Signaling Events During Cyclic Guanosine Monophosphate-Regulated Pigment Aggregation in Freshwater Shrimp Chromatophores

The aim of this study was to determine whether polydatin, a glucoside of resveratrol isolated from the root of Polygonum cuspidatum, warranted development as a potential therapeutic for ameliorating the pain originating from gallbladder spasm disorders and the underlying mechanisms. Guinea pig gallbladder smooth muscles were treated with polydatin and specific inhibitors to explore the mechanisms underpinning polydatin-induced relaxation of carbachol-precontracted guinea pig gallbladder. Our results shown that polydatin relaxed carbachol-induced contraction in a dose-dependent manner through the nitric oxide/cyclic guanosine monophosphate/protein kinase G and the cyclic adenosine monophosphate/protein kinase A signaling pathways as well as the myosin light chain kinase and potassium channels. Our findings suggested that there was value in further exploring the potential therapeutic use of polydatin in gallbladder spasm disorders.

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Soluble Guanylate Cyclase Stimulators and Activators: Where are We and Where to Go?

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557519666190730110600 ◽

2019 ◽

Vol 19 (18) ◽

pp. 1544-1557 ◽

Cited By ~ 6

Author(s):

Sijia Xiao ◽

Qianbin Li ◽

Liqing Hu ◽

Zutao Yu ◽

Jie Yang ◽

...

Keyword(s):

Guanylate Cyclase ◽

Soluble Guanylate Cyclase ◽

Muscle Relaxation ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Smooth Muscle Relaxation ◽

Secondary Messenger ◽

Physiological Processes ◽

Cgmp Pathway ◽

Preclinical And Clinical Studies

Soluble Guanylate Cyclase (sGC) is the intracellular receptor of Nitric Oxide (NO). The activation of sGC results in the conversion of Guanosine Triphosphate (GTP) to the secondary messenger cyclic Guanosine Monophosphate (cGMP). cGMP modulates a series of downstream cascades through activating a variety of effectors, such as Phosphodiesterase (PDE), Protein Kinase G (PKG) and Cyclic Nucleotide-Gated Ion Channels (CNG). NO-sGC-cGMP pathway plays significant roles in various physiological processes, including platelet aggregation, smooth muscle relaxation and neurotransmitter delivery. With the approval of an sGC stimulator Riociguat for the treatment of Pulmonary Arterial Hypertension (PAH), the enthusiasm in the discovery of sGC modulators continues for broad clinical applications. Notably, through activating the NO-sGC-cGMP pathway, sGC stimulator and activator potentiate for the treatment of various diseases, such as PAH, Heart Failure (HF), Diabetic Nephropathy (DN), Systemic Sclerosis (SS), fibrosis as well as other diseases including Sickle Cell Disease (SCD) and Central Nervous System (CNS) disease. Here, we review the preclinical and clinical studies of sGC stimulator and activator in recent years and prospect for the development of sGC modulators in the near future.

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The cGMP-Dependent Protein Kinase 2 Contributes to Cone Photoreceptor Degeneration in the Cnga3-Deficient Mouse Model of Achromatopsia

International Journal of Molecular Sciences ◽

10.3390/ijms22010052 ◽

2020 ◽

Vol 22 (1) ◽

pp. 52

Author(s):

Mirja Koch ◽

Constanze Scheel ◽

Hongwei Ma ◽

Fan Yang ◽

Michael Stadlmeier ◽

...

Keyword(s):

Protein Kinase ◽

Mouse Model ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Cone Photoreceptor ◽

Photoreceptor Degeneration ◽

Dependent Protein Kinase ◽

Genetic Ablation ◽

Cgmp Dependent Protein Kinase ◽

Dependent Protein

Mutations in the CNGA3 gene, which encodes the A subunit of the cyclic guanosine monophosphate (cGMP)-gated cation channel in cone photoreceptor outer segments, cause total colour blindness, also referred to as achromatopsia. Cones lacking this channel protein are non-functional, accumulate high levels of the second messenger cGMP and degenerate over time after induction of ER stress. The cell death mechanisms that lead to loss of affected cones are only partially understood. Here, we explored the disease mechanisms in the Cnga3 knockout (KO) mouse model of achromatopsia. We found that another important effector of cGMP, the cGMP-dependent protein kinase 2 (Prkg2) is crucially involved in cGMP cytotoxicity of cones in Cnga3 KO mice. Virus-mediated knockdown or genetic ablation of Prkg2 in Cnga3 KO mice counteracted degeneration and preserved the number of cones. Analysis of markers of endoplasmic reticulum stress and unfolded protein response confirmed that induction of these processes in Cnga3 KO cones also depends on Prkg2. In conclusion, we identified Prkg2 as a novel key mediator of cone photoreceptor degeneration in achromatopsia. Our data suggest that this cGMP mediator could be a novel pharmacological target for future neuroprotective therapies.

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Current Modulation of Guanylate Cyclase Pathway Activity—Mechanism and Clinical Implications

Molecules ◽

10.3390/molecules26113418 ◽

2021 ◽

Vol 26 (11) ◽

pp. 3418

Author(s):

Grzegorz Grześk ◽

Alicja Nowaczyk

Keyword(s):

Guanylate Cyclase ◽

Natriuretic Peptides ◽

Soluble Guanylate Cyclase ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Pharmacological Intervention ◽

First Line ◽

Phosphodiesterase Type ◽

Activity Mechanism

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.

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Inflammation in the Human Periodontium Induces Downregulation of the α1- and β1-Subunits of the sGC in Cementoclasts

International Journal of Molecular Sciences ◽

10.3390/ijms22020539 ◽

2021 ◽

Vol 22 (2) ◽

pp. 539

Author(s):

Yüksel Korkmaz ◽

Behrus Puladi ◽

Kerstin Galler ◽

Peer W. Kämmerer ◽

Agnes Schröder ◽

...

Keyword(s):

Protein Expression ◽

Alveolar Bone ◽

Soluble Guanylyl Cyclase ◽

Cathepsin K ◽

Staining Intensity ◽

Cyclic Guanosine Monophosphate ◽

Heme Iron ◽

Guanosine Monophosphate ◽

Independent Manner ◽

Periodontal Tissues

Nitric oxide (NO) binds to soluble guanylyl cyclase (sGC), activates it in a reduced oxidized heme iron state, and generates cyclic Guanosine Monophosphate (cGMP), which results in vasodilatation and inhibition of osteoclast activity. In inflammation, sGC is oxidized and becomes insensitive to NO. NO- and heme-independent activation of sGC requires protein expression of the α1- and β1-subunits. Inflammation of the periodontium induces the resorption of cementum by cementoclasts and the resorption of the alveolar bone by osteoclasts, which can lead to tooth loss. As the presence of sGC in cementoclasts is unknown, we investigated the α1- and β1-subunits of sGC in cementoclasts of healthy and inflamed human periodontium using double immunostaining for CD68 and cathepsin K and compared the findings with those of osteoclasts from the same sections. In comparison to cementoclasts in the healthy periodontium, cementoclasts under inflammatory conditions showed a decreased staining intensity for both α1- and β1-subunits of sGC, indicating reduced protein expression of these subunits. Therefore, pharmacological activation of sGC in inflamed periodontal tissues in an NO- and heme-independent manner could be considered as a new treatment strategy to inhibit cementum resorption.

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Lipid Emulsion Enhances Vasoconstriction Induced by Dexmedetomidine in the Isolated Endothelium-Intact Aorta

International Journal of Molecular Sciences ◽

10.3390/ijms22073309 ◽

2021 ◽

Vol 22 (7) ◽

pp. 3309

Author(s):

Soo Hee Lee ◽

Seong-Ho Ok ◽

Seung Hyun Ahn ◽

Hyun-Jin Kim ◽

Sung Il Bae ◽

...

Keyword(s):

Lipid Emulsion ◽

Umbilical Vein ◽

Src Kinase ◽

Cyclic Guanosine Monophosphate ◽

Rat Aorta ◽

Guanosine Monophosphate ◽

Caveolin 1 ◽

Umbilical Vein Endothelial Cells ◽

Endothelial Nitric Oxide ◽

Cgmp Formation

This study aimed to examine the effect of lipid emulsion (LE) on the vasoconstriction induced by dexmedetomidine (DMT) in the isolated rat aorta and elucidate the associated cellular mechanism. The effect of LE, NW-nitro-L-arginine methyl ester (L-NAME), and methyl-β-cyclodextrin (MβCD) on the DMT-induced contraction was examined. We investigated the effect of LE on the DMT-induced cyclic guanosine monophosphate (cGMP) formation and DMT concentration. The effect of DMT, LE, 4-Amino-3-(4-chlorophenyl)-1-(t-butyl)-1H-pyrazolo[3,4-d]pyrimidine,4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), and rauwolscine on the phosphorylation of endothelial nitric oxide synthase (eNOS), caveolin-1, and Src kinase was examined in the human umbilical vein endothelial cells. L-NAME, MβCD, and LE (1%, standardized mean difference (SMD): 2.517) increased the DMT-induced contraction in the endothelium-intact rat aorta. LE (1%) decreased the DMT (10−6 M) concentration (SMD: −6.795) and DMT-induced cGMP formation (SMD: −2.132). LE (1%) reversed the DMT-induced eNOS (Ser1177 and Thr496) phosphorylation. PP2 inhibited caveolin-1 and eNOS phosphorylation induced by DMT. DMT increased the Src kinase phosphorylation. Thus, LE (1%) enhanced the DMT-induced contraction by inhibition of NO synthesis, which may be caused by the decreased DMT concentration. DMT-induced NO synthesis may be caused by the increased eNOS (Ser1177) phosphorylation and decreased eNOS (Thr495) phosphorylation potentially mediated by Src kinase-induced caveolin-1 phosphorylation.

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Cyclic Guanosine Monophosphate Modulates Locomotor Acceleration Induced by Nitric Oxide but not Serotonin in Clione limacina Central Pattern Generator Swim Interneurons

Integrative Organismal Biology ◽

10.1093/iob/obaa045 ◽

2020 ◽

Author(s):

Thomas J Pirtle ◽

Richard A Satterlie

Keyword(s):

Nitric Oxide ◽

Central Pattern Generator ◽

Guanylyl Cyclase ◽

Signal Transduction Pathway ◽

Soluble Guanylyl Cyclase ◽

Cyclic Guanosine Monophosphate ◽

Pattern Generator ◽

Guanosine Monophosphate ◽

Cellular Changes ◽

Clione Limacina

Abstract Typically, the marine mollusk, Clione limacina, exhibits a slow, hovering locomotor gait to maintain its position in the water column. However, the animal exhibits behaviorally relevant locomotor swim acceleration during escape response and feeding behavior. Both nitric oxide and serotonin mediate this behavioral swim acceleration. In this study, we examine the role that the second messenger, cGMP, plays in mediating nitric oxide and serotonin-induced swim acceleration. We observed that the application of an analog of cGMP or an activator of soluble guanylyl cyclase increased fictive locomotor speed recorded from Pd-7 interneurons of the animal’s locomotor central pattern generator. Moreover, inhibition of soluble guanylyl cyclase decreased fictive locomotor speed. These results suggest that basal levels of cGMP are important for slow swimming and that increased production of cGMP mediates swim acceleration in Clione. Because nitric oxide has its effect through cGMP signaling and because we show herein that cGMP produces cellular changes in Clione swim interneurons that are consistent with cellular changes produced by serotonin application, we hypothesize that both nitric oxide and serotonin function via a common signal transduction pathway that involves cGMP. Our results show that cGMP mediates nitric oxide-induced but not serotonin-induced swim acceleration in Clione.

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ANP and BNP Exert Anti-Inflammatory Action via NPR-1/cGMP Axis by Interfering with Canonical, Non-Canonical, and Alternative Routes of Inflammasome Activation in Human THP1 Cells

International Journal of Molecular Sciences ◽

10.3390/ijms22010024 ◽

2020 ◽

Vol 22 (1) ◽

pp. 24

Author(s):

Letizia Mezzasoma ◽

Vincenzo Nicola Talesa ◽

Rita Romani ◽

Ilaria Bellezza

Keyword(s):

Natriuretic Peptide ◽

Specific Inhibitor ◽

Cyclic Guanosine Monophosphate ◽

Guanosine Monophosphate ◽

Caspase 8 ◽

Inflammasome Activation ◽

Intracellular Cgmp ◽

Dependent Protein ◽

Anti Inflammatory ◽

Alternative Routes

Dysregulated inflammasome activation and interleukin (IL)-1β production are associated with several inflammatory disorders. Three different routes can lead to inflammasome activation: a canonical two-step, a non-canonical Caspase-4/5- and Gasdermin D-dependent, and an alternative Caspase-8-mediated pathway. Natriuretic Peptides (NPs), Atrial Natriuretic Peptide (ANP) and B-type Natriuretic Peptide (BNP), binding to Natriuretic Peptide Receptor-1 (NPR-1), signal by increasing cGMP (cyclic guanosine monophosphate) levels that, in turn, stimulate cGMP-dependent protein kinase-I (PKG-I). We previously demonstrated that, by counteracting inflammasome activation, NPs inhibit IL-1β secretion. Here we aimed to decipher the molecular mechanism underlying NPs effects on THP-1 cells stimulated with lipopolysaccharide (LPS) + ATP. Involvement of cGMP and PKG-I were assessed pre-treating THP-1 cells with the membrane-permeable analogue, 8-Br-cGMP, and the specific inhibitor KT-5823, respectively. We found that NPs, by activating NPR-1/cGMP/PKG-I axis, lead to phosphorylation of NLRP3 at Ser295 and to inflammasome platform disassembly. Moreover, by increasing intracellular cGMP levels and activating phosphodiesterases, NPs interfere with both Gasdermin D and Caspase-8 cleavage, indicating that they disturb non-canonical and alternative routes of inflammasome activation. These results showed that ANP and BNP anti-inflammatory and immunomodulatory actions may involve the inhibition of all the known routes of inflammasome activation. Thus, NPs might be proposed for the treatment of the plethora of diseases caused by a dysregulated inflammasome activation.

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