>GUCY1A3</scp></i> mutations increases risk for moyamoya disease, achalasia and hypertension

Wallace, Stephanie E; Guo, Dongchuan; Regalado, Ellen S.; Mellor‐Crummey, Lauren; Bamshad, Michael J.; Nickerson, Debbie; Dauser, Robert C.; Hanchard, Neil A.; Marom, Ronit; Martin, Emil; Berka, Vladimír; Sharina, Iraida; Ganesan, Vijeya; Saunders, Dawn; Morris, Shaine A.; Milewicz, Dianna M.

doi:10.1111/cge.12739

Cited by 67 publications

(51 citation statements)

References 31 publications

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“…It was later shown by site-directed mutagenesis that SNO-αC516 is involved in desensitization of sGC to NO stimulation in cells treated with stress-induced angiotensin II [8]. A recent study also identified in two different families that mutation αC516 to a Tyrosine as an increased risk for the Moyamoya disease (vasculopathy), achalasia and hypertension [23]. A specific role for the three other Cys in the catalytic domain αC609, αC628 and βC571, identified as S-nitrosated in the current study, is not yet known.…”

Section: Resultsmentioning

confidence: 99%

Identification of novel S-nitrosation sites in soluble guanylyl cyclase, the nitric oxide receptor

Beuve

Cui

et al. 2016

Journal of Proteomics

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Soluble Guanylyl Cyclase (sGC) is the main receptor for nitric oxide (NO). NO activates sGC to synthesize cGMP, triggering a plethora of signals. Recently, we discovered that NO covalently modifies select sGC cysteines via a post-translational modification termed S-nitrosation or S-nitrosylation. Earlier characterization was conducted on a purified sGC treated with S-nitrosoglutathione, and identified three S-nitrosated cysteines (SNO-Cys). Here we describe a more biologically relevant mapping of sGC SNO-Cys in cells to better understand the multi-faceted interactions between SNO and sGC. Since SNO-Cys are labile during LC/MS/MS, MS analysis of nitrosation typically occurs after a biotin switch reaction, in which a SNO-Cys is converted to a biotin-Cys. Here we report the identification of ten sGC SNO-Cys in rat neonatal cardiomyocytes using an Orbitrap MS. A majority of the SNO-Cys identified is located at the solvent-exposed surface of the sGC, and half of them in the conserved catalytic domain, suggesting biological significance. These findings provide a solid basis for future studies of the regulations and functions of diverse sGC S-nitrosation events in cells.

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Section: Resultsmentioning

confidence: 99%

Identification of novel S-nitrosation sites in soluble guanylyl cyclase, the nitric oxide receptor

Beuve

Cui

et al. 2016

Journal of Proteomics

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“…The physiological role of the solvent exposed, potentially reactive Cys in sGC, still needs to be addressed. Interestingly, a recent study described an increased risk for Moyamoya disease (vasculopathy), achalasia, and hypertension linked to mutation of aC517 to tyrosine (109). Many questions regarding the potential roles of Cys remain unanswered, including the role of the PDI-sGC association.…”

Section: Discussionmentioning

confidence: 99%

Thiol-Based Redox Modulation of Soluble Guanylyl Cyclase, the Nitric Oxide Receptor

Beuve

2017

Antioxidants & Redox Signaling

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Significance: Soluble guanylyl cyclase (sGC), which produces the second messenger cyclic guanosine 3¢, 5¢-monophosphate (cGMP), is at the crossroads of nitric oxide (NO) signaling: sGC catalytic activity is both stimulated by NO binding to the heme and inhibited by NO modification of its cysteine (Cys) thiols (S-nitrosation). Modulation of sGC activity by thiol oxidation makes sGC a therapeutic target for pathologies originating from oxidative or nitrosative stress. sGC has an unusually high percentage of Cys for a cytosolic protein, the majority solvent exposed and therefore accessible modulatory targets for biological and pathophysiological signaling. Recent Advances: Thiol oxidation of sGC contributes to the development of cardiovascular diseases by decreasing NO-dependent cGMP production and thereby vascular reactivity. This thiol-based resistance to NO (e.g., increase in peripheral resistance) is observed in hypertension and hyperaldosteronism. Critical Issues: Some roles of specific Cys thiols have been identified in vitro. So far, it has not been possible to pinpoint the roles of specific Cys of sGC in vivo and to investigate the molecular mechanisms in an animal model. Future Directions: The role of Cys as redox sensors, intermediates of activation, and mediators of change in sGC conformation, activity, and dimerization remains largely unexplored. To understand modulation of sGC activity, it is critical to investigate the roles of specific oxidative thiol modifications that are formed during these processes. Where the redox state of sGC thiols contribute to pathologies (vascular resistance and sGC desensitization by NO donors), it becomes crucial to design therapeutic strategies to restore sGC to its normal, physiological thiol redox state. Antioxid. Redox Signal. 26,[137][138][139][140][141][142][143][144][145][146][147][148][149]

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“…Of note, variants in GUCY1A3 have also been associated with blood pressure [16], an important cardiovascular risk factor [18]. Additionally, mutations in GUCY1A3 have also been found in patients suffering from Moyamoya syndrome, a rare progressive cerebrovascular disorder [14,29].…”

Section: Discussionmentioning

confidence: 99%

Stimulators of the soluble guanylyl cyclase: promising functional insights from rare coding atherosclerosis-related GUCY1A3 variants

et al. 2016

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Stimulators of the soluble guanylyl cyclase (sGC) are emerging therapeutic agents in cardiovascular diseases. Genetic alterations of the GUCY1A3 gene, which encodes the α1 subunit of the sGC, are associated with coronary artery disease. Studies investigating sGC stimulators in subjects with CAD and carrying risk-related variants in sGC are, however, lacking. Here, we functionally investigate the impact of coding GUCY1A3 variants on sGC activity and the therapeutic potential of sGC stimulators in vitro. In addition to a known loss-of-function variant, eight coding variants in GUCY1A3 were cloned and expressed in HEK 293 cells. Protein levels and dimerization capability with the β1 subunit were analysed by immunoblotting and co-immunoprecipitation, respectively. All α1 variants found in MI patients dimerized with the β1 subunit. Protein levels were reduced by 72 % in one variant (p < 0.01). Enzymatic activity was analysed using cGMP radioimmunoassay after stimulation with a nitric oxide (NO) donor. Five variants displayed decreased cGMP production upon NO stimulation (p < 0.001). The addition of the sGC stimulator BAY 41-2272 increased cGMP formation in all of these variants (p < 0.01). Except for the variant leading to decreased protein level, cGMP amounts reached the wildtype NO-induced level after addition of BAY 41-2272. In conclusion, rare coding variants in GUCY1A3 lead to reduced cGMP formation which can be rescued by a sGC stimulator in vitro. These results might therefore represent the starting point for discovery of novel treatment strategies for patients at risk with coding GUCY1A3 variants.

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Disrupted nitric oxide signaling due to GUCY1A3 mutations increases risk for moyamoya disease, achalasia and hypertension

Cited by 67 publications

References 31 publications

Identification of novel S-nitrosation sites in soluble guanylyl cyclase, the nitric oxide receptor

Identification of novel S-nitrosation sites in soluble guanylyl cyclase, the nitric oxide receptor

Thiol-Based Redox Modulation of Soluble Guanylyl Cyclase, the Nitric Oxide Receptor

Stimulators of the soluble guanylyl cyclase: promising functional insights from rare coding atherosclerosis-related GUCY1A3 variants

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