Nontoxic RsDPLA As a Potent Antagonist of Toxic Lipopolysaccharide
Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison in Endotoxin in Health and Disease, 2020
The formation of cGMP from GTP is catalyzed by an enzyme called guanylate cyclase. The cellular effects of cGMP appear to be mediated by several types of cGMP receptor proteins. The best characterized are the cGMP-dependent protein kinases, which are a class of closely related enzymes. Cyclic GMP-dependent protein kinases are serine/threonine protein kinases that belong to the very large protein kinase family. There are two catalytic site inhibitors of the cGMP-dependent protein kinase: the isoquinoline H-8 and KT5823 (68). These inhibitors selectively inhibit purified cGMP-dependent protein kinase with a Ki of 0.48 μM and 0.234 μM, respectively. These compounds also inhibit cAMP-dependent protein kinase but with much higher Ki of 1.2 μM and >10 μjlM, respectively. Cyclic GMP plays a major role in pathological situations, which range from endotoxic shock to various types of cardiovascular disorders, hypertension, and atherosclerosis (69).
Sperm Chemotaxis
Claude Gagnon in Controls of Sperm Motility, 2020
The binding of the peptide induces a transient activation of guanylate cyclase activity, which in turn produces an elevation of cyclic GMP, followed by the concomittant inactivation and dephosphorylation of the enzyme. The phosphorylated form of guanylate cyclase is supposed to respond efficiently to receptor occupancy by an increased synthesis of cyclic GMP.105 The elevation of guanylate cyclase activity and cyclic GMP levels would therefore be part of the transducing system, which have to transform the signal of receptor occupancy into a signal that would modify the flagellar motor direction. This last part of the sequence or how transient elevation of cyclic GMP will result in increased asymmetry of the flagellar waveform is quite far from being understood! It is probably at this level that Ca2+ exerts its control on the chemotactic response since none of the steps from peptide binding to its receptor to the dephosphorylation of guanylate cyclase requires external Ca2+ and since modulation of flagellar asymmetry is known to be under the control of Ca2+ ions. The fact that uniform concentrations of attractants have been shown to modify the flagellar asymmetry of siphonophore spermatozoa in a Ca2+-dependent manner suggest a role for the attractant in the regulation of internal Ca2+ levels.
Cyclic Nucleotide Metabolism and Action During Senescence
Richard C. Adelman, George S. Roth in Endocrine and Neuroendocrine Mechanisms of Aging, 2017
In discussing the regulation of cyclase activity in the action of hormones or neurotransmitters believed to act through cyclic nucleotides, a sharp contrast exists between adenylate and guanylate cyclase. While many agents are known to stimulate adenylate cyclase, and while the list of physiologically relevant proteins known to be regulated by cyclic AMP-mediated phosphorylation continues to grow (see Krebs and Beavo4 for a review), no hormones or neurotransmitters have been shown convincingly in an in vitro cyclase assay to activate guanylate cyclase, and virtually no protein has been found with a demonstrated function related to a physiological response to agents which elevate intracellular cyclic GMP. Nevertheless, the ability of cyclic GMP analogues to mimic the actions of some of these agents, plus the antagonism that exist in some cases with agents known to stimulate adenylate cyclase, argues for some discussion of the regulation of cyclic GMP synthesis in the present context. A more extensive discussion of the properties and subcellular distribution of guanylate cyclase can be found in reviews by Kimura and Murad32 and Murad et al.33,34
A review on pharmacological options for the treatment of erectile dysfunction: state of the art and new strategies
Published in Expert Opinion on Pharmacotherapy, 2023
Mattia Longoni, Alessandro Bertini, Nicolò Schifano, Emanuele Zaffuto, Paolo Maggio, Rossi Piercarlo, Sara Baldini, Giulio Carcano, Gabriele Antonini, Andrea Salonia, Francesco Montorsi, Federico Dehò, Paolo Capogrosso
The nitric oxide (NO) pathway has emerged as a fundamental and essential element of penile vasodilation; upon sexual stimulation, the cavernous nerves release NO and acetylcholine directly, generating a more sustained release of NO [10]. NO activates soluble guanylate cyclase, an enzyme that catalyzes the conversion of guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP). The increased levels of cGMP play a critical role in the activation of protein kinase G (PKG) [7], thus leading to cytosolic free calcium depletion. As a consequence of free cytosolic calcium drop in smooth muscle cells of penile arteries and corporal erectile tissue, the actin–myosin cross-bridge formation occurs, leading to muscular relaxation and subsequent vasodilation. With vasodilation, penile blood flow increases, and the corporal bodies become engorged with blood [7].
Novel therapeutic approaches in the management of chronic kidney disease: a narrative review
Published in Postgraduate Medicine, 2023
Panagiotis Theofilis, Aikaterini Vordoni, Rigas G. Kalaitzidis
The administration of guanylate cyclase (GC) activators could also be efficacious in improving the treatment targets in diabetic CKD. In humans, soluble guanylate cyclase is a receptor for nitric oxide (NO). It is an important and established target in improving cardiovascular and renal diseases. It is expressed in the arterial system of the kidneys and neuroendocrine cells, contributing to the regulation of renal perfusion and renin excretion [56]. GC is activated by NO and induces the production of cyclic guanin monophosphate (cGMP) from guanosine triphosphate [57]. The complex NO/cGMP has an important effect on renal blood flow, along with anti-inflammatory, anti-fibrotic, and anti-proliferative actions in vascularized and non-vascularized regions of the renal cortex [58]. The dysregulation of NO-GC-cGMP is associated with an increased risk of CKD. It is believed that targeting the NO-sGC-cGMP axis is a potential therapeutic target, which may confer renal protection in experimental models. sGC can also be activated pharmacologically through specialized stimulators and activators, such as BI 685,509. Several trials are underway (NCT04750577, NCT04736628), and the role of this drug class in renal protection is still to be determined.
The state of the art of fetal hemoglobin-inducing agents
Published in Expert Opinion on Drug Discovery, 2022
Aline Renata Pavan, Juliana Romano Lopes, Jean Leandro Dos Santos
Another pathway that regulates γ-globin gene expression is the guanylate cyclase and the ⋅NO/cGMP signaling pathway. Soluble guanylate cyclase (sGC) converts guanosine triphosphate (GTP) to cyclic guanosine monophosphate (cGMP), which is an important second messenger that mediates several physiological processes, such as smooth muscle relaxation and platelet adhesion [86]. To demonstrate the role of sGC in γ-globin gene expression, researchers evaluated the level of expression of the subunits (α and β) that compose the enzyme in K562 cells. The results demonstrated that these cells expressed high levels of the α and β subunits, comparable to the levels found in the lungs and the brain cells. Also, a positive correlation was found between the expression of the α subunit and the expression of γ-globin. Furthermore, an sGC activator increased the γ-globin mRNA levels by five-fold to six-fold, and this effect disappeared when the cells were pre-treated with an sGC inhibitor. Similar results were found after the treatment of K562 cells and primary erythroblasts from healthy individuals and β-thalassemic patients with a cGMP analog (8-Br-cGMP), which indicated that modulation of sGC might be performed to regulate γ-globin gene expression and HbF induction [87].
Related Knowledge Centers
- Biochemical Cascade
- Cyclic Adenosine Monophosphate
- Cyclic Guanosine Monophosphate
- Enzyme
- G Protein
- Pyrophosphate
- Second Messenger System
- Guanosine Triphosphate
- Calcium Encoding
- Ion Channel