Non-canonical chemical feedback self-limits nitric oxide-cyclic GMP signaling in health and disease

Dao, Vu Thao-Vi; Elbatreek, Mahmoud H.; Deile, Martin; Nedvetsky, Pavel I.; Güldner, Andreas; Ibarra‐Alvarado, César; Gödecke, Axel; Schmidt, Harald

doi:10.1038/s41598-020-66639-w

Cited by 12 publications

(6 citation statements)

References 80 publications

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“…These agonists provided a means to assess the relative levels of the different sGC forms present in cells or tissues. They have been utilized in studies with human umbilical vein endothelial cells, primary human airway smooth muscle cells, a cell line that naturally expresses sGC (RFL6), transfected COS-7 or HEK cells, and tissues from a number of animal disease models ( 53 , 65 , 66 , 67 , 68 , 69 ). In all cases, results with the pharmacologic agonists indicated that heme-free or heme-oxidized forms of sGC were present.…”

Section: Sgc Maturation To a Heterodimermentioning

confidence: 99%

Maturation, inactivation, and recovery mechanisms of soluble guanylyl cyclase

Stuehr

Misra

Dai

et al. 2021

Journal of Biological Chemistry

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Soluble guanylate cyclase (sGC) is a heme-containing heterodimeric enzyme that generates many molecules of cGMP in response to its ligand nitric oxide (NO); sGC thereby acts as an amplifier in NO-driven biological signaling cascades. Because sGC helps regulate the cardiovascular, neuronal, and gastrointestinal systems through its cGMP production, boosting sGC activity and preventing or reversing sGC inactivation are important therapeutic and pharmacologic goals. Work over the last two decades is uncovering the processes by which sGC matures to become functional, how sGC is inactivated, and how sGC is rescued from damage. A diverse group of small molecules and proteins have been implicated in these processes, including NO itself, reactive oxygen species, cellular heme, cell chaperone Hsp90, and various redox enzymes as well as pharmacologic sGC agonists. This review highlights their participation and provides an update on the processes that enable sGC maturation, drive its inactivation, or assist in its recovery in various settings within the cell, in hopes of reaching a better understanding of how sGC function is regulated in health and disease.

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Section: Sgc Maturation To a Heterodimermentioning

confidence: 99%

Maturation, inactivation, and recovery mechanisms of soluble guanylyl cyclase

Stuehr

Misra

Dai

et al. 2021

Journal of Biological Chemistry

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“…Indeed, under physiological conditions, treatment with an sGC activator only accounts for a small amount of sGC activity compared to NO 16 . However, under high NO conditions, Fe(II)sGC is known to be degraded, hence sGC signalling can be functionally recovered in a mechanism-based manner by apo-sGC activators that re-establish cGMP formation 45 .…”

Section: Discussionmentioning

confidence: 99%

The sGC stimulator BAY-747 and activator runcaciguat can enhance memory in vivo via differential hippocampal plasticity mechanisms

Nelissen

Possemis

Goethem

et al. 2022

Sci Rep

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Soluble guanylate cyclase (sGC) requires a heme-group bound in order to produce cGMP, a second messenger involved in memory formation, while heme-free sGC is inactive. Two compound classes can increase sGC activity: sGC stimulators acting on heme-bound sGC, and sGC activators acting on heme-free sGC. In this rodent study, we investigated the potential of the novel brain-penetrant sGC stimulator BAY-747 and sGC activator runcaciguat to enhance long-term memory and attenuate short-term memory deficits induced by the NOS-inhibitor L-NAME. Furthermore, hippocampal plasticity mechanisms were investigated. In vivo, oral administration of BAY-747 and runcaciguat to male Wistar rats enhanced memory acquisition in the object location task (OLT), while only BAY-747 reversed L-NAME induced memory impairments in the OLT. Ex vivo, both BAY-747 and runcaciguat enhanced hippocampal GluA1-containing AMPA receptor (AMPAR) trafficking in a chemical LTP model for memory acquisition using acute mouse hippocampal slices. In vivo only runcaciguat acted on the glutamatergic AMPAR system in hippocampal memory acquisition processes, while for BAY-747 the effects on the neurotrophic system were more pronounced as measured in male mice using western blot. Altogether this study shows that sGC stimulators and activators have potential as cognition enhancers, while the underlying plasticity mechanisms may determine disease-specific effectiveness.

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“…It will be useful to explore if specific SNO modifications destabilize the sGC heterodimer or promote complex formation between the haem-containing sGCβ subunit and Hsp90. By resolving the molecular changes to sGCβ and the sGC heterodimer that take place during NOC12 inactivation in cells, our work helps to explain how NO can engage in non-canonical feedback to self-limit NO-driven cGMP signalling in health and disease (Dao et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Inactivation of soluble guanylyl cyclase in living cells proceeds without loss of haem and involves heterodimer dissociation as a common step

Dai

Stuehr

2021

British J Pharmacology

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Background and Purpose Nitric oxide (NO) activates soluble guanylyl cyclase (sGC) for cGMP production, but in disease, sGC becomes insensitive towards NO activation. What changes occur to sGC during its inactivation in cells is not clear. Experimental Approach We utilized HEK293 cells expressing sGC proteins to study the changes that occur regarding its haem content, heterodimer status and sGCβ protein partners when the cells were given the oxidant ODQ or the NO donor NOC12 to inactivate sGC. Haem content of sGCβ was monitored in live cells through use of a fluorescent‐labelled sGCβ construct, whereas sGC heterodimer status and protein interactions were studied by Western blot analysis. Experiments with purified proteins were also performed. Key Results ODQ‐ or NOC12‐driven inactivation of sGC in HEK293 cells was associated with haem oxidation (by ODQ), S‐nitrosation of the sGCβ subunit (by NOC12), sGC heterodimer breakup and association of the freed sGCβ subunit with cell chaperone Hsp90. These changes occurred without detectable loss of haem from the sGCβ reporter construct. Treating a purified ferrous haem‐containing sGCβ with ODQ or NOC12 caused it to bind with Hsp90 without showing any haem loss. Conclusion and Implications Oxidative (ODQ) or nitrosative (NOC12) inactivation of cell sGC involves sGC heterodimer dissociation and rearrangement of the sGCβ protein partners without any haem loss from sGCβ. Clarifying what changes do and do not occur to sGC during its inactivation in cells may direct strategies to preserve or recover NO‐dependent cGMP signalling in health and disease. LINKED ARTICLES This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc

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Non-canonical chemical feedback self-limits nitric oxide-cyclic GMP signaling in health and disease

Cited by 12 publications

References 80 publications

Maturation, inactivation, and recovery mechanisms of soluble guanylyl cyclase

Maturation, inactivation, and recovery mechanisms of soluble guanylyl cyclase

The sGC stimulator BAY-747 and activator runcaciguat can enhance memory in vivo via differential hippocampal plasticity mechanisms

Inactivation of soluble guanylyl cyclase in living cells proceeds without loss of haem and involves heterodimer dissociation as a common step

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