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The Beneficial Effect of Omega-3 PUFA and L-Arginine on Endothelial Nitric Oxide (NO) Bioavailability
Published in Robert Fried, Richard M. Carlton, Flaxseed, 2023
Robert Fried, Richard M. Carlton
NO diffuses across the muscle cell membrane and binds to guanylyl cyclase. Guanylyl cyclase in turn catalyzes the synthesis of cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP). cGMP then activates a cGMP-dependent protein kinase, which stimulates the uptake of calcium by the endoplasmic reticulum of the smooth muscle cell. The reduced levels of cytoplasmic calcium cause the muscle cell to relax.
The Role of Nitric Oxide Signaling in the Pathogenesis of Necrotizing Enterocolitis
Published in David J. Hackam, Necrotizing Enterocolitis, 2021
Anatoly Grishin, Patrick T. Delaplain, Jin Wang, Michael Mallicote, Michelle Nguyen, Michael Philippe-Auguste, Christopher P. Gayer, Henri R. Ford
NO-cGMP-PKG cascade: In a variety of cell types, soluble NO-dependent guanylate cyclase (NO-GC) serves as a specific high-affinity NO receptor. Guanylate cyclase activity converts GTP into cGMP, an intracellular second messenger. NO-GC is a heme-containing heterodimer consisting of α- and β-subunits. Binding of NO to the heme prosthetic group increases guanylate cyclase activity of NO-GC two orders of magnitude (27). NO-GC was found in all tissues tested (28), particularly in the intestine (29), where it is histochemically prominent in fibroblast-like cells, neurons, interstitial cells of Cajal, and smooth muscle cells (30) and functionally expressed in the epithelium (31–33). NO-GC–derived cGMP activates the isoforms of cGMP-dependent protein kinase (PKG) (34), which in turn phosphorylates multiple substrates whose repertory in various cell types determines the physiological outcomes of NO-cGMP-PKG signaling (34). Although low (nanomolar) concentrations of eNOS- or nNOS-derived NO are typically sufficient for activation of the NO-cGMP-PKG cascade, this cascade cannot be insulated from high concentrations of iNOS-derived NO (35). Accordingly, sustained activation of NO-cGMP-PKG signaling should be considered to occur under inflammatory conditions. An important consequence of such sustained activation is the loss of homeostatic effects of NO, which require a delicate balance with other stimuli.
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).
Signaling mechanisms of the platelet glycoprotein Ib-IX complex
Published in Platelets, 2022
Yaping Zhang, Samuel M Ehrlich, Cheng Zhu, Xiaoping Du
Both VWF and low-dose thrombin induce elevation of intracellular cGMP (cyclic guanosine monophosphate), which activates the cGMP-dependent protein kinase (PKG) [88]. cGMP plays biphasic role in platelet activation: low concentrations of cGMP generated in the early phase of platelet activation, via PKG, promote integrin activation and granule secretion mediated by GPIb-IX and other receptors [88,90]. High concentrations of cGMP and cGMP generated at later phases of thrombus formation inhibit platelet activation and limit the growth of platelet thrombi [88,91] via PKG and PKA-dependent signaling pathways [12]. The biphasic role of cGMP provides a potential explanation as to why GPIb-IX-mediated platelet activation is often seen as “measured” or “weak” and platelets adherent on the surface of a thrombus exposed to high shear appear less activated despite clear evidence of integrin activation.
Vericiguat for the treatment of heart failure: mechanism of action and pharmacological properties compared with other emerging therapeutic options
Published in Expert Opinion on Pharmacotherapy, 2021
Jean-Sébastien Hulot, Jean-Noël Trochu, Erwan Donal, Michel Galinier, Damien Logeart, Pascal De Groote, Yves Juillière
sGC has a key role in generating cGMP [9] with sGC-derived production of cGMP being essential for normal cardiac and vascular function [10–12]. cGMP is indeed a key second messenger to mediate vaso- and cardiac relaxation. In HF, NO availability and functionality of sGC are impaired, resulting in an increased oxidative stress and loss of cGMP production. In other terms, the NO−sGC−cGMP pathway is impaired in HF which may contribute to the progression of cardiovascular disease (CVD) in terms of endothelial, myocardial and vascular dysfunction [11,13]. Notably, a deficiency in cGMP is common to both HFrEF and HFpEF [12]. Oxidative stress can also stimulate autophagy, apoptosis, or necrosis, leading to the loss of cardiomyocytes and their replacement with collagen, and to fibrosis [14,15]. Moreover, left-ventricular remodeling/stiffness is associated with hypophosphorylation of titin found in cardiomyocytes which is associated with an impaired cGMP-dependent protein kinase G (PKG) activity [16–18]. Titin is the third myofilament of the cardiac muscle [19]. By having direct and indirect links with several signaling molecules and having multiple phosphorylation sites in the Z-disk, M-band, and I-band (containing the N2B element) segments, titin is recognized as a major regulator of cardiomyocyte stiffness. For example, the level of phosphorylation of the N2B element, notably through PKG, regulates the myofibrillar stiffness [19].
Learning about quantitative genetics from Marla Sokolowski
Published in Journal of Neurogenetics, 2021
When I first met Marla, I was at New York University and she was on the faculty at York University outside Toronto. My postdoc, Alain Robichon, an experienced biochemist, was eager to carry out the enzymological studies of cGMP-dependent protein kinase in Rover, sitter, and wild-type Drosophila. This proved to be a productive line of research, as expected given Marla’s careful genetic identification of the gene encoding that enzyme as the structural locus of foraging. Her mapping of the gene had already proven her genetic acumen and persistence. She had used the rather esoteric approach of mapping the gene to a chromosome arm through the use of compound autosomes (2nd and 3rd chromosomes rearranged so as to have both left arms and both right arms attached to the same centromeres). This strategy was necessary at that time. In the late 90’s, there was no other way to map the gene in the absence of any known polymorphisms.