Genetic alterations in the NO-cGMP pathway and cardiovascular risk

Wobst, Jana; Schunkert, Heribert; Kessler, Thorsten

doi:10.1016/j.niox.2018.03.019

Cited by 38 publications

(31 citation statements)

References 105 publications

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“…Nitric oxide (NO) and its primary receptor soluble guanylyl cyclase (sGC) are critical for regulating blood pressure, wound healing, neural function, and numerous other physiological activities. Failures in NO signaling are highly correlated with cardiovascular diseases and genome‐wide association studies (GWAS) implicate underlying genetic components are often responsible, including mutations to the sGC gene or to genes regulating sGC expression . Numerous pharmaceutical interventions targeting NO signaling pathways are under development or in use, including those targeting sGC .…”

Section: Introductionmentioning

confidence: 99%

“…Failures in NO signaling are highly correlated with cardiovascular diseases and genome-wide association studies (GWAS) implicate underlying genetic components are often responsible, including mutations to the sGC gene or to genes regulating sGC expression. 1,2 Numerous pharmaceutical interventions targeting NO signaling pathways are under development or in use, including those targeting sGC. 3,4 Despite these advances, sGC structure, function, and regulation remain poorly characterized.…”

Section: Introductionmentioning

confidence: 99%

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Instability in a coiled‐coil signaling helix is conserved for signal transduction in soluble guanylyl cyclase

et al. 2019

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How nitric oxide (NO) activates its primary receptor, α1/β1 soluble guanylyl cyclase (sGC or GC‐1), remains unknown. Likewise, how stimulatory compounds enhance sGC activity is poorly understood, hampering development of new treatments for cardiovascular disease. NO binding to ferrous heme near the N‐terminus in sGC activates cyclase activity near the C‐terminus, yielding cGMP production and physiological response. CO binding can also stimulate sGC, but only weakly in the absence of stimulatory small‐molecule compounds, which together lead to full activation. How ligand binding enhances catalysis, however, has yet to be discovered. Here, using a truncated version of sGC from Manduca sexta, we demonstrate that the central coiled‐coil domain, the most highly conserved region of the ~150,000 Da protein, not only provides stability to the heterodimer but is also conformationally active in signal transduction. Sequence conservation in the coiled coil includes the expected heptad‐repeating pattern for coiled‐coil motifs, but also invariant positions that disfavor coiled‐coil stability. Full‐length coiled coil dampens CO affinity for heme, while shortening of the coiled coil leads to enhanced CO binding. Introducing double mutation αE447L/βE377L, predicted to replace two destabilizing glutamates with leucines, lowers CO binding affinity while increasing overall protein stability. Likewise, introduction of a disulfide bond into the coiled coil results in reduced CO affinity. Taken together, we demonstrate that the heme domain is greatly influenced by coiled‐coil conformation, suggesting communication between heme and catalytic domains is through the coiled coil. Highly conserved structural imperfections in the coiled coil provide needed flexibility for signal transduction.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Instability in a coiled‐coil signaling helix is conserved for signal transduction in soluble guanylyl cyclase

et al. 2019

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“…29 We detected it twice in a heterozygous and once in a homozygous form out of (PDE5A), and MRVI1. 35 Although we thoroughly investigated our patients concerning cardiovascular or hemostasiologic symptoms neither altered blood pressure or bleeding time nor any other symptom could be detected. However, it has to be emphasized that the IRAGmutant mice did reveal only a mild cardiovascular phenotype with a slight hypotension and showed unaltered basal platelet aggregation at injured artery.…”

Section: Discussionmentioning

confidence: 99%

Homozygous mutation in murine retrovirus integration site 1 gene associated with a non‐syndromic form of isolated familial achalasia

Koehler

Hmida

Schlossmann

et al. 2020

Neurogastroenterology Motil

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“…In recent years, genetic sequencing and genome-wide association studies provided further evidence that mutations in genes of the cGMP cascades are linked to cardiovascular, cardiopulmonary, and cardiorenal diseases (Wobst et al 2018). Recently, a clinically relevant mutation of PKG-I (a missense variant of PKG-Iα with replacement of valine by isoleucine (V219I)) was detected in a patient with congenital heart disease, aortic root dilation, and aneurism formation.…”

Section: New Developments In Cgmp-based Treatment Approaches and Thermentioning

confidence: 99%

cGMP: a unique 2nd messenger molecule – recent developments in cGMP research and development

Friebe

Sandner

Schmidtko

2019

Naunyn-Schmiedeberg's Arch Pharmacol

101

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Cyclic guanosine monophosphate (cGMP) is a unique second messenger molecule formed in different cell types and tissues. cGMP targets a variety of downstream effector molecules and, thus, elicits a very broad variety of cellular effects. Its production is triggered by stimulation of either soluble guanylyl cyclase (sGC) or particulate guanylyl cyclase (pGC); both enzymes exist in different isoforms. cGMP-induced effects are regulated by endogenous receptor ligands such as nitric oxide (NO) and natriuretic peptides (NPs). Depending on the distribution of sGC and pGC and the formation of ligands, this pathway regulates not only the cardiovascular system but also the kidney, lung, liver, and brain function; in addition, the cGMP pathway is involved in the pathogenesis of fibrosis, inflammation, or neurodegeneration and may also play a role in infectious diseases such as malaria. Moreover, new pharmacological approaches are being developed which target sGC-and pGC-dependent pathways for the treatment of various diseases. Therefore, it is of key interest to understand this pathway from scratch, beginning with the molecular basis of cGMP generation, the structure and function of both guanylyl cyclases and cGMP downstream targets; research efforts also focus on the subsequent signaling cascades, their potential crosstalk, and also the translational and, ultimately, the clinical implications of cGMP modulation. This review tries to summarize the contributions to the "9th International cGMP Conference on cGMP Generators, Effectors and Therapeutic Implications" held in Mainz in 2019. Presented data will be discussed and extended also in light of recent landmark findings and ongoing activities in the field of preclinical and clinical cGMP research.

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Genetic alterations in the NO-cGMP pathway and cardiovascular risk

Cited by 38 publications

References 105 publications

Instability in a coiled‐coil signaling helix is conserved for signal transduction in soluble guanylyl cyclase

Instability in a coiled‐coil signaling helix is conserved for signal transduction in soluble guanylyl cyclase

Homozygous mutation in murine retrovirus integration site 1 gene associated with a non‐syndromic form of isolated familial achalasia

cGMP: a unique 2nd messenger molecule – recent developments in cGMP research and development

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