NO-independent regulatory site on soluble guanylate cyclase

  title={NO-independent regulatory site on soluble guanylate cyclase},
  author={J-P. Stasch and Eva-Maria Becker and Cristina Alonso-Alija and Heiner Apeler and Klaus Dembowsky and Achim Feurer and Rupert Gerzer and Torsten Minuth and Elisabeth Perzborn and Ulrich Pleiss and Henning Schröder and Werner Dr Schroeder and Elke Stahl and Wolfram Steinke and Alexander T. Straub and Matthias Schramm},
Nitric oxide (NO) is a widespread, potent, biological mediator that has many physiological and pathophysiological roles. Research in the field of NO appears to have followed a straightforward path, and the findings have been progressive: NO and cyclic GMP are involved in vasodilatation; glycerol trinitrate relaxes vascular smooth muscles by bioconversion to NO; mammalian cells synthesize NO; and last, NO mediates vasodilatation by stimulating the soluble guanylate cyclase (sGC), a heterodimeric… 

Structure and regulation of soluble guanylate cyclase.

This review summarizes the current understanding of sGC structure and regulation as well as recent developments in NO signaling to aid therapeutic intervention in diseases involving the NO/cGMP-signaling pathway.

Guanylate Cyclase and Cyclic GMP

The NO/cGMP signalling cascade participates in the regulation of physiological parameters such as smooth muscle relaxation, inhibition of platelet aggregation, and neuronal transmission. cGMP is

Soluble guanylate cyclase in NO signaling transduction

The progress of sGC on structural, functional investigations, as well as the proposed activation/deactivation mechanism are reviewed, and the heme-dependent sGC stimulators and he me-independent sGC activators are summarized briefly.

Soluble Guanylyl Cyclase: Physiological Role as an NO Receptor and the Potential Molecular Target for Therapeutic Application

  • M. Nakane
  • Biology, Chemistry
    Clinical chemistry and laboratory medicine
  • 2003
The NO/cGMP signal transduction pathway is reviewed and soluble guanylyl cyclase modulators are defined as a novel approach for the treatment of cardiovascular diseases and erectile dysfunction.

NO-independent, haem-dependent soluble guanylate cyclase stimulators.

Pharmacological stimulators of sGC may be beneficial in the treatment of a range of diseases, including systemic and pulmonary hypertension, heart failure, atherosclerosis, erectile dysfunction, and renal fibrosis.

Spare guanylyl cyclase NO receptors ensure high NO sensitivity in the vascular system.

It is concluded that the majority of NO-sensitive GC is not required for cGMP-forming activity but as NO receptor reserve to increase sensitivity toward the labile messenger NO in vivo.

The Mechanism of Allosteric Regulation in Soluble Guanylate Cyclase

This dissertation describes experiments designed to uncover the molecular basis for signal transduction in sGC by NO and small molecule stimulators and shows that the coiled coil domain plays a pocket important in allostery and drug action.



Potent and selective inhibition of nitric oxide-sensitive guanylyl cyclase by 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one.

ODQ is the first inhibitor that acts selectively at the level of a physiological NO "receptor" and, as such, is likely to prove useful for investigating the function of the cGMP pathway in NO signal transduction.

Mechanism of YC-1-induced activation of soluble guanylyl cyclase.

Results indicate that YC-1 increases the maximal catalytic rate and sensitizes the enzyme toward its gaseous activators by binding to an allosteric site on sGC molecules, thereby reducing the ligand dissociation rate from the heme group.

Human soluble guanylate cyclase: functional expression and revised isoenzyme family.

Having access to the human key enzyme of NO signalling will now permit the study of novel sGC-modulating compounds with therapeutic potential, as both alpha and beta subunits were detected in human tissues, suggesting co-expression also in vivo.

Novel guanylyl cyclase inhibitor potently inhibits cyclic GMP accumulation in endothelial cells and relaxation of bovine pulmonary artery.

Results suggest that ODQ inhibits nitrovasodilator-induced and endothelium-dependent relaxation through inhibition of guanylyl cyclase activation, but also point to the presence of a cyclic GMP-independent component of relaxation in bovine pulmonary artery.

The vasodilator-stimulated phosphoprotein (VASP): target of YC-1 and nitric oxide effects in human and rat platelets.

YC-1-like substances are interesting tools for the development of new cardiovascular drugs with vasodilatory and antithrombotic properties and synergize with NO, the physiologic stimulator of sGC.

Effects of the soluble guanylyl cyclase activator, YC‐1, on vascular tone, cyclic GMP levels and phosphodiesterase activity

YC‐1 is a highly effective vasodilator compound with a prolonged duration of action, and mechanisms that are unprecedented for any previously known sGC activator.

Localization of the heme binding region in soluble guanylate cyclase.

The data suggest that the heme in the beta1(1-385) is similar to that in the heterodimeric sGC, and suggests that the N-terminal region of thebeta1 subunit of sGC is itself sufficient for heme binding.

Discovery of Some of the Biological Effects of Nitric Oxide and Its Role in Cell Signaling (Nobel Lecture).

  • F. Murad
  • Chemistry, Biology
    Angewandte Chemie
  • 1999
The free radical nitric oxide not only mediates a long list of biological effects by activating guanylyl cyclase and increasing cyclic GMP synthesis from GTP, but can also interact with transition metals such as iron, thiol groups, other free radicals, oxygen, superoxide anion, unsaturated fatty acids, and other molecules.

Effect of YC‐1, an NO‐independent, superoxide‐sensitive stimulator of soluble guanylyl cyclase, on smooth muscle responsiveness to nitrovasodilators

The results indicate that YC‐1 is an NO‐independent, O2−‐sensitive, direct activator of sGC in VSMC and exerts vasorelaxation by increasing intracellular cyclic GMP levels and the synergism revealed in this in vitro study suggests that low doses of YC-1 may be of therapeutic value by permitting the reduction of nitrovasodilator dosage.

YC‐1 inhibited human platelet aggregation through NO‐independent activation of soluble guanylate cyclase

The results would suggest that YC‐1 activates sGC of human platelets by a NO‐independent mechanism, and exerts its antiplatelet effects through the sGC/cyclic GMP pathway.