Intestinal Chloride Secretion: Cyclic Amp and Ca2+ Interactions
T. S. Gaginella in Regulatory Mechanisms — in — Gastrointestinal Function, 2017
Cyclic GMP, discovered shortly after cAMP, is an intracellular signaling molecule that interacts with three types of intracellular receptor proteins: cGMP-dependent protein kinases, cGMP-regulated ion channels, and cyclic nucleotide PDEs.315 The role of cGMP as a second messenger was perceived for some time as antagonistic to the role of cAMP, with the concentration of the former rising when the concentration of the latter went down and conversely.245 It is now clear, however, that cGMP acts as a signaling molecule in many different cells, and it likely serves as a second messenger in virtually all cells.316 Two classes of cGMP kinases exist: a type I, with a mass of ~78 kDa, and type II of -86 kDa, present only in the plasma membrane of enterocytes.315,317 Interestingly, the proteins phosphorylated by cGMP kinases also include protein kinase A. The effects of cGMP on ion channels are strictly dependent on cell type: cGMP increases Na+ and Ca2+ influx through a cation channel in the retinal rod outer segment,318 whereas in the inner medullary collecting duct it inhibits Na+transport through an amiloride-sensitive cation channel by a pathway involving a G protein.319
Vascular Reactivity in Streptozotocin-Induced Diabetes
John H. McNeill in Experimental Models of Diabetes, 2018
Cyclic GMP is believed to be responsible for mediating the relaxant responses of vascular smooth muscle to endothelial NO released tonically in the absence of vasodilators, and in response to receptor stimulation (see Reference 44 for a review). It follows that tonic release of NO from the endothelium of rat arteries can be monitored by measuring basal cGMP levels in these arteries. In an investigation from this laboratory, no significant difference in cGMP levels in endothelium-intact aortae from 12- to 14-week diabetic rats compared with control was detected, while removal of the endothelium resulted in a decrease in cGMP levels of both control and diabetic aortae to the same extent.37 In contrast, a marked and significant decrease in basal cGMP levels was detected in 8- to 10-week endothelium-intact diabetic aortae compared with control by another group.91 The only difference of note in experimental procedures between the two studies was the duration of diabetes, leading to the possibility that the basal release of NO is diminished at 8 weeks of diabetes but has returned to normal 1 month later. However, it is impossible to rule out other factors that may have contributed to a difference in results between the two studies. Interestingly, in a later investigation from the same laboratory, cGMP levels in the effluent of the perfused mesenteric bed from 10-week diabetic rats were not significantly different from control, suggesting that basal release of NO may not be altered in this preparation at this stage of diabetes.92
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).
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.
An update on arginine in sickle cell disease
Published in Expert Review of Hematology, 2019
Bruno Deltreggia Benites, Sara Teresinha Olalla-Saad
Parallel to the effect on the local availability of O2, additional mechanisms recently highlighted for the regulation of this process by RBCs is their ability to scavenge nitric oxide and effects on the endothelial production of nitric oxide itself. First described in the 1980s as the endothelium relaxation factor (EDRF) [20], nitric oxide (NO) has since been recognized as a potent blood vessel relaxant. NO molecules are constitutively synthesized in endothelial cells by the action of the endothelial nitric oxide synthase (eNOS), which uses L-arginine and molecular oxygen (O2) as the substrate to produce NO and l-citrulline. This chain of reactions occurs by electron transfer from tetrahydrobiopterin (BH4), to reduce and activate O2, culminating in the oxidation of l-arginine to NO. The gas then diffuses through the endothelium to the vascular smooth muscle cells, promoting vasodilation through binding to soluble guanylyl cyclase and consequently increasing intracellular cyclic GMP [21].
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)).
Related Knowledge Centers
- Atrial Natriuretic Peptide
- Catalysis
- Cyclic Adenosine Monophosphate
- Cyclic Nucleotide
- Guanylate Cyclase
- Peptide Hormone
- Protein Kinase
- Second Messenger System
- Cell Membrane
- Guanosine Triphosphate