scholarly journals Four key signaling pathways mediating chemotaxis in Dictyostelium discoideum

2008 ◽  
Vol 180 (4) ◽  
pp. 747-753 ◽  
Author(s):  
Douwe M. Veltman ◽  
Ineke Keizer-Gunnik ◽  
Peter J.M. Van Haastert
Keyword(s):  
Signaling Pathways ◽  
Dictyostelium Discoideum ◽  
Soluble Guanylyl Cyclase ◽  
Leading Edge ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Genetic Screens ◽  
Myosin Filaments ◽  
Phosphoinositide 3 Kinase ◽  
Multiple Signaling

Chemotaxis is the ability of cells to move in the direction of an external gradient of signaling molecules. Cells are guided by actin-filled protrusions in the front, whereas myosin filaments retract the rear of the cell. Previous work demonstrated that chemotaxis of unpolarized amoeboid Dictyostelium discoideum cells is mediated by two parallel pathways, phosphoinositide-3-kinase (PI3K) and phospholipase A2 (PLA2). Here, we show that polarized cells exhibit very good chemotaxis with inhibited PI3K and PLA2 activity. Using genetic screens, we demonstrate that this activity is mediated by a soluble guanylyl cyclase, providing two signals. The protein localizes to the leading edge where it interacts with actin filaments, whereas the cyclic guanosine monophosphate product induces myosin filaments in the rear of the cell. We conclude that chemotaxis is mediated by multiple signaling pathways regulating protrusions at the front and rear of the cell. Cells that express only rear activity are polarized but do not exhibit chemotaxis, whereas cells with only front signaling are unpolarized but undergo chemotaxis.

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

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.

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

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.

scholarly journals cGMP: a unique 2nd messenger molecule – recent developments in cGMP research and development

2019 ◽  
Vol 393 (2) ◽  
pp. 287-302 ◽  
Author(s):  
Andreas Friebe ◽  
Peter Sandner ◽  
Achim Schmidtko
Keyword(s):  
Guanylyl Cyclase ◽  
Soluble Guanylyl Cyclase ◽  
Cell Types ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Therapeutic Implications ◽  
Cellular Effects ◽  
Recent Developments ◽  
And Function ◽  
Messenger Molecule

AbstractCyclic guanosine monophosphate (cGMP) is a unique second messenger molecule formed in different cell types and tissues. cGMP targets a variety of downstream effector molecules and, thus, elicits a very broad variety of cellular effects. Its production is triggered by stimulation of either soluble guanylyl cyclase (sGC) or particulate guanylyl cyclase (pGC); both enzymes exist in different isoforms. cGMP-induced effects are regulated by endogenous receptor ligands such as nitric oxide (NO) and natriuretic peptides (NPs). Depending on the distribution of sGC and pGC and the formation of ligands, this pathway regulates not only the cardiovascular system but also the kidney, lung, liver, and brain function; in addition, the cGMP pathway is involved in the pathogenesis of fibrosis, inflammation, or neurodegeneration and may also play a role in infectious diseases such as malaria. Moreover, new pharmacological approaches are being developed which target sGC- and pGC-dependent pathways for the treatment of various diseases. Therefore, it is of key interest to understand this pathway from scratch, beginning with the molecular basis of cGMP generation, the structure and function of both guanylyl cyclases and cGMP downstream targets; research efforts also focus on the subsequent signaling cascades, their potential crosstalk, and also the translational and, ultimately, the clinical implications of cGMP modulation. This review tries to summarize the contributions to the “9th International cGMP Conference on cGMP Generators, Effectors and Therapeutic Implications” held in Mainz in 2019. Presented data will be discussed and extended also in light of recent landmark findings and ongoing activities in the field of preclinical and clinical cGMP research.

Sulfur dioxide induces vascular relaxation through PI3K/Akt/eNOS and NO/cGMP signaling pathways in rats

2020 ◽  
Vol 39 (8) ◽  
pp. 1108-1117
Author(s):  
Q Zhang ◽  
W Lyu ◽  
M Yu ◽  
Y Niu
Keyword(s):  
Nitric Oxide ◽  
Sulfur Dioxide ◽  
Signaling Pathways ◽  
Underlying Mechanism ◽  
Cyclic Guanosine Monophosphate ◽  
Rat Aorta ◽  
Guanosine Monophosphate ◽  
Signal Pathways ◽  
Atmospheric Pollutant ◽  
Protein Levels

Sulfur dioxide (SO2) is a common exogenous atmospheric pollutant. Studies have shown that SO2 can cause vasodilation as a gas signaling molecule, but the specific signaling pathways are not well understood. This study aimed to explore the underlying mechanism behind the effects of SO2 on vasodilation of isolated rat aorta. The results showed that when the dose of SO2 was 30 μM, the vasodilation of endothelium-intact rings was partially suppressed by LY294002 and NG-nitro-l-arginine methyl ester, and the protein levels of phosphoinositide 3-kinase (PI3K), p-Akt, and p-endothelial nitric oxide synthase ( p-eNOS) were significantly increased. When the dose of SO2 was 300 μM or 1500 μM, the vasodilation of endothelium-denuded rings did not change after application of the inhibitor, but the protein levels of PI3K, p-Akt, and p-eNOS were significantly decreased, and the activity of NOS and the level of nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) were significantly increased. We speculate that the mechanism of SO2-induced vasodilatation likely involved the endothelial PI3K/Akt/eNOS and NO/cGMP signal pathways. In addition, at the concentration of 1500 μM, SO2 markedly increased the level of caspase-3 and caspase-9. The results suggest that high concentrations of SO2 may cause damage to blood vessels. This study will help to further inform the etiologies of SO2-related cardiovascular disease.

Nitric oxide donor stimulated increase of cyclic GMP in the goldfish retina

2001 ◽  
Vol 18 (6) ◽  
pp. 849-856 ◽  
Author(s):  
WILLIAM H. BALDRIDGE ◽  
ANDY J. FISCHER
Keyword(s):  
Nitric Oxide ◽  
Optic Nerve ◽  
Ganglion Cells ◽  
Soluble Guanylyl Cyclase ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Nitric Oxide Donor ◽  
No Donor ◽  
Intracellular Signalling Pathway ◽  
Teleost Retina

Nitric oxide (NO) activates soluble guanylyl cyclase (sGC) and the resulting increase in cyclic guanosine monophosphate (cGMP) is an important intracellular signalling pathway in the vertebrate retina. Immunocytochemical detection of cGMP following exposure to NO donors has proven an effective method of identifying cells that express sGC. While such an approach has proven useful for the study of several vertebrate retinas, it has not been applied to the well-characterized teleost retina. Therefore, in the present study, we have applied this approach to the retina of the goldfish (Carassius auratus). In the presence of the phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine (IBMX), incubation of goldfish eyecups in Ringer's solution containing (±)-S-nitroso-N-acetylpenicillamine (SNAP) increased cGMP-like immunoreactivity (cG-ir) in bipolar, horizontal, amacrine, and ganglion cells and in ganglion cell axons and optic nerve. Weak labeling was observed in horizontal cells but no change in cG-ir was noted within photoreceptors. The NO donor-stimulated increases of cG-ir in horizontal, bipolar, amacrine, and ganglion cells are consistent with known physiological effects of NO on these neurons. The physiological significance of NO action at the level of optic nerve is not known. The lack of an effect of SNAP on cG-ir in photoreceptors was unexpected, as there are known physiological actions of NO, mediated by cGMP, on these neurons. Although this may be due to insufficient sensitivity of immunolabeling, this result may indicate a difference between isoforms of sGC or cGMP PDE in these neurons, compared to neurons where exogenous NO increased cG-ir.

Investigation of distinct molecular pathways in migraine induction using calcitonin gene-related peptide and sildenafil

Cephalalgia ◽  
2019 ◽  
Vol 39 (14) ◽  
pp. 1776-1788 ◽  
Author(s):  
Samaira Younis ◽  
Casper E Christensen ◽  
Nikolaj M Toft ◽  
Thomas Søborg ◽  
Faisal M Amin ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Cyclic Guanosine Monophosphate ◽  
Calcitonin Gene Related Peptide ◽  
Guanosine Monophosphate ◽  
Related Peptide ◽  
Intracellular Signaling Pathways ◽  
Calcitonin Gene

Objective Migraine displays clinical heterogeneity of attack features and attack triggers. The question is whether this heterogeneity is explained by distinct intracellular signaling pathways leading to attacks with distinct clinical features. One well-known migraine-inducing pathway is mediated by cyclic adenosine monophosphate and another by cyclic guanosine monophosphate. Calcitonin gene-related peptide triggers migraine via the cyclic adenosine monophosphate pathway and sildenafil via the cyclic guanosine monophosphate pathway. To date, no studies have examined whether migraine induction mediated via the cyclic adenosine monophosphate and cyclic guanosine monophosphate pathways yields similar attacks within the same patients. Methods Patients were subjected to migraine induction on two separate days using calcitonin gene-related peptide (1.5 µg/min for 20 minutes) and sildenafil (100 mg) in a double-blind, randomized, double-dummy, cross-over design. Data on headache intensity, characteristics and accompanying symptoms were collected until 24 hours after drug administration. Results Thirty-four patients were enrolled and 27 completed both study days. Seventeen patients developed migraine after both study drugs (63%; 95% CI: 42–81). Eight patients developed migraine on one day only (seven after sildenafil and one after calcitonin gene-related peptide). Two patients did not develop migraine on either day. Headache laterality, nausea, photophobia and phonophobia were similar between drugs in 77%, 65%, 100%, and 94%, respectively, of the 17 patients who developed attacks on both days. Conclusion A majority of patients developed migraine after both calcitonin gene-related peptide and sildenafil. This supports the hypothesis that the cyclic adenosine monophosphate and cyclic guanosine monophosphate intracellular signaling pathways in migraine induction converge in a common cellular determinator, which ultimately triggers the same attacks. Trial registration: ClinicalTrials.gov Identifier: NCT03143465.

scholarly journals Nitric Oxide-cGMP Signaling in Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (4) ◽  
pp. 1055-1068
Author(s):  
Ehsan Ataei Ataabadi ◽  
Keivan Golshiri ◽  
Annika Jüttner ◽  
Guido Krenning ◽  
A.H. Jan Danser ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Drug Targets ◽  
Soluble Guanylyl Cyclase ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Protein Kinase G ◽  
Current Status ◽  
Systemic Hypertension ◽  
Pharmacological Intervention ◽  
Cgmp Signaling

For the treatment of systemic hypertension, pharmacological intervention in nitric oxide-cyclic guanosine monophosphate signaling is a well-explored but unexploited option. In this review, we present the identified drug targets, including oxidases, mitochondria, soluble guanylyl cyclase, phosphodiesterase 1 and 5, and protein kinase G, important compounds that modulate them, and the current status of (pre)clinical development. The mode of action of these compounds is discussed, and based upon this, the clinical opportunities. We conclude that drugs that directly target the enzymes of the nitric oxide-cyclic guanosine monophosphate cascade are currently the most promising compounds, but that none of these compounds is under investigation as a treatment option for systemic hypertension.

scholarly journals Methanolic Extract ofClinacanthus nutansExerts Antinociceptive Activity via the Opioid/Nitric Oxide-Mediated, but cGMP-Independent, Pathways

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Mohammad Hafiz Abdul Rahim ◽  
Zainul Amiruddin Zakaria ◽  
Mohd Hijaz Mohd Sani ◽  
Maizatul Hasyima Omar ◽  
Yusnita Yakob ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Antinociceptive Effect ◽  
Soluble Guanylyl Cyclase ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
Antinociceptive Activity ◽  
Opioid Antagonist ◽  
Clinacanthus Nutans ◽  
Synthase Inhibitor

The objectives of the present study were to determine the mechanisms of antinociceptive effect of methanol extract ofClinacanthus nutans(Acanthaceae) leaves (MECN) using various animal nociceptive models. The antinociceptive activity of orally administered 10% DMSO, 100 mg/kg acetylsalicylic acid (ASA), 5 mg/kg morphine, or MECN (100, 250, and 500 mg/kg) was determined using the acetic acid-induced abdominal constriction (ACT), formalin-induced paw licking (FT), and hot plate tests (HPT). The role of opioid and nitric oxide/cyclic guanosine monophosphate (NO/cGMP) systems was also investigated. The results showed that MECN produced a significant (p<0.05) antinociceptive response in all nociceptive models with the recordedED50value of 279.3 mg/kg for the ACT, while, for the early and late phases of the FT, the value was >500 mg/kg or 227.7 mg/kg, respectively. This antinociceptive activity was fully antagonized by naloxone (a nonselective opioid antagonist) but was partially reversed byL-arginine (L-arg; a nitric oxide [NO] precursor), Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME; an NO synthase inhibitor), or their combinations thereof. In contrast, 1H-[1,2,4]oxadiazole[4,3-a]quinoxalin-1-one (ODQ; a soluble guanylyl cyclase inhibitor) enhanced the extract’s antinociception. UHPLC analysis revealed the presence of several flavonoid-based compounds with antinociceptive action. In conclusion, MECN exerted the peripherally and centrally mediated antinociceptive activity via the modulation of the opioid/NO-mediated, but cGMP-independent, systems.

Cytosolisch guanylaatcyclase als therapeutisch target

2021 ◽  
Author(s):  
S. Cottyn ◽  
C. Boydens ◽  
J. Van de Voorde
Keyword(s):  
Signaling Pathway ◽  
Therapeutic Target ◽  
Soluble Guanylyl Cyclase ◽  
Cyclic Guanosine Monophosphate ◽  
Guanosine Monophosphate ◽  
No Donors ◽  
Physiological Importance ◽  
Pde Inhibitors ◽  
Cgmp Signaling ◽  
Sgc Stimulators

Cytosolic guanylate cyclase as a therapeutic target The nitric oxide (NO) - soluble guanylyl cyclase (sGC) - cyclic guanosine monophosphate (cGMP) signaling pathway contributes to homeostasis of various systems in an organism. Dysfunction of the system may therefore induce heterogeneous pathologies. Pharmacological interventions in this signaling pathway using NO donors and phosphodiesterase (PDE) inhibitors have been successful in the past, but still leave room for improvement. This is why the interest in sGC stimulators and activators has been growing. Their NO-independent action increases the activity of sGC, resulting in a higher production of cGMP. Riociguat is the first sGC stimulator available on the market and is currently used in the treatment of pulmonary hypertension. In addition, other high-potential sGC stimulators or activators are also being tested in several clinical studies. This article describes the physiological importance of sGC, as well as its potential as a therapeutic target.

Sign in / Sign up

Export Citation Format

Share Document