scholarly journals Mapping TRPM7 Function by NS8593

2020 ◽  
Vol 21 (19) ◽  
pp. 7017
Author(s):  
Vladimir Chubanov ◽  
Thomas Gudermann
Keyword(s):  
Animal Models ◽  
Transient Receptor Potential ◽  
Therapeutic Potential ◽  
Tumour Progression ◽  
Critical Role ◽  
Receptor Potential ◽  
Research Area ◽  
Genetic Inactivation ◽  
Giant Platelet ◽  
Platelet Disorder

The transient receptor potential cation channel, subfamily M, member 7 (TRPM7) is a ubiquitously expressed membrane protein, which forms a channel linked to a cytosolic protein kinase. Genetic inactivation of TRPM7 in animal models uncovered the critical role of TRPM7 in early embryonic development, immune responses, and the organismal balance of Zn2+, Mg2+, and Ca2+. TRPM7 emerged as a new therapeutic target because malfunctions of TRPM7 have been associated with anoxic neuronal death, tissue fibrosis, tumour progression, and giant platelet disorder. Recently, several laboratories have identified pharmacological compounds allowing to modulate either channel or kinase activity of TRPM7. Among other small molecules, NS8593 has been defined as a potent negative gating regulator of the TRPM7 channel. Consequently, several groups applied NS8593 to investigate cellular pathways regulated by TRPM7. Here, we summarize the progress in this research area. In particular, two notable milestones have been reached in the assessment of TRPM7 druggability. Firstly, several laboratories demonstrated that NS8593 treatment reliably mirrors prominent phenotypes of cells manipulated by genetic inactivation of TRPM7. Secondly, it has been shown that NS8593 allows us to probe the therapeutic potential of TRPM7 in animal models of human diseases. Collectively, these studies employing NS8593 may serve as a blueprint for the preclinical assessment of TRPM7-targeting drugs.

scholarly journals Saikosaponin D Ameliorates Mechanical Hypersensitivity in Animal Models of Neuropathic Pain

2020 ◽  
Vol 07 (04) ◽  
pp. e145-e149
Author(s):  
Gyeongbeen Lee ◽  
Yeon-Ju Nam ◽  
Woo Jung Kim ◽  
Bo Hye Shin ◽  
Jong Suk Lee ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Animal Models ◽  
Oral Administration ◽  
Transient Receptor Potential ◽  
Therapeutic Potential ◽  
Receptor Potential ◽  
Repeated Administration ◽  
Therapeutic Effects ◽  
Mechanical Hypersensitivity ◽  
Pain Outcomes

AbstractWe have previously identified saikosaponins as transient receptor potential ankyrin 1 antagonists and showed that saikosaponin D improves neuropathic pain induced by the anticancer drug vincristine in mice. In order to gain more insight into the therapeutic effects of saikosaponin D, we tested saikosaponin D in animal models of neuropathic pain induced by either streptozotocin, which mimics diabetes, or paclitaxel, a commonly used chemotherapy treatment. Our findings indicate that although saikosaponin D improved pain outcomes in neuropathic pain models, the mechanisms underlying the therapeutic effects of saikosaponin D appear to differ between streptozotocin- and paclitaxel-induced pain. Streptozotocin-induced neuropathic pain was significantly alleviated 30 minutes after oral administration of saikosaponin D, while 1-day oral administration of saikosaponin D had little effect on paclitaxel-induced mechanical hypersensitivity. Attenuation of paclitaxel-induced mechanical hypersensitivity was evident only after repeated administration of saikosaponin D. Although the mechanisms underlying the therapeutic effects of saikosaponin D remain to be elucidated, our results shed new light on the therapeutic potential of saikosaponin D in the management of neuropathic pain caused by diabetes or chemotherapy.

scholarly journals Emerging Roles for Ion Channels in Ovarian Cancer: Pathomechanisms and Pharmacological Treatment

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 668
Author(s):  
Concetta Altamura ◽  
Maria Raffaella Greco ◽  
Maria Rosaria Carratù ◽  
Rosa Angela Cardone ◽  
Jean-François Desaphy
Keyword(s):  
Ovarian Cancer ◽  
Ion Channels ◽  
Transient Receptor Potential ◽  
Critical Role ◽  
Gynecologic Cancer ◽  
Receptor Potential ◽  
Transient Receptor Potential Channels ◽  
Platinum Resistance

Ovarian cancer (OC) is the deadliest gynecologic cancer, due to late diagnosis, development of platinum resistance, and inadequate alternative therapy. It has been demonstrated that membrane ion channels play important roles in cancer processes, including cell proliferation, apoptosis, motility, and invasion. Here, we review the contribution of ion channels in the development and progression of OC, evaluating their potential in clinical management. Increased expression of voltage-gated and epithelial sodium channels has been detected in OC cells and tissues and shown to be involved in cancer proliferation and invasion. Potassium and calcium channels have been found to play a critical role in the control of cell cycle and in the resistance to apoptosis, promoting tumor growth and recurrence. Overexpression of chloride and transient receptor potential channels was found both in vitro and in vivo, supporting their contribution to OC. Furthermore, ion channels have been shown to influence the sensitivity of OC cells to neoplastic drugs, suggesting a critical role in chemotherapy resistance. The study of ion channels expression and function in OC can improve our understanding of pathophysiology and pave the way for identifying ion channels as potential targets for tumor diagnosis and treatment.

scholarly journals Cannabidiol as a Potential Treatment for Anxiety and Mood Disorders: Molecular Targets and Epigenetic Insights from Preclinical Research

2021 ◽  
Vol 22 (4) ◽  
pp. 1863
Author(s):  
Philippe A. Melas ◽  
Maria Scherma ◽  
Walter Fratta ◽  
Carlo Cifani ◽  
Paola Fadda
Keyword(s):  
Mood Disorders ◽  
Cannabinoid Receptors ◽  
Transient Receptor Potential ◽  
Therapeutic Potential ◽  
Molecular Targets ◽  
Receptor Potential ◽  
Transient Receptor Potential Vanilloid ◽  
Preclinical Research ◽  
Neuropsychiatric Diseases ◽  
Transient Receptor

Cannabidiol (CBD) is the most abundant non-psychoactive component of cannabis; it displays a very low affinity for cannabinoid receptors, facilitates endocannabinoid signaling by inhibiting the hydrolysis of anandamide, and stimulates both transient receptor potential vanilloid 1 and 2 and serotonin type 1A receptors. Since CBD interacts with a wide variety of molecular targets in the brain, its therapeutic potential has been investigated in a number of neuropsychiatric diseases, including anxiety and mood disorders. Specifically, CBD has received growing attention due to its anxiolytic and antidepressant properties. As a consequence, and given its safety profile, CBD is considered a promising new agent in the treatment of anxiety and mood disorders. However, the exact molecular mechanism of action of CBD still remains unknown. In the present preclinical review, we provide a summary of animal-based studies that support the use of CBD as an anxiolytic- and antidepressant-like compound. Next, we describe neuropharmacological evidence that links the molecular pharmacology of CBD to its behavioral effects. Finally, by taking into consideration the effects of CBD on DNA methylation, histone modifications, and microRNAs, we elaborate on the putative role of epigenetic mechanisms in mediating CBD’s therapeutic outcomes.

scholarly journals How Cold is It? TRPM8 and TRPA1 in the Molecular Logic of Cold Sensation

2005 ◽  
Vol 1 ◽  
pp. 1744-8069-1-16 ◽  
Author(s):  
David D McKemy
Keyword(s):  
Transient Receptor Potential ◽  
Critical Role ◽  
Somatosensory System ◽  
Receptor Potential ◽  
Critical Element ◽  
Cold Sensation ◽  
Noxious Heat ◽  
Cold Temperatures ◽  
Molecular Logic ◽  
Noxious Cold

Recognition of temperature is a critical element of sensory perception and allows us to evaluate both our external and internal environments. In vertebrates, the somatosensory system can discriminate discrete changes in ambient temperature, which activate nerve endings of primary afferent fibers. These thermosensitive nerves can be further segregated into those that detect either innocuous or noxious (painful) temperatures; the latter neurons being nociceptors. We now know that thermosensitive afferents express ion channels of the transient receptor potential (TRP) family that respond at distinct temperature thresholds, thus establishing the molecular basis for thermosensation. Much is known of those channels mediating the perception of noxious heat; however, those proposed to be involved in cool to noxious cold sensation, TRPM8 and TRPA1, have only recently been described. The former channel is a receptor for menthol, and links the sensations provided by this and other cooling compounds to temperature perception. While TRPM8 almost certainly performs a critical role in cold signaling, its part in nociception is still at issue. The latter channel, TRPA1, is activated by the pungent ingredients in mustard and cinnamon, but has also been postulated to mediate our perception of noxious cold temperatures. However, a number of conflicting reports have suggested that the role of this channel in cold sensation needs to be confirmed. Thus, the molecular logic for the perception of cold-evoked pain remains enigmatic. This review is intended to summarize our current understanding of these cold thermoreceptors, as well as address the current controversy regarding TRPA1 and cold signaling.

scholarly journals TRPC6 channel as an emerging determinant of the podocyte injury susceptibility in kidney diseases

2015 ◽  
Vol 309 (5) ◽  
pp. F393-F397 ◽  
Author(s):  
Daria V. Ilatovskaya ◽  
Alexander Staruschenko
Keyword(s):  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Kidney Diseases ◽  
Critical Role ◽  
Receptor Potential ◽  
Calcium Flux ◽  
Calcium Handling ◽  
Podocyte Injury ◽  
Trpc6 Channel ◽  
Transient Receptor

Podocytes (terminally differentiated epithelial cells of the glomeruli) play a key role in the maintenance of glomerular structure and permeability and in the incipiency of various renal abnormalities. Injury to podocytes is considered a major contributor to the development of kidney disease as their loss causes proteinuria and progressive glomerulosclerosis. The physiological function of podocytes is critically dependent on proper intracellular calcium handling; excessive calcium influx in these cells may result in the effacement of foot processes, apoptosis, and subsequent glomeruli damage. One of the key proteins responsible for calcium flux in the podocytes is transient receptor potential cation channel, subfamily C, member 6 (TRPC6); a gain-of-function mutation in TRPC6 has been associated with the onset of the familial forms of focal segmental glomerulosclerosis (FSGS). Recent data also revealed a critical role of this channel in the onset of diabetic nephropathy. Therefore, major efforts of the research community have been recently dedicated to unraveling the TRPC6-dependent effects in the initiation of podocyte injury. This mini-review focuses on the TRPC6 channel in podocytes and colligates recent data in an attempt to shed some light on the mechanisms underlying the pathogenesis of TRPC6-mediated glomeruli damage and its potential role as a therapeutic target for the treatment of chronic kidney diseases.

scholarly journals TRPM4 Channels Couple Purinergic Receptor Mechanoactivation and Myogenic Tone Development in Cerebral Parenchymal Arterioles

2014 ◽  
Vol 34 (10) ◽  
pp. 1706-1714 ◽  
Author(s):  
Yao Li ◽  
Rachael L Baylie ◽  
Matthew J Tavares ◽  
Joseph E Brayden
Keyword(s):  
Transient Receptor Potential ◽  
Purinergic Receptor ◽  
Critical Role ◽  
Receptor Potential ◽  
Transient Receptor Potential Channel ◽  
Receptor Activation ◽  
Myogenic Tone ◽  
Pial Arteries ◽  
Myogenic Regulation

Cerebral parenchymal arterioles (PAs) have a critical role in assuring appropriate blood flow and perfusion pressure within the brain. They are unique in contrast to upstream pial arteries, as defined by their critical roles in neurovascular coupling, distinct sensitivities to chemical stimulants, and enhanced myogenic tone development. The objective of the present study was to reveal some of the unique mechanisms of myogenic tone regulation in the cerebral microcirculation. Here, we report that in vivo suppression of TRPM4 (transient receptor potential) channel expression, or inhibition of TRPM4 channels with 9-phenanthrol substantially reduced myogenic tone of isolated PAs, supporting a key role of TRPM4 channels in PA myogenic tone development. Further, downregulation of TRPM4 channels inhibited vasoconstriction induced by the specific P2Y4 and P2Y6 receptor ligands (UTP γS and UDP) by 37% and 42%, respectively. In addition, 9-phenanthrol substantially attenuated purinergic ligand-induced membrane depolarization and constriction of PAs, and inhibited ligand-evoked TRPM4 channel activation in isolated PA myocytes. In concert with our previous work showing the essential contributions of P2Y4 and P2Y6 receptors to myogenic regulation of PAs, the current results point to TRPM4 channels as an important link between mechanosensitive P2Y receptor activation and myogenic constriction of cerebral PAs.

scholarly journals Carvacrol Attenuates Hippocampal Neuronal Death after Global Cerebral Ischemia via Inhibition of Transient Receptor Potential Melastatin 7

Cells ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 231 ◽  
Author(s):  
Dae Hong ◽  
Bo Choi ◽  
A Kho ◽  
Song Lee ◽  
Jeong Jeong ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Neuronal Death ◽  
Transient Receptor Potential ◽  
Therapeutic Potential ◽  
Receptor Potential ◽  
Global Cerebral Ischemia ◽  
Neuroprotective Effects ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor ◽  
Zinc Translocation

Over the last two decades, evidence supporting the concept of zinc-induced neuronal death has been introduced, and several intervention strategies have been investigated. Vesicular zinc is released into the synaptic cleft, where it then translocates to the cytoplasm, which leads to the production of reactive oxygen species and neurodegeneration. Carvacrol inhibits transient receptor potential melastatin 7 (TRPM7), which regulates the homeostasis of extracellular metal ions, such as calcium and zinc. In the present study, we test whether carvacrol displays any neuroprotective effects after global cerebral ischemia (GCI), via a blockade of zinc influx. To test our hypothesis, we used eight-week-old male Sprague–Dawley rats, and a GCI model was induced by bilateral common carotid artery occlusion (CCAO), accompanied by blood withdrawal from the femoral artery. Ischemic duration was defined as a seven-minute electroencephalographic (EEG) isoelectric period. Carvacrol (50 mg/kg) was injected into the intraperitoneal space once per day for three days after the onset of GCI. The present study found that administration of carvacrol significantly decreased the number of degenerating neurons, microglial activation, oxidative damage, and zinc translocation after GCI, via downregulation of TRPM7 channels. These findings suggest that carvacrol, a TRPM7 inhibitor, may have therapeutic potential after GCI by reducing intracellular zinc translocation.

scholarly journals TRPC1 participates in the HSV-1 infection process by facilitating viral entry

2020 ◽  
Vol 6 (12) ◽  
pp. eaaz3367 ◽  
Author(s):  
DongXu He ◽  
AiQin Mao ◽  
YouRan Li ◽  
SiuCheung Tam ◽  
YongTang Zheng ◽  
...  
Keyword(s):  
Viral Entry ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Critical Role ◽  
Receptor Potential ◽  
Infection Process ◽  
Ocular Abnormality ◽  
Simplex Virus ◽  
Hsv 1

Mammalian transient receptor potential (TRP) channels are major components of Ca2+ signaling pathways and control a diversity of physiological functions. Here, we report a specific role for TRPC1 in the entry of herpes simplex virus type 1 (HSV-1) into cells. HSV-1–induced Ca2+ release and entry were dependent on Orai1, STIM1, and TRPC1. Inhibition of Ca2+ entry or knockdown of these proteins attenuated viral entry and infection. HSV-1 glycoprotein D interacted with the third ectodomain of TRPC1, and this interaction facilitated viral entry. Knockout of TRPC1 attenuated HSV-1–induced ocular abnormality and morbidity in vivo in TRPC1−/− mice. There was a strong correlation between HSV-1 infection and plasma membrane localization of TRPC1 in epithelial cells within oral lesions in buccal biopsies from HSV-1–infected patients. Together, our findings demonstrate a critical role for TRPC1 in HSV-1 infection and suggest the channel as a potential target for anti-HSV therapy.

scholarly journals Transient Receptor Potential Melastatin 2 Negatively Regulates LPS-ATP-Induced Caspase-1-Dependent Pyroptosis of Bone Marrow-Derived Macrophage by Modulating ROS Production

2017 ◽  
Vol 2017 ◽  
pp. 1-8
Author(s):  
Haihong Wang ◽  
Xinyi Zhou ◽  
Hui Li ◽  
Xiaowei Qian ◽  
Yan Wang ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Critical Role ◽  
Morphological Characteristics ◽  
Receptor Potential ◽  
Ros Production ◽  
Caspase 1 ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor

Background. Pyroptosis, a new form of cell death, which has special morphological characteristics, depends on caspase-1 activation and occupies an important role in inflammatory immune diseases and ischemia-reperfusion injury. ROS is a common activator of NLR/caspase-1. Transient receptor potential melastatin 2 (TRPM2), a selective cation channel, is involved in inflammatory regulation. This study was designed to explore the role of TRPM2 in activating caspase-1 and caspase-1-dependent pyroptosis of mouse BMDMs. Methods. BMDMs isolated from WT and TRPM2−/− mice were treated with LPS and ATP, along with ROS inhibitor (NAC and DPI), caspase-1 inhibitor (Z-YVAD), or not. The activation of caspase-1 was measured by western blot. EtBr and EthD-2 staining were used to assess the incidence of pyroptosis. Results. Compared with WT, the activated caspase-1-P10 was higher and the percentage of EtBr positive cells was also increased in TRPM2−/− group, which were both inhibited by Z-YVAD, NAC, or DPI. ASC oligomerization was increased in TRPM2−/− group. Conclusion. Deletion of TRPM2 can enhance the activation of caspase-1 and pyroptosis, which may be via modulating ROS production, suggesting that TRPM2 plays a critical role in immune adjustment.

Sign in / Sign up

Export Citation Format

Share Document