Guanylyl cyclases and signaling by cyclic GMP. Pharmacol Rev
ABSTRACT Guanylyl cyclases are a family of enzymes that catalyze the conversion of GTP to cGMP. The family comprises both membrane-bound and soluble isoforms that are expressed in nearly all cell types. They are regulated by diverse extracellular agonists that include peptide hormones, bacterial toxins, and free radicals, as well as intracellular molecules, such as calcium and adenine nucleotides. Stimulation of guanylyl cyclases and the resultant accumulation of cGMP regulates complex signaling cascades through immediate downstream effectors, including cGMP-dependent protein kinases, cGMP-regulated phosphodiesterases, and cyclic nucleotide-gated ion channels. Guanylyl cyclases and cGMP-mediated signaling cascades play a central role in the regulation of diverse (patho)physiological processes, including vascular smooth muscle motility, intestinal fluid and electrolyte homeostasis, and retinal phototransduction. Topics addressed in this review include the structure and chromosomal localization of the genes for guanylyl cyclases, structure and function of the members of the guanylyl cyclase family, molecular mechanisms regulating enzymatic activity, and molecular sequences coupling ligand binding to catalytic activity. A brief overview is presented of the downstream events controlled by guanylyl cyclases, including the effectors that are regulated by cGMP and the role that guanylyl cyclases play in cell physiology and pathophysiology.
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- "In order to evaluate if the CPA effect on basal cGMP accumulation is still observed under increased concentrations of cGMP, accumulation of cGMP was stimulated using sodium nitroprusside (100 μM), a NO donor and activator of soluble guanylyl cyclase (see Lucas et al., 2000). The effect of CPA on cGMP accumulation, in the absence or in the presence of SNP, was evaluated in both males and females Wistar rats. "
ABSTRACT: Adenosine A1 receptor is highly expressed in hippocampus where it inhibits neurotransmitter release and has neuroprotective activity. Similar actions are obtained by increasing cGMP concentration, but a clear link between adenosine A1 receptor and cGMP levels remains to be established. The present work aims to investigate if cGMP formation is modulated by adenosine A1 receptors at the hippocampus and if this effect is gender dependent. cGMP accumulation, induced by phosphodiesterases inhibitors Zaprinast (100μM) and Bay 60-7550 (10μM), and cAMP accumulation, induced by Forskolin (20μM) and Rolipram (50μM), were quantified in rat hippocampal slices using specific enzymatic immunoassays. N6-cyclopentyladenosine (CPA, 100nM) alone failed to modify basal cGMP accumulation. However, the presence of adenosine deaminase (ADA, 2U/ml) unmasked a CPA (0.03-300nM) stimulatory effect on basal cGMP accumulation (EC50: 4.2±1.4nM; Emax: 17%±0.9%). ADA influence on CPA activity was specific for cGMP, since inhibition of cAMP accumulation by CPA wasn't affected by the presence of ADA, though ADA inhibited cAMP accumulation in the absence of CPA. Increasing cGMP accumulation, by about four-fold, with sodium nitroprusside (SNP, 100μM) abolished the CPA (100nM) effect on cGMP accumulation in males but didn't modify the effect of CPA in female rats. This effect was reversed by 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX, 100nM), indicating an adenosine A1 receptor mediated effect on cGMP accumulation. In conclusion, adenosine A1 receptors increase intracellular cGMP formation at hippocampus both in males and females under basal conditions, but only in females when cGMP levels are increased by SNP.European Journal of Pharmacology 10/2014; 744. DOI:10.1016/j.ejphar.2014.09.045 · 2.68 Impact Factor
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- "The synthesis of NO is catalyzed by 3 NO synthase (NOS) isoforms . Neuronal NOS (nNOS or NOS1) and endothelial NOS (eNOS or NOS3) are constitutively expressed and their activity is regulated by intracellular calcium concentrations and calmodulin  . In an alternative pathway, eNOS can be activated by phosphorylation which renders it calcium-independent . "
ABSTRACT: Nitric oxide (NO) is a gaseotransmitter, which is involved in many signalling processes in health and disease. Three enzymes generate NO from L-arginine, with citrulline formed as a by-product: neuronal NO synthase (nNOS or NOS1), endothelial NOS (eNOS or NOS3) and inducible NOS (iNOS or NOS2). NO is a ligand of soluble guanylyl cyclase (sGC), an intracellular heterodimer enzyme that catalyzes the conversion of guanosine triphosphate (GTP) to cyclic GMP (cGMP). cGMP further activates protein kinase G that eventually reduces the smooth muscle tone in bronchi or vessels. Phosphodiesterase 5 (PDE5) degrades cGMP to GMP. However, NO reacts with superoxide anion (O2-), leading to formation of the proinflammatory molecule peroxynitrite. Under physiological conditions, NO plays a homeostatic bronchoprotective role in healthy subjects. In obstructive airway diseases, NO can be beneficial by its bronchodilating effect, but could also be detrimental by the formation of peroxynitrite. Since asthma and COPD are associated with increased levels of exhaled NO, chronic inflammation and increased airway smooth muscle tone, the NO/sGC/cGMP pathway could be involved in these highly prevalent obstructive airway diseases. Here we review the involvement of NO, NO synthases, guanylyl cyclases, cGMP and phophodiesterase-5 in asthma and COPD and potential therapeutic approaches to modulate this pathway.Pulmonary Pharmacology & Therapeutics 10/2014; 29(1). DOI:10.1016/j.pupt.2014.07.004 · 2.57 Impact Factor
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- "Guanylate cyclase-C (GC-C) is a type I transmembrane receptor with intrinsic guanylate cyclase activity, belonging to a larger family of enzymes comprising both soluble and receptor guanylate cyclases that respond to a diverse range of signals by catalyzing the conversion of guanosine triphosphate to cyclic guanosine-3 ,5 monophosphate (cGMP; Lucas et al., 2000; Vaandrager, 2002). "
ABSTRACT: Activation of guanylate cyclase-C (GC-C) expressed predominantly on intestinal epithelial cells by guanylin, uroguanylin or the closely related GC-C agonist peptide, linaclotide, stimulates generation, and release of cyclic guanosine-3',5'-monophosphate (cGMP). Evidence that the visceral analgesic effects of linaclotide are mediated by a novel, GC-C-dependent peripheral sensory mechanism was first demonstrated in animal models of visceral pain. Subsequent studies with uroguanylin or linaclotide have confirmed the activation of a GC-C/cGMP pathway leading to increased submucosal cGMP mediated by cGMP efflux pumps, which modulates intestinal nociceptor function resulting in peripheral analgesia. These effects can be reproduced by the addition of exogenous cGMP and support a role for GC-C/cGMP signaling in the regulation of visceral sensation, a physiological function that has not previously been linked to the GC-C/cGMP pathway. Notably, targeting the GC-C/cGMP pathway for treatment of gastrointestinal pain and abdominal sensory symptoms has now been validated in the clinic. In 2012, linaclotide was approved in the United States and European Union for the treatment of adult patients with irritable bowel syndrome with constipation.Frontiers in Molecular Neuroscience 04/2014; 7:31. DOI:10.3389/fnmol.2014.00031 · 4.08 Impact Factor