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Ischemic Inhibition of Calcium Slow Current in the Heart
Published in Samuel Sideman, Rafael Beyar, Analysis and Simulation of the Cardiac System — Ischemia, 2020
The Ca2+ influx of the myocardial cell is controlled by extrinsic factors. For example, stimulation of the sympathetic nerves of the heart has a positive inotropic action, whereas stimulation of the parasympathetic neurons has a negative inotropic effect. The mechanism for some of these effects is mediated by changes in the levels of the cyclic nucleotides. This extrinsic control of the Ca2+ influx is made possible by the peculiar properties of the slow channels, as, for example, their regulation by the cyclic nucleotides and phosphorylation.
Serotonin in the Intestinal Tract: A Synopsis
Published in T.S. Gaginella, J.J. Galligan, SEROTONIN and GASTROINTESTINAL FUNCTION, 2020
Sympathomimetic stimulation can also influence 5-HT release. The effect may be direct or through stimulation of the vagus and splanchnic nerves.42,77 Noradrenergic nerve fibers have been observed in close proximity to EC cells.78 Propranolol, the P-adrenoceptor antagonist, blocks the 5-HT release induced by catecholamines or vagal stimulation.79–81 This effect is still observed after neural blockade with tetrodotoxin, suggesting that the release is mediated by (β-adrenoceptors localized to EC cells. That cyclic AMP is involved in this response is indicated by findings that 8-bromo-cyclic-AMP, as well as an inhibitor cyclic nucleotide phosphodiesterase, and the stimulant of adenylate cyclase forskolin all increased the release of 5-HT by the rabbit small intestine.54 Alpha-adrenoceptors of the α2-subtype mediate an inhibitory effect on 5-HT release.77
The Application of Fragment-based Approaches to the Discovery of Drugs for Neglected Tropical Diseases
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Christina Spry, Anthony G. Coyne
Cyclic nucleotide phosphodiesterases (PDEs) play a key role in regulating levels of cyclic nucleotides in cells through hydrolysis of the phosphodiester bond of cAMP and/or cGMP. Two 3’,5’-cyclic nucleotide phosphodiesterases (PDEB1 and B2, which are 76.2% similar to each other) have been shown using RNAi (Oberholzer et al. 2007), as well as with a small molecule inhibitor (de Koning et al. 2012), to be essential for proliferation of T. brucei in vitro and in vivo when knocked down together. Two distinct fragment-based approaches targeting these enzymes have been published.
Erianin Exerts Antineoplastic Effects on Esophageal Squamous Cell Carcinoma Cells by Activating the cGMP-PKG Signaling Pathway
Published in Nutrition and Cancer, 2023
Xin Deng, Qianfeng Wu, Dong Li, Youping Liu
Protein Kinase G (PKG) is a cyclic adenosine phosphate-dependent protein kinase found in vascular smooth muscle cells, platelets, and intestinal mucosa (11). By acting on multiple effectors such as cyclic nucleotide signaling, cytoskeletal-related peptides, and calcium signaling regulatory proteins, activated PKG regulates vascular smooth muscle relaxation, platelet functions, mitochondrial biogenesis, bone remodeling, tumor cell survival, cardiac protection, and other physiological processes (12–16). Imbalance in the cGMP/PKG signaling pathway is a critical regulator of tumor aggressiveness; however, its role in cancer is tumor specific. Activation of the cGMP/PKG signaling pathway, for example, results in antitumor effects in prostate and renal cancer but enhances tumor stemness and metastasis in cervical and breast cancer (17–20). Therefore, it is vital to evaluate whether the cGMP/PKG signaling pathway plays a role in the anti-ESCC effects of erianin.
Potential and limitations of PKA/ PKG inhibitors for platelet studies
Published in Platelets, 2022
Valentina Shpakova, Natalia Rukoyatkina, Ulrich Walter, Stepan Gambaryan
Cyclic nucleotides (cAMP and cGMP) and corresponding protein kinases, protein kinase A (PKA) and protein kinase G (PKG), are the main mediators of the intracellular effects of endothelium-derived platelet inhibitors [1–3]. Endothelial cells of blood vessels release short-lived mediators such as nitric oxide (NO) and prostacyclin (PGI2) which activate soluble guanylate cyclase (sGC) and adenylate cyclase (AC) respectively. The main source of NO which can reach platelets is the NO synthase of endothelial cells (eNOS), however, a minor amount of NO can also be produced by reduction of nitrite to NO, a reaction which includes activation of carbonic anhydrase [4,5]. NO activates sGC, which is the only enzyme responsible for cGMP synthesis in platelets [6] which leads to PKG activation and phosphorylation of target proteins involved in platelet inhibitory pathways. cAMP synthesis is started by binding of prostacyclin (PGI2) or adenosine to G protein-coupled receptors (GPCRs) which are linked to Gs heterotrimeric G-protein and stimulate adenylate cyclase. Elevated cAMP activates PKA by binding to regulatory (PKAr) subunits, which causes dissociation of the kinase complex, a release of free active catalytic subunits (PKAc) [7], and phosphorylation of target proteins also involved in platelet inhibitory pathways.
An update of cyclic nucleotide phosphodiesterase as a target for cardiac diseases
Published in Expert Opinion on Drug Discovery, 2021
There has been increasing interest and effort to understand how the versatility/specificity of diverse cyclic nucleotide-mediated functions are achieved in individual cell types. In the past decade, approaches using subcellular-targeted Fluorescence Resonance Energy Transfer (FRET)-based cAMP/cGMP sensors have significantly advanced this field by demonstrating that cAMP/cGMP are not freely diffusible and multiple compartmentalized cAMP/cGMP ‘pools’ exist in the cell [24–28] (for detailed reviews, see references [29–31]). It is believed that the versatility/specificity of cAMP/cGMP signaling is achieved through compartmentalization of diverse, discrete cAMP/cGMP pools that are associated with different multi-protein complexes each containing unique cyclases, PDEs, kinases, and other signaling molecules, leading to different biological functions (Figure 1).