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Dopamine Receptors, Signaling Pathways, and Drugs
Published in Nira Ben-Jonathan, Dopamine, 2020
Several PDE5 inhibitors, e.g., sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra) are used to treat erectile dysfunction and have an excellent safety record [58]. Cialis is the longest acting of the three drugs and has been recently on clinical trials to treat head and neck cancer [59]. The main targets of cGMP are two kinases—PKG-I and PKG-II [60]—both of which are inhibited by KT5823. The PKG-I gene is expressed as cytosolic PKG-Iα or PKG-Iβ isoform, while the PKG-II gene is expressed as a membrane-associated PKG-II protein. The kinetics, localization and substrates of the PKG enzymes differ. The PKGs phosphorylate many downstream effectors, some of which overlap with those that are targeted by PKA, while others are distinct. In many, but not all, cell types, activated PKG leads to the suppression of cell proliferation and/or apoptosis.
Heart failure with preserved ejection fraction in older adults
Published in Wilbert S. Aronow, Jerome L. Fleg, Michael W. Rich, Tresch and Aronow’s Cardiovascular Disease in the Elderly, 2019
Bharathi Upadhya, Dalane W. Kitzman
Aging changes along with multiple comorbidities, such as obesity, diabetes, and HTN in HFpEF may initiate and/or aggravate chronic systemic inflammation that may affect myocardial remodeling and dysfunction in HFpEF through a signaling cascade, which may begin with coronary microvascular endothelial dysfunction (14,123). It subsequently involves myocardial infiltration by activated macrophages, which induce reactive interstitial fibrosis (124) and altered paracrine communication between endothelial cells and surrounding cardiomyocytes (123). This reduces myocardial nitric oxide (NO) bioavailability and leads to reduced protein kinase G (PKG) activity in cardiomyocytes, which become stiff and hypertrophied (14). These alterations also promote microvascular dysfunction and rarefaction in cardiac (48) and skeletal muscle (107,125). In addition, chronic systemic inflammation affects other organs such as lungs and kidneys. This new paradigm led to a recent study which aims to determine whether the combination of systematic screening and optimal management of prespecified comorbidities associated with HFpEF improves outcomes (126).
Cell Biology
Published in John D Firth, Professor Ian Gilmore, MRCP Part 1 Self-Assessment, 2017
John D Firth, Professor Ian Gilmore
Signal transduction within a cell commonly results in phosphorylation and activation of key intracellular proteins such as ion channels, enzymes or transporters that are the effectors of biological responses. These phosphorylation reactions often occur at serine or threonine residues and are catalysed by kinases, which are themselves activated by the binding of intracellular messengers. Protein kinase A is activated by cAMP, protein kinase G by cGMP, and protein kinase C by diacylglycerol.
Zinc improves sexual and erectile function in HAART-treated rats via the upregulation of erectogenic enzymes and maintenance of redox balance
Published in The Aging Male, 2023
R. E. Akhigbe, M. A. Hamed, A. F. Odetayo, T. M. Akhigbe, P. A. Oyedokun
Erectile function is maintained by NO/cGMP signaling [41,42]. On sexual stimulation, NO is released from the parasympathetic nerves into the smooth muscle cells of the arteries of the corporal cavernosum to activate soluble guanylate cyclase (sGC), which converts guanosine triphosphate to cGMP that in turn causes the smooth muscle relaxation and increased blood flow to the penis via protein kinase G [41,42]. The expression and activity of cGMP are inhibited by PGE-5, an enzyme that degrades cGMP to inactive GMP [43]. The observed decline in cGMP levels in HAART-treated rats may be due to HAART-driven rise in PDE-5, which may cause rapid hydrolysis of cGMP. This may explain the noted impaired penile erection seen in HAART-treated rats as cGMP is essential for the relaxation of the trabecular smooth muscle, increased penile blood flow, and erection.
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.
Emerging drugs for the treatment of bladder storage dysfunction
Published in Expert Opinion on Emerging Drugs, 2022
NO binds to the heme group on the β-subunit of sGC, activating its catalytic domain to convert GTP to cGMP. This in turn activates protein kinase G (PKG), phosphorylating multiple downstream proteins. Therapeutically, direct delivery of NO donor drugs has disadvantages, for example, vasodilatation and development of tolerance during long-term administration, and therefore attempts were made to find drugs that act directly on sGC in an NO-independent manner. YC-1 was the first NO-independent and heme-dependent sGC stimulator but owing to the poor adverse effect profile of YC-1, novel compounds with increased potency and selectivity were developed [112–114], primarily for treatment of cardiovascular diseases: NO-independent, heme-dependent stimulators of sGC (BAY 41–2272, BAY 41–8523, BAY 63–2521, and BAY 60–4552) and NO-independent, heme-independent sGC activators (HMR 1766, BAY 58–2667, and BAY 60–2770). These drugs may be effective for patients who are refractory to PDE5Is.