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Cell Reports. Medicine Apr 2023Diabetic kidney disease (DKD) is the most common cause of renal failure. Therapeutics development is hampered by our incomplete understanding of animal models on a...
Diabetic kidney disease (DKD) is the most common cause of renal failure. Therapeutics development is hampered by our incomplete understanding of animal models on a cellular level. We show that ZSF1 rats recapitulate human DKD on a phenotypic and transcriptomic level. Tensor decomposition prioritizes proximal tubule (PT) and stroma as phenotype-relevant cell types exhibiting a continuous lineage relationship. As DKD features endothelial dysfunction, oxidative stress, and nitric oxide depletion, soluble guanylate cyclase (sGC) is a promising DKD drug target. sGC expression is specifically enriched in PT and stroma. In ZSF1 rats, pharmacological sGC activation confers considerable benefits over stimulation and is mechanistically related to improved oxidative stress regulation, resulting in enhanced downstream cGMP effects. Finally, we define sGC gene co-expression modules, which allow stratification of human kidney samples by DKD prevalence and disease-relevant measures such as kidney function, proteinuria, and fibrosis, underscoring the relevance of the sGC pathway to patients.
Topics: Humans; Rats; Animals; Soluble Guanylyl Cyclase; Diabetic Nephropathies; Guanylate Cyclase; Kidney; Fibrosis; Diabetes Mellitus
PubMed: 37023747
DOI: 10.1016/j.xcrm.2023.100992 -
Molecules (Basel, Switzerland) Jun 2021For years, guanylate cyclase seemed to be homogenic and tissue nonspecific enzyme; however, in the last few years, in light of preclinical and clinical trials, it became... (Review)
Review
For years, guanylate cyclase seemed to be homogenic and tissue nonspecific enzyme; however, in the last few years, in light of preclinical and clinical trials, it became an interesting target for pharmacological intervention. There are several possible options leading to an increase in cyclic guanosine monophosphate concentrations. The first one is related to the uses of analogues of natriuretic peptides. The second is related to increasing levels of natriuretic peptides by the inhibition of degradation. The third leads to an increase in cyclic guanosine monophosphate concentration by the inhibition of its degradation by the inhibition of phosphodiesterase type 5. The last option involves increasing the concentration of cyclic guanosine monophosphate by the additional direct activation of soluble guanylate cyclase. Treatment based on the modulation of guanylate cyclase function is one of the most promising technologies in pharmacology. Pharmacological intervention is stable, effective and safe. Especially interesting is the role of stimulators and activators of soluble guanylate cyclase, which are able to increase the enzymatic activity to generate cyclic guanosine monophosphate independently of nitric oxide. Moreover, most of these agents are effective in chronic treatment in heart failure patients and pulmonary hypertension, and have potential to be a first line option.
Topics: Animals; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Guanylate Cyclase; Humans; Molecular Targeted Therapy; Natriuretic Peptides; Signal Transduction; Soluble Guanylyl Cyclase; Up-Regulation
PubMed: 34200064
DOI: 10.3390/molecules26113418 -
Frontiers in Endocrinology 2022Receptor Guanylyl Cyclase C (GC-C) was initially characterized as an important regulator of intestinal fluid and ion homeostasis. Recent findings demonstrate that GC-C... (Review)
Review
Receptor Guanylyl Cyclase C (GC-C) was initially characterized as an important regulator of intestinal fluid and ion homeostasis. Recent findings demonstrate that GC-C is also causally linked to intestinal inflammation, dysbiosis, and tumorigenesis. These advances have been fueled in part by identifying mutations or changes in gene expression in GC-C or its ligands, that disrupt the delicate balance of intracellular cGMP levels and are associated with a wide range of clinical phenotypes. In this review, we highlight aspects of the current knowledge of the GC-C signaling pathway in homeostasis and disease, emphasizing recent advances in the field. The review summarizes extra gastrointestinal functions for GC-C signaling, such as appetite control, energy expenditure, visceral nociception, and behavioral processes. Recent research has expanded the homeostatic role of GC-C and implicated it in regulating the ion-microbiome-immune axis, which acts as a mechanistic driver in inflammatory bowel disease. The development of transgenic and knockout mouse models allowed for in-depth studies of GC-C and its relationship to whole-animal physiology. A deeper understanding of the various aspects of GC-C biology and their relationships with pathologies such as inflammatory bowel disease, colorectal cancer, and obesity can be leveraged to devise novel therapeutics.
Topics: Animals; Cyclic GMP; Inflammatory Bowel Diseases; Mice; Receptors, Enterotoxin; Receptors, Guanylate Cyclase-Coupled; Signal Transduction
PubMed: 35846281
DOI: 10.3389/fendo.2022.911459 -
Methods in Enzymology 2022Cyclic GMP is produced by enzymes called guanylyl cyclases, of which the membrane-associated forms contain an intracellular pseudokinase domain that allosterically... (Review)
Review
Cyclic GMP is produced by enzymes called guanylyl cyclases, of which the membrane-associated forms contain an intracellular pseudokinase domain that allosterically regulates the C-terminal guanylyl cyclase domain. Ligand binding to the extracellular domain of these single transmembrane-spanning domain receptors elicits an increase in cGMP levels in the cell. The pseudokinase domain (or kinase-homology domain) in these receptors appears to be critical for ligand-mediated activation. While the pseudokinase domain does not possess kinase activity, biochemical evidence indicates that the domain can bind ATP and thereby allosterically regulate the catalytic activity of these receptors. The pseudokinase domain also appears to be the site of interaction of regulatory proteins, as seen in the retinal guanylyl cyclases that are involved in visual signal transduction. In the absence of structural information on the pseudokinase-guanylyl cyclase domain organization of any member of this family of receptors, biochemical evidence has provided clues to the physical interaction of the pseudokinase and guanylyl cyclase domain. An α-helical linker region between the pseudokinase domain and the guanylyl cyclase domain regulates the basal activity of these receptors in the absence of a stimulatory ligand and is important for stabilizing the structure of the pseudokinase domain that can bind ATP. Here, we present an overview of salient features of ATP-mediated regulation of receptor guanylyl cyclases and describe biochemical approaches that allow a clearer understanding of the intricate interplay between the pseudokinase domain and catalytic domain in these proteins.
Topics: Adenosine Triphosphate; Amino Acid Sequence; Cyclic GMP; Guanylate Cyclase; Ligands
PubMed: 35525553
DOI: 10.1016/bs.mie.2022.03.046 -
British Journal of Pharmacology Jun 2022In the late 1960s, several labatories identified guanylyl cyclase (GC) as the cGMP-producing enzyme. Subsequently, two different types of GC were described that differed... (Review)
Review
In the late 1960s, several labatories identified guanylyl cyclase (GC) as the cGMP-producing enzyme. Subsequently, two different types of GC were described that differed in their cellular localization. Primarily found in the cytosol, nitric oxide (NO)-sensitive guanylyl cyclase (NO-GC) acts as receptor for the signalling molecule NO, in contrast the membrane-bound isoenzyme is activated by natriuretic peptides. The lung compared with other tissues exhibits the highest expression of NO-GC. The enzyme has been purified from lung for biochemical analysis. Although expressed in smooth muscle cells (SMCs) and in pericytes, the function of NO-GC in lung, especially in pericytes, is still not fully elucidated. However, pharmacological compounds that target NO-GC are available and have been implemented for the therapy of pulmonary arterial hypertension. In addition, NO-GC has been suggested as drug target for the therapy of asthma, acute respiratory distress syndrome and pulmonary fibrosis. LINKED ARTICLES: This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc.
Topics: Cyclic GMP; Guanylate Cyclase; Lung; Nitric Oxide; Soluble Guanylyl Cyclase
PubMed: 33332689
DOI: 10.1111/bph.15345 -
Trends in Pharmacological Sciences Feb 2022Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by abdominal pain and altered bowel habit that affects ~11% of the global population.... (Review)
Review
Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by abdominal pain and altered bowel habit that affects ~11% of the global population. Over the past decade, preclinical and clinical studies have revealed a variety of novel mechanisms relating to the visceral analgesic effects of guanylate cyclase-C (GC-C) agonists. Here we discuss the mechanisms by which GC-C agonists target the GC-C/cyclic guanosine-3',5'-monophosphate (cGMP) pathway, resulting in visceral analgesia as well as clinically relevant relief of abdominal pain and other sensations in IBS patients. Due to the preponderance of evidence we focus on linaclotide, a 14-amino acid GC-C agonist with very low oral bioavailability that acts within the gut. Collectively, the weight of experimental and clinical evidence supports the concept that GC-C agonists act as peripherally acting visceral analgesics.
Topics: Abdominal Pain; Chronic Pain; Guanylate Cyclase; Guanylyl Cyclase C Agonists; Humans; Irritable Bowel Syndrome; Visceral Pain
PubMed: 34865885
DOI: 10.1016/j.tips.2021.11.002 -
Antioxidants & Redox Signaling Jan 2017Soluble guanylyl/guanylate cyclase (sGC) is the primary receptor for nitric oxide (NO) and is central to the physiology of blood pressure regulation, wound healing,... (Review)
Review
SIGNIFICANCE
Soluble guanylyl/guanylate cyclase (sGC) is the primary receptor for nitric oxide (NO) and is central to the physiology of blood pressure regulation, wound healing, memory formation, and other key physiological activities. sGC is increasingly implicated in disease and is targeted by novel therapeutic compounds. The protein displays a rich evolutionary history and a fascinating signal transduction mechanism, with NO binding to an N-terminal heme-containing domain, which activates the C-terminal cyclase domains. Recent Advances: Crystal structures of individual sGC domains or their bacterial homologues coupled with small-angle x-ray scattering, electron microscopy, chemical cross-linking, and Förster resonance energy transfer measurements are yielding insight into the overall structure for sGC, which is elongated and likely quite dynamic. Transient kinetic measurements reveal a role for individual domains in lowering NO affinity for heme. New sGC stimulatory drugs are now in the clinic and appear to function through binding near or directly to the sGC heme domain, relieving inhibitory contacts with other domains. New sGC-activating drugs show promise for recovering oxidized sGC in diseases with high inflammation by replacing lost heme.
CRITICAL ISSUES
Despite the many recent advances, sGC regulation, NO activation, and mechanisms of drug binding remain unclear. Here, we describe the molecular evolution of sGC, new molecular models, and the linked equilibria between sGC NO binding, drug binding, and catalytic activity.
FUTURE DIRECTIONS
Recent results and ongoing studies lay the foundation for a complete understanding of structure and mechanism, and they open the door for new drug discovery targeting sGC. Antioxid. Redox Signal. 26, 107-121.
Topics: Animals; Drug Discovery; Enzyme Activation; Gene Expression; Guanosine Triphosphate; Guanylate Cyclase; Heme; Humans; Models, Molecular; Molecular Conformation; Nitric Oxide; Protein Binding; Protein Interaction Domains and Motifs; Protein Subunits; Signal Transduction; Soluble Guanylyl Cyclase; Structure-Activity Relationship
PubMed: 26979942
DOI: 10.1089/ars.2016.6693 -
International Journal of Molecular... Jan 2021Plants as sessile organisms face daily environmental challenges and have developed highly nuanced signaling systems to enable suitable growth, development, defense, or... (Review)
Review
Plants as sessile organisms face daily environmental challenges and have developed highly nuanced signaling systems to enable suitable growth, development, defense, or stalling responses. Moonlighting proteins have multiple tasks and contribute to cellular signaling cascades where they produce additional variables adding to the complexity or fuzziness of biological systems. Here we examine roles of moonlighting kinases that also generate 3',5'-cyclic guanosine monophosphate (cGMP) in plants. These proteins include receptor like kinases and lipid kinases. Their guanylate cyclase activity potentiates the development of localized cGMP-enriched nanodomains or niches surrounding the kinase and its interactome. These nanodomains contribute to allosteric regulation of kinase and other molecules in the immediate complex directly or indirectly modulating signal cascades. Effects include downregulation of kinase activity, modulation of other members of the protein complexes such as cyclic nucleotide gated channels and potential triggering of cGMP-dependent degradation cascades terminating signaling. The additional layers of information provided by the moonlighting kinases are discussed in terms of how they may be used to provide a layer of fuzziness to effectively modulate cellular signaling cascades.
Topics: Cyclic GMP; Guanylate Cyclase; Models, Molecular; Plant Proteins; Plants; Protein Kinases; Proteolysis; Signal Transduction
PubMed: 33573037
DOI: 10.3390/ijms22031367 -
Aging Cell Sep 2022DNA damage is a causative factor in ageing of the vasculature and other organs. One of the most important vascular ageing features is reduced nitric oxide (NO)soluble...
DNA damage is a causative factor in ageing of the vasculature and other organs. One of the most important vascular ageing features is reduced nitric oxide (NO)soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling. We hypothesized that the restoration of NO-sGC-cGMP signaling with an sGC activator (BAY 54-6544) may have beneficial effects on vascular ageing and premature death in DNA repair-defective mice undergoing accelerated ageing. Eight weeks of treatment with a non-pressor dosage of BAY 54-6544 restored the decreased in vivo microvascular cutaneous perfusion in progeroid Ercc1 mice to the level of wild-type mice. In addition, BAY 54-6544 increased survival of Ercc1 mice. In isolated Ercc1 aorta, the decreased endothelium-independent vasodilation was restored after chronic BAY 54-6544 treatment. Senescence markers p16 and p21, and markers of inflammation, including Ccl2, Il6 in aorta and liver, and circulating IL-6 and TNF-α were increased in Ercc1 , which was lowered by the treatment. Expression of antioxidant genes, including Cyb5r3 and Nqo1, was favorably changed by chronic BAY 54-6544 treatment. In summary, BAY 54-6544 treatment improved the vascular function and survival rates in mice with accelerated ageing, which may have implication in prolonging health span in progeria and normal ageing.
Topics: Animals; Mice; Aging; Cyclic GMP; Disease Models, Animal; Guanylate Cyclase; Nitric Oxide; Pyrazoles; Pyridines; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase
PubMed: 36029161
DOI: 10.1111/acel.13683 -
Biochimica Et Biophysica Acta May 1999Signal transduction with the diatomic radical nitric oxide (NO) is involved in a number of important physiological processes, including smooth muscle relaxation and... (Review)
Review
Signal transduction with the diatomic radical nitric oxide (NO) is involved in a number of important physiological processes, including smooth muscle relaxation and neurotransmission. Soluble guanylate cyclase (sGC), a heterodimeric enzyme that converts guanosine triphosphate to cyclic guanosine monophosphate, is a critical component of this signaling pathway. sGC is a hemoprotein; it is through the specific interaction of NO with the sGC heme that sGC is activated. Over the last decade, much has been learned about the unique heme environment of sGC and its interaction with ligands like NO and carbon monoxide. This review will focus on the role of sGC in signaling, its relationship to the other nucleotide cyclases, and on what is known about sGC genetics, heme environment and catalysis. The latest understanding in regard to sGC will be incorporated to build a model of sGC structure, activation, catalytic mechanism and deactivation.
Topics: Animals; Catalysis; Cell Line; Cyclic GMP; Enzyme Activation; Free Radicals; Gene Expression; Guanylate Cyclase; Humans; Models, Chemical; Nitric Oxide; Nitric Oxide Synthase; Signal Transduction; Structure-Activity Relationship
PubMed: 10320667
DOI: 10.1016/s0005-2728(99)00024-9