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Nontoxic RsDPLA As a Potent Antagonist of Toxic Lipopolysaccharide
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Nilofer Qureshi, Bruce W. Jarvis, Kuni Takayama
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
Published in Claude Gagnon, 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.
Neurophysiology in neurotrauma
Published in Hemanshu Prabhakar, Charu Mahajan, Indu Kapoor, Essentials of Anesthesia for Neurotrauma, 2018
Endothelium-derived relaxing factor (EDRF) has been identified as nitric oxide (NO) or a NO-containing substance that is produced in cerebral blood vessels. Its action is mediated by the activation of guanylate cyclase and formation of cyclic GMP. An impaired endothelium-dependent response with a decreased production of EDRF but increased release of endothelium-derived contracting factors, such as endothelin and arachidonic acid, has been reported in subarachnoid hemorrhage.
Cyclic guanosine monophosphate and 10-year change in left ventricular mass: the Multi-Ethnic Study of Atherosclerosis (MESA)
Published in Biomarkers, 2021
Vinita Subramanya, Di Zhao, Pamela Ouyang, Wendy Ying, Dhananjay Vaidya, Chiadi E. Ndumele, Joao A. Lima, Eliseo Guallar, Ron C. Hoogeveen, Sanjiv J. Shah, Susan R. Heckbert, David A. Kass, Wendy S. Post, Erin D. Michos
Cyclic GMP is synthesized intracellularly from either sGC, which is responsive to NO activation, or receptor guanylyl cyclase which is stimulated by NP. Both NO and NPs can stimulate production of cGMP via intracellular and cell surface pathways, respectively. To get into the plasma, the cGMP must be secreted and this has been shown to occur far more with NP than with NO stimulation (Castro et al.2006, Takimoto 2007). This is because NO-sGC derived cGMP is formed in small amounts in intracellular nanodomains and is often hard to detect, whereas NP-generated cGMP occurs at the plasma membrane and can be secreted by ABC transporters. Thus, our associations of plasma cGMP and LVM most likely reflect NP more than NO pathways. In these same statistical models, we found that baseline and 10-year change in NT-proBNP were positively associated with increased LVM. The positive association we found of cGMP and greater 10-year change in LVM index was still significant after adjustment for NT-proBNP indicating this association was not all entirely mediated by NT-proBNP status.
Fever-range hyperthermia promotes cGAS-STING pathway and synergizes DMXAA-induced antiviral immunity
Published in International Journal of Hyperthermia, 2021
Inam Ullah Khan, Gabriel Brooks, Nina Ni Guo, Junsong Chen, Fang Guo
Cyclic GMP-AMP Synthase (cGAS) triggers the reaction of GTP and ATP to form cGAMP. To test if the increased expression of cGAS and hence FRT, could also increase the production of cGAMP in the cells; cells with and without htDNA transfection were heated at 39.5 °C and the synthesis of cGAMP was assessed by its ability to induce IRF3 phosphorylation and thus its dimerization, using native gel electrophoresis. HT at 39.5 °C showed higher IRF3 phosphorylation in htDNA transfected cells indicating increased production of cGAMP as compared to 37 °C. No significant difference in the degree of phosphorylation was seen in cells with or without htDNA transfection at 37 °C or in cells at 39.5 °C without DNA transfection showing no increased production of cGAMP (Figure 3(A). As expected, cGAS−/− did not show such difference in the degree of phosphorylation among the four groups with or without htDNA (Figure 3(B)).
Effect of tadalafil and nitric oxide agonist sodium nitroprusside on penicillin-induced epileptiform activity
Published in Neurological Research, 2020
Tadalafil is commonly used in the pharmacological treatment of sexual dysfunction. It is a potent and selective inhibitor of phosphodiesterase 5 (PDE5), an enzyme that hydrolyzes cyclic GMP (cGMP). It increases cGMP in smooth muscles and helping to remedy erectile function [5]. Although tadalafil is known to have side effects such as headache, redness, nasal congestion, dyspepsia, visual impairment, its precise effect on seizure formation is not known in men. The safety of tadalafil on epileptic patients is questionable [6].Calabro et al. [7] reported development of generalized tonic-clonic seizures in a healthy young man following tadalafil intake. Studying EEG records of 35 erectile dysfunction patients who had 20 mg/kg tadalafil, Okuyucu et al. [8] demonstrated EEG abnormalities 2 and 48 h after a single administration. In an experimental epilepsy study, tadalafil has facilitated seizure development in rats exposed to hyperbaric oxygen [9]. In the PTZ-induced experimental epilepsy model, seizures increased after injection of 20 mg/kg tadalafil [10]. Thus, it seems that tadalafil may exert proconvulsive effects.