scholarly journals TLQP-21, A VGF-Derived Peptide Endowed of Endocrine and Extraendocrine Properties: Focus on In Vitro Calcium Signaling

2019 ◽  
Vol 21 (1) ◽  
pp. 130 ◽  
Author(s):  
Elena Bresciani ◽  
Roberta Possenti ◽  
Silvia Coco ◽  
Laura Rizzi ◽  
Ramona Meanti ◽  
...  
Keyword(s):  
Nervous System ◽  
Driving Force ◽  
Endocrine Cells ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Pathological Conditions ◽  
The Central Nervous System ◽  
Transient Receptor

VGF gene encodes for a neuropeptide precursor of 68 kDa composed by 615 (human) and 617 (rat, mice) residues, expressed prevalently in the central nervous system (CNS), but also in the peripheral nervous system (PNS) and in various endocrine cells. This precursor undergoes proteolytic cleavage, generating a family of peptides different in length and biological activity. Among them, TLQP-21, a peptide of 21 amino acids, has been widely investigated for its relevant endocrine and extraendocrine activities. The complement complement C3a receptor-1 (C3aR1) has been suggested as the TLQP-21 receptor and, in different cell lines, its activation by TLQP-21 induces an increase of intracellular Ca2+. This effect relies both on Ca2+ release from the endoplasmic reticulum (ER) and extracellular Ca2+ entry. The latter depends on stromal interaction molecules (STIM)-Orai1 interaction or transient receptor potential channel (TRPC) involvement. After Ca2+ entry, the activation of outward K+-Ca2+-dependent currents, mainly the KCa3.1 currents, provides a membrane polarizing influence which offset the depolarizing action of Ca2+ elevation and indirectly maintains the driving force for optimal Ca2+ increase in the cytosol. In this review, we address the main endocrine and extraendocrine actions displayed by TLQP-21, highlighting recent findings on its mechanism of action and its potential in different pathological conditions.

scholarly journals Design, Synthesis and In Vitro Experimental Validation of Novel TRPV4 Antagonists Inspired by Labdane Diterpenes

Marine Drugs ◽  
2020 ◽  
Vol 18 (10) ◽  
pp. 519
Author(s):  
Sarah Mazzotta ◽  
Gabriele Carullo ◽  
Aniello Schiano Moriello ◽  
Pietro Amodeo ◽  
Vincenzo Di Marzo ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Biological Activities ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Design Synthesis ◽  
Cellular Assays ◽  
Transient Receptor ◽  
Trpv4 Channel

Labdane diterpenes are widespread classes of natural compounds present in variety of marine and terrestrial organisms and plants. Many of them represents “natural libraries” of compounds with interesting biological activities due to differently functionalized drimane nucleus exploitable for potential pharmacological applications. The transient receptor potential channel subfamily V member 4 (TRPV4) channel has recently emerged as a pharmacological target for several respiratory diseases, including the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Inspired by the labdane-like bicyclic core, a series of homodrimane-derived esters and amides was designed and synthesized by modifying the flexible tail in position 1 of (+)-sclareolide, an oxidized derivative of the bioactive labdane-type diterpene sclareol. The potency and selectivity towards rTRPV4 and hTRPV1 receptors were assessed by calcium influx cellular assays. Molecular determinants critical for eliciting TRPV4 antagonism were identified by structure-activity relationships. Among the selective TRPV4 antagonists identified, compound 6 was the most active with an IC50 of 5.3 μM. This study represents the first report of semisynthetic homodrimane TRPV4 antagonists, selective over TRPV1, and potentially useful as pharmacological tools for the development of novel TRPV4 channel modulators.

scholarly journals Osmoregulatory thirst in mice lacking the transient receptor potential vanilloid type 1 (TRPV1) and/or type 4 (TRPV4) receptor

2014 ◽  
Vol 307 (9) ◽  
pp. R1092-R1100 ◽  
Author(s):  
Brian Kinsman ◽  
James Cowles ◽  
Jennifer Lay ◽  
Sarah S. Simmonds ◽  
Kirsteen N. Browning ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Consistent Finding ◽  
Cellular Dehydration ◽  
Genes Encoding ◽  
The Central Nervous System ◽  
Transient Receptor

Recent studies suggest the ability of the central nervous system to detect changes in osmolality is mediated by products of the genes encoding the transient receptor potential vanilloid-1 (TRPV1) or vanilloid-4 (TRPV4) channel. The purpose of the present study was to determine whether deletion of TRPV1 and/or TRPV4 channels altered thirst responses to cellular dehydration in mice. Injection of 0.5 or 1.0 M NaCl produced dose-dependent increases in cumulative water intakes of wild-type (WT), TRPV1−/−, TRPV4−/−, and TRPV1−/−V4−/− mice. However, there were no differences in cumulative water intakes between WT versus any other strain despite similar increases in plasma electrolytes and osmolality. Similar results were observed after injection of hypertonic mannitol. This was a consistent finding regardless of the injection route (intraperitoneal vs. subcutaneous) or timed access to water (delayed vs. immediate). There were also no differences in cumulative intakes across strains after injection of 0.15 M NaCl or during a time-controlled period (no injection). Chronic hypernatremia produced by sole access to 2% NaCl for 48 h also produced similar increases in water intake across strains. In a final set of experiments, subcutaneous injection of 0.5 M NaCl produced similar increases in the number of Fos-positive nuclei within the organum vasculosum of the lamina terminalis and median preoptic nucleus across strains but significantly smaller number in the subfornical organ of WT versus TRPV1−/−V4−/− mice. Collectively, these findings suggest that TRPV1 and/or TRPV4 channels are not the primary mechanism by which the central nervous system responds to cellular dehydration during hypernatremia or hyperosmolality to increase thirst.

Caveolae-associated signalling in smooth muscle

2004 ◽  
Vol 82 (5) ◽  
pp. 289-299 ◽  
Author(s):  
Andreas Bergdahl ◽  
Karl Swärd
Keyword(s):  
Smooth Muscle ◽  
Transient Receptor Potential ◽  
Muscle Tone ◽  
Receptor Potential ◽  
Transgenic Animals ◽  
Transient Receptor Potential Channel ◽  
Structural Protein ◽  
Outward Currents ◽  
Transient Receptor

Caveolae are flask-shaped invaginations in the membrane that depend on the contents of cholesterol and on the structural protein caveolin. The organisation of caveolae in parallel strands between dense bands in smooth muscle is arguably unique. It is increasingly recognised, bolstered in large part by recent studies in caveolae deficient animals, that caveolae sequester and regulate a variety of signalling intermediaries. The role of caveolae in smooth muscle signal transduction, as inferred from studies on transgenic animals and in vitro approaches, is the topic of the current review. Both G-protein coupled receptors and tyrosine kinase receptors are believed to cluster in caveolae, and the exciting possibility that caveolae provide a platform for interactions between the sarcoplasmic reticulum and plasmalemmal ion channels is emerging. Moreover, messengers involved in Ca2+ sensitization of myosin phosphorylation and contraction may depend on caveolae or caveolin. Caveolae thus appear to constitute an important signalling domain that plays a role not only in regulation of smooth muscle tone, but also in proliferation, such as seen in neointima formation and atherosclerosis.Key words: caveolin, RhoA, transient receptor potential channel, endothelin, spontaneous transient outward currents.

scholarly journals Transient Receptor Potential Channel, Vanilloid 5, Induces Chondrocyte Apoptosis in a Rat Osteoarthritis Model Through the Mediation of Ca2+ Influx

2018 ◽  
Vol 46 (2) ◽  
pp. 687-698 ◽  
Author(s):  
Yingliang Wei ◽  
Dianbin Zheng ◽  
Xiaocheng Guo ◽  
Min Zhao ◽  
Linlin Gao ◽  
...  
Keyword(s):  
Articular Cartilage ◽  
Western Blotting ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Chondrocyte Apoptosis ◽  
Caspase 8 ◽  
Pathological Feature ◽  
Transient Receptor

Background/Aims: Chondrocyte apoptosis is the most common pathological feature in cartilage in osteoarthritis (OA). Transient receptor potential channel vanilloid 5 (TRPV5) is important in regulating calcium ion (Ca2+) influx. Accumulating evidences suggest that Ca2+ is a major intracellular second messenger that can trigger cell apoptosis. Therefore, we investigate the potential role of TRPV5 in mediating Ca2+ influx to promote chondrocyte apoptosis in OA. Methods: The monoiodoacetic acid (MIA)-induced rat OA model was assessed by macroscopic and radiographic analyses. Calmodulin protein immunolocalization was detected by immunohistochemistry. The mRNA and protein level of TRPV5, calmodulin and cleaved caspase-8 in articular cartilage were assessed by real time polymerase chain reaction and western blotting. Primary chondrocytes were isolated and cultured in vitro. TRPV5 small interfering RNA was used to silence TRPV5 in chondrocytes. Then, calmodulin and cleaved caspase-8 were immunolocalized by immunofluorescence in chondrocyte. Fluo-4AM staining was used to assess intracellular Ca2+ to reflect TRPV5 function of mediation Ca2+ influx. Annexin V-fluorescein isothiocyanatepropidium iodide flow cytometric analysis was performed to determine chondrocytes apoptosis. Western blotting techniques were used to measure the apoptosis-related proteins in chondrocyte level. Results: Here, we reported TRPV5 was up-regulated in MIA-induced OA articular cartilage. Ruthenium red (a TRPV5 inhibitor) can relieve progression of joint destruction in vivo which promoted us to demonstrate the effect of TRPV5 in OA. We found that TRPV5 had a specific role in mediating extracellular Ca2+ influx leading to chondrocytes apoptosis in vitro. The apoptotic effect was inhibited even reversed by silencing TRPV5. Furthermore, we found that the increase Ca2+ influx triggered apoptosis by up-regulating the protein of death-associated protein, FAS-associated death domain, cleaved caspase-8, cleaved caspase-3, cleaved caspase-6, and cleaved caspase-7, and the up-regulated proteins were abolished by silencing TRPV5 or 1, 2-bis-(o-Aminophenoxy)-ethane-N,N,N’,N’-tetraacetic acid, tetraacetoxymethyl ester (a Ca2+ chelating agent). Conclusion: The up-regulated TRPV5 could used be as an initiating factor that induces extrinsic chondrocyte apoptosis via the mediation of Ca2+ influx. These findings suggested TRPV5 could be an intriguing mediator for drug target in OA.

scholarly journals Severely blunted allergen-induced pulmonary Th2 cell response and lung hyperresponsiveness in type 1 transient receptor potential channel-deficient mice

2012 ◽  
Vol 303 (6) ◽  
pp. L539-L549 ◽  
Author(s):  
Eda Yildirim ◽  
Michelle A. Carey ◽  
Jeffrey W. Card ◽  
Alexander Dietrich ◽  
Gordon P. Flake ◽  
...  
Keyword(s):  
Cell Response ◽  
Transient Receptor Potential ◽  
Cell Function ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Transient Receptor Potential Channels ◽  
Airway Hyperreactivity ◽  
Th2 Cell ◽  
Transient Receptor

Transient receptor potential channels (TRPCs) are widely expressed and regulate Ca2+entry in the cells that participate in the pathophysiology of airway hyperreactivity, inflammation, and remodeling. In vitro studies point to a role for TRPC1-mediated Ca2+signaling in several of these cell types; however, physiological evidence is lacking. Here we identify TRPC1 signaling as proinflammatory and a regulator of lung hyperresponsiveness during allergen-induced pulmonary response. TRPC1-deficient ( Trpc1−/−) mice are hyposensitive to methacholine challenge and have significantly reduced allergen-induced pulmonary leukocyte infiltration coupled with an attenuated T helper type 2 (Th2) cell response. Upon in vitro allergen exposure, Trpc1−/−splenocytes show impaired proliferation and T cell receptor-induced IL-2 production. A high number of germinal centers in spleens of Trpc1−/−mice and elevated levels of immunoglobulins in their serum are indicative of dysregulated B cell function and homeostasis. Thus we propose that TRPC1 signaling is necessary in lymphocyte biology and in regulation of allergen-induced lung hyperresponsiveness, making TRPC1 a potential target for treatment of immune diseases and asthma.

scholarly journals Resolvins: Potent Pain Inhibiting Lipid Mediators via Transient Receptor Potential Regulation

2020 ◽  
Vol 8 ◽  
Author(s):  
Jueun Roh ◽  
Eun Jin Go ◽  
Jin-Woo Park ◽  
Yong Ho Kim ◽  
Chul-Kyu Park
Keyword(s):  
Chronic Pain ◽  
Nervous System ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Nerve Damage ◽  
Lipid Mediators ◽  
Kinase Activation ◽  
Nociceptive Neurons ◽  
The Central Nervous System ◽  
Transient Receptor

Chronic pain is a serious condition that occurs in the peripheral nervous system (PNS) and the central nervous system (CNS). It is caused by inflammation or nerve damage that induces the release of inflammatory mediators from immune cells and/or protein kinase activation in neuronal cells. Both nervous systems are closely linked; therefore, inflammation or nerve damage in the PNS can affect the CNS (central sensitization). In this process, nociceptive transient receptor potential (TRP) channel activation and expression are increased. As a result, nociceptive neurons are activated, and pain signals to the brain are amplified and prolonged. In other words, suppressing the onset of pain signals in the PNS can suppress pain signals to the CNS. Resolvins, endogenous lipid mediators generated during the resolution phase of acute inflammation, inhibit nociceptive TRP ion channels and alleviate chronic pain. This paper summarizes the effect of resolvins in chronic pain control and discusses future scientific perspectives. Further study on the effect of resolvins on neuropathic pain will expand the scope of pain research.

scholarly journals The Transient Receptor Potential Channel, Vanilloid 5, Induces Chondrocyte Apoptosis via Ca2+ CaMKII–Dependent MAPK and Akt/ mTOR Pathways in a Rat Osteoarthritis Model

2018 ◽  
Vol 51 (5) ◽  
pp. 2309-2323 ◽  
Author(s):  
Yingliang Wei ◽  
Zhaofeng Jin ◽  
He Zhang ◽  
Shang Piao ◽  
Jinghan Lu ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Western Blotting ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Chondrocyte Apoptosis ◽  
Pathological Feature ◽  
Transient Receptor

Background/Aims: Chondrocyte apoptosis is a central pathological feature of cartilage in osteoarthritis (OA). Accumulating evidence suggests that calcium ions (Ca2+) are an important regulator of apoptosis. Previously, we reported that the transient receptor potential channel vanilloid (TRPV5) is upregulated in monoiodoacetic acid (MIA)-induced OA articular cartilage. Methods: The protein levels of TRPV5, phosphorylated Ca2+/calmodulin-dependent kinase II (p-CaMKII), and total CaMKII were detected in vivo using western blotting techniques. Primary chondrocytes were isolated and cultured in vitro. Then, p-CAMKII was immunolocalized by immunofluorescence in chondrocytes. Fluo-4AM staining was used to assess intracellular Ca2+. Annexin V-fluorescein isothiocyanate / propidium iodide flow cytometric analysis was performed to determine chondrocyte apoptosis. Western blotting techniques were used to measure the expression of apoptosis-related proteins. Results: We found that ruthenium red (aTRPV5inhibitor)or(1-[N,O-bis-(5-isoquinolinesulfonyl)-N-methyl-L-tyrosyl]-4-phenylpiperaze (KN-62) (an inhibitor of Ca2+/calmodulin-dependent kinase II (CaMKII) phosphorylation) can relieve or even reverse OA in vivo. We found that TRPV5 has a specific role in mediating extracellular Ca2+ influx leading to chondrocyte apoptosis in vitro. The apoptotic effect in chondrocytes was inhibited by KN-62. We found that activated p-CaMKII could elicit the phosphorylation of extracellular signal-regulated protein kinase 1/2, c-Jun N-terminal kinase, and p38, three important regulators of the mitogen-activated protein kinase (MAPK) cascade. Moreover, we also showed that activated p-CaMKII could elicit the phosphorylation of protein kinase B (Akt) and two important downstream regulators of mammalian target of rapamycin (mTOR): 4E-binding protein, and S61 kinase. Conclusion: Our results demonstrate that upregulated TRPV5 may be an important initiating factor that activates CaMKII phosphorylation via the mediation of Ca2+ influx. In turn, activated p-CaMKII plays a critical role in chondrocyte apoptosis via MAPK and Akt/mTOR pathways.

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