Intracellular pools of DAG-activated TRPC3 channels are essential for TLR4 activation

ABSTRACTToll-like receptor 4, the receptor for bacterial lipopolysaccharide (LPS), drives inflammatory responses that protect against pathogens and boost the adaptive immunity. LPS responses are known to depend on calcium fluxes, but the molecular mechanisms involved are poorly understood. Here we present evidence that the transient receptor potential canonical channel 3 (TRPC3) is activated intracellularly during macrophage exposure to LPS and is essential for Ca2+ release from internal stores. In this way TRPC3 participates in cytosolic Ca2+ elevations, TLR4 endocytosis, activation of inflammatory transcription factors and cytokine upregulation. We also report that TRPC3 is activated by diacylglycerol (DAG) generated by the phosphatidic acid phosphatase lipin-1. In accord with this, lipin-1-deficient cells show reduced Ca2+ responses to LPS challenge. A cameleon indicator directed to the endoplasmic reticulum shows that this is the organelle from which TRPC3 mediates the Ca2+ release. Finally, pharmacological inhibition of TRPC3 reduces systemic inflammation induced by LPS in mice. Collectively, our study unveils a central component of LPS-triggered Ca2+ signaling that involves intracellular sensing of lipin-1-derived DAG by TRPC3.

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Canonical Transient Receptor Potential (TRPC) Channels in Nociception and Pathological Pain

Neural Plasticity ◽

10.1155/2020/3764193 ◽

2020 ◽

Vol 2020 ◽

pp. 1-13 ◽

Cited By ~ 2

Author(s):

Zhi-Chuan Sun ◽

Sui-Bin Ma ◽

Wen-Guang Chu ◽

Dong Jia ◽

Ceng Luo

Keyword(s):

Chronic Pain ◽

Molecular Mechanisms ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Trpc Channels ◽

Canonical Transient Receptor Potential ◽

Abnormal Increase ◽

Pathological Pain ◽

Transient Receptor ◽

Underlying Mechanisms

Chronic pathological pain is one of the most intractable clinical problems faced by clinicians and can be devastating for patients. Despite much progress we have made in understanding chronic pain in the last decades, its underlying mechanisms remain elusive. It is assumed that abnormal increase of calcium levels in the cells is a key determinant in the transition from acute to chronic pain. Exploring molecular players mediating Ca2+ entry into cells and molecular mechanisms underlying activity-dependent changes in Ca2+ signaling in the somatosensory pain pathway is therefore helpful towards understanding the development of chronic, pathological pain. Canonical transient receptor potential (TRPC) channels form a subfamily of nonselective cation channels, which permit the permeability of Ca2+ and Na+ into the cells. Initiation of Ca2+ entry pathways by these channels triggers the development of many physiological and pathological functions. In this review, we will focus on the functional implication of TRPC channels in nociception with the elucidation of their role in the detection of external stimuli and nociceptive hypersensitivity.

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Transient Receptor Potential Channels as an Emerging Target for the Treatment of Parkinson’s Disease: An Insight Into Role of Pharmacological Interventions

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.584513 ◽

2020 ◽

Vol 8 ◽

Author(s):

Bhupesh Vaidya ◽

Shyam Sunder Sharma

Keyword(s):

Oxidative Stress ◽

Parkinson’S Disease ◽

Parkinson's Disease ◽

Molecular Mechanisms ◽

Transient Receptor Potential ◽

Trp Channels ◽

Neurodegenerative Disorder ◽

Receptor Potential ◽

Transient Receptor Potential Channels ◽

Transient Receptor

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by the symptoms of motor deficits and cognitive decline. There are a number of therapeutics available for the treatment of PD, but most of them suffer from serious side effects such as bradykinesia, dyskinesia and on-off effect. Therefore, despite the availability of these pharmacological agents, PD patients continue to have an inferior quality of life. This has warranted a need to look for alternate strategies and molecular targets. Recent evidence suggests the Transient Receptor Potential (TRP) channels could be a potential target for the management of motor and non-motor symptoms of PD. Though still in the preclinical stages, agents targeting these channels have shown immense potential in the attenuation of behavioral deficits and signaling pathways. In addition, these channels are known to be involved in the regulation of ionic homeostasis, which is disrupted in PD. Moreover, activation or inhibition of many of the TRP channels by calcium and oxidative stress has also raised the possibility of their paramount involvement in affecting the other molecular mechanisms associated with PD pathology. However, due to the paucity of information available and lack of specificity, none of these agents have gone into clinical trials for PD treatment. Considering their interaction with oxidative stress, apoptosis and excitotoxicity, TRP channels could be considered as a potential future target for the treatment of PD.

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Eugenol Inhibits Sodium Currents in Dental Afferent Neurons

Journal of Dental Research ◽

10.1177/154405910608501005 ◽

2006 ◽

Vol 85 (10) ◽

pp. 900-904 ◽

Cited By ~ 56

Author(s):

C.-K. Park ◽

H.Y. Li ◽

K.-Y. Yeon ◽

S.J. Jung ◽

S.-Y. Choi ◽

...

Keyword(s):

Molecular Mechanisms ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Inhibitory Effect ◽

Transient Receptor Potential Vanilloid ◽

Afferent Neurons ◽

Patch Clamp Technique ◽

Independent Manner ◽

Pre Treatment ◽

Transient Receptor

Although eugenol is widely used in dentistry, little is known about the molecular mechanisms responsible for its anesthetic properties. In addition to calcium channels, recently demonstrated by our group, there could be another molecular target for eugenol. Using a whole-cell patch-clamp technique, we investigated the effect of eugenol on voltage-gated sodium channel currents ( I Na) in rat dental primary afferent neurons identified by retrograde labeling with a fluorescent dye in maxillary molars. Eugenol inhibited action potentials and I Na in both capsaicin-sensitive and capsaicin-insensitive neurons. The pre-treatment with capsazepine, a competitive antagonist of transient receptor potential vanilloid 1 (TRPV1), failed to block the inhibitory effect of eugenol on I Na, suggesting no involvement of TRPV1. Two types of I Na, tetrodotoxin (TTX)-resistant and TTX-sensitive I Na, were inhibited by eugenol. Our results demonstrated that eugenol inhibits I Na in a TRPV1-independent manner. We suggest that I Na inhibition by eugenol contributes to its analgesic effect.

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The Role of Transient Receptor Potential (TRP) Channels in the Transduction of Dental Pain

International Journal of Molecular Sciences ◽

10.3390/ijms20030526 ◽

2019 ◽

Vol 20 (3) ◽

pp. 526 ◽

Cited By ~ 11

Author(s):

Mohammad Hossain ◽

Marina Bakri ◽

Farhana Yahya ◽

Hiroshi Ando ◽

Shumpei Unno ◽

...

Keyword(s):

Molecular Mechanisms ◽

Transient Receptor Potential ◽

Trp Channels ◽

Glutamate Release ◽

Receptor Potential ◽

Functional Expression ◽

Dental Pain ◽

Post Translational Modifications ◽

Transient Receptor ◽

External Stimuli

Dental pain is a common health problem that negatively impacts the activities of daily living. Dentine hypersensitivity and pulpitis-associated pain are among the most common types of dental pain. Patients with these conditions feel pain upon exposure of the affected tooth to various external stimuli. However, the molecular mechanisms underlying dental pain, especially the transduction of external stimuli to electrical signals in the nerve, remain unclear. Numerous ion channels and receptors localized in the dental primary afferent neurons (DPAs) and odontoblasts have been implicated in the transduction of dental pain, and functional expression of various polymodal transient receptor potential (TRP) channels has been detected in DPAs and odontoblasts. External stimuli-induced dentinal tubular fluid movement can activate TRP channels on DPAs and odontoblasts. The odontoblasts can in turn activate the DPAs by paracrine signaling through ATP and glutamate release. In pulpitis, inflammatory mediators may sensitize the DPAs. They could also induce post-translational modifications of TRP channels, increase trafficking of these channels to nerve terminals, and increase the sensitivity of these channels to stimuli. Additionally, in caries-induced pulpitis, bacterial products can directly activate TRP channels on DPAs. In this review, we provide an overview of the TRP channels expressed in the various tooth structures, and we discuss their involvement in the development of dental pain.

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Calciotropic and Magnesiotropic TRP Channels

Physiology ◽

10.1152/physiol.00039.2007 ◽

2008 ◽

Vol 23 (1) ◽

pp. 32-40 ◽

Cited By ~ 66

Author(s):

Joost G. J. Hoenderop ◽

René J. M. Bindels

Keyword(s):

Divalent Cation ◽

Molecular Mechanisms ◽

Transient Receptor Potential ◽

Trp Channels ◽

Receptor Potential ◽

Transient Receptor Potential Channel ◽

Significant Progress ◽

Functional Aspects ◽

Health And Disease ◽

Transient Receptor

Significant progress has been made into our understanding of the molecular mechanisms responsible for Ca2+ and Mg2+ homeostasis. Members of the transient receptor potential channel (TRP) superfamily proved essential to the maintenance of divalent cation levels by regulating their absorption from renal and intestinal lumina. This review highlights the molecular and functional aspects of these new calciotropic and magnesiotropic TRPs in health and disease.

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Transient receptor potential ion channels as participants in thermosensation and thermoregulation

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.00446.2006 ◽

2007 ◽

Vol 292 (1) ◽

pp. R64-R76 ◽

Cited By ~ 248

Author(s):

Michael J. Caterina

Keyword(s):

Ion Channels ◽

Molecular Mechanisms ◽

Transient Receptor Potential ◽

Trp Channels ◽

Core Body Temperature ◽

Expression Patterns ◽

Receptor Potential ◽

Genetic Ablation ◽

Transient Receptor ◽

Living Organisms

Living organisms must evaluate changes in environmental and internal temperatures to mount appropriate physiological and behavioral responses conducive to survival. Classical physiology has provided a wealth of information regarding the specialization of thermosensory functions among subclasses of peripheral sensory neurons and intrinsically thermosensitive neurons within the hypothalamus. However, until recently, the molecular mechanisms by which these cells carry out thermometry have remained poorly understood. The demonstration that certain ion channels of the transient receptor potential (TRP) family can be activated by increases or decreases in ambient temperature, along with the recognition of their heterogeneous expression patterns and heterogeneous temperature sensitivities, has led investigators to evaluate these proteins as candidate endogenous thermosensors. Much of this work has involved one specific channel, TRP vanilloid 1 (TRPV1), which is both a receptor for capsaicin and related pungent vanilloid compounds and a “heat receptor,” capable of directly depolarizing neurons in response to temperatures >42°C. Evidence for a contribution of TRPV1 to peripheral thermosensation has come from pharmacological, physiological, and genetic approaches. In contrast, although capsaicin-sensitive mechanisms clearly influence core body temperature regulation, the specific contribution of TRPV1 to this process remains a matter of debate. Besides TRPV1, at least six additional thermally sensitive TRP channels have been identified in mammals, and many of these also appear to participate in thermosensation. Moreover, the identification of invertebrate TRP channels, whose genetic ablation alters thermally driven behaviors, makes it clear that thermosensation represents an evolutionarily conserved role of this ion channel family.

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Role of lysophosphatidic acid in ion channel function and disease

Journal of Neurophysiology ◽

10.1152/jn.00226.2018 ◽

2018 ◽

Vol 120 (3) ◽

pp. 1198-1211 ◽

Cited By ~ 10

Author(s):

Ileana Hernández-Araiza ◽

Sara L. Morales-Lázaro ◽

Jesús Aldair Canul-Sánchez ◽

León D. Islas ◽

Tamara Rosenbaum

Keyword(s):

Ion Channels ◽

Ion Channel ◽

Lysophosphatidic Acid ◽

Protein Interactions ◽

Molecular Mechanisms ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Channel Function ◽

Transient Receptor ◽

Lipid Protein Interactions

Lysophosphatidic acid (LPA) is a bioactive phospholipid that exhibits a wide array of functions that include regulation of protein synthesis and adequate development of organisms. LPA is present in the membranes of cells and in the serum of several mammals and has also been shown to participate importantly in pathophysiological conditions. For several decades it was known that LPA produces some of its effects in cells through its interaction with specific G protein-coupled receptors, which in turn are responsible for signaling pathways that regulate cellular function. Among the target proteins for LPA receptors are ion channels that modulate diverse aspects of the physiology of cells and organs where they are expressed. However, recent studies have begun to unveil direct effects of LPA on ion channels, highlighting this phospholipid as a direct agonist and adding to the knowledge of the field of lipid-protein interactions. Moreover, the roles of LPA in pathophysiological conditions associated with the function of some ion channels have also begun to be clarified, and molecular mechanisms have been identified. This review focuses on the effects of LPA on ion channel function under normal and pathological conditions and highlights our present knowledge of the mechanisms by which it regulates the function and expression of N- and T-type Ca++ channels; M-type K+ channel and inward rectifier K+ channel subunit 2.1; transient receptor potential (TRP) melastatin 2, TRP vanilloid 1, and TRP ankyrin 1 channels; and TWIK-related K+ channel 1 (TREK-1), TREK-2, TWIK-related spinal cord K+ channel (TRESK), and TWIK-related arachidonic acid-stimulated K+ channel (TRAAK).

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Irritants: a modern redefining of relevance to the armed forces and the prospect of creating medical means of protection

Vestnik of Russian military medical Academy ◽

10.17816/brmma50558 ◽

2020 ◽

Vol 22 (3) ◽

pp. 188-193

Author(s):

A. A. Kuzmin ◽

E. V. Ivchenko ◽

A. B. Seleznev ◽

S. P. Sidorov ◽

M. A. Yudin

Keyword(s):

Emergency Treatment ◽

Molecular Mechanisms ◽

Chelating Agents ◽

Transient Receptor Potential ◽

Analytical Data ◽

Receptor Potential ◽

Armed Forces ◽

Structural Formulas ◽

The Russian Federation ◽

Transient Receptor

Absract. Arguments are presented in favor of the increasing relevance of irritants to ensure the fulfillment of tasks by military personnel of the Armed Forces of the Russian Federation, as well as the need to reassess the risks to human health arising from their use. The results of an information-analytical data on methods and adverse effects of irritant application for purposes which are not prohibited by the Convention on the Prohibition of the Development, Production, Stockpiling and Use of Chemical Weapons and on Their Destruction are presented. Modern ideas about molecular mechanisms of the effect of irritants on structures of the nervous system are considered, which are based on the fact that the provocative effect of irritants is realized by changing the permeability of cation channels of the transient receptor potential of type A1, expressed at the ends of sensitive neurons. The results of experimental and clinical studies of specific modulation of these channels using their natural and synthetic antagonists are analyzed. Structural formulas and basic pharmacological characteristics of the most active antagonists are given and the prospect of their use as a basis for the development of drugs for the treatment of irritant lesions is substantiated. The data on the use of solutions based on amphoteric and chelating agents for emergency treatment of skin areas infected with irritants is presented. A number of promising areas of research on the creation of effective medical means of protection against lesions by irritants has been identified.

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