scholarly journals Mammalian Transient Receptor Potential TRPA1 Channels: From Structure to Disease

2020 ◽  
Vol 100 (2) ◽  
pp. 725-803 ◽  
Author(s):  
Karel Talavera ◽  
Justyna B. Startek ◽  
Julio Alvarez-Collazo ◽  
Brett Boonen ◽  
Yeranddy A. Alpizar ◽  
...  
Keyword(s):  
Transient Receptor Potential ◽  
Current Knowledge ◽  
Receptor Potential ◽  
Cellular Damage ◽  
Mechanical Stimuli ◽  
Amino Acid Residues ◽  
Nonselective Cation Channels ◽  
Organ Systems ◽  
Complex Regulation ◽  
Transient Receptor

The transient receptor potential ankyrin (TRPA) channels are Ca2+-permeable nonselective cation channels remarkably conserved through the animal kingdom. Mammals have only one member, TRPA1, which is widely expressed in sensory neurons and in non-neuronal cells (such as epithelial cells and hair cells). TRPA1 owes its name to the presence of 14 ankyrin repeats located in the NH2 terminus of the channel, an unusual structural feature that may be relevant to its interactions with intracellular components. TRPA1 is primarily involved in the detection of an extremely wide variety of exogenous stimuli that may produce cellular damage. This includes a plethora of electrophilic compounds that interact with nucleophilic amino acid residues in the channel and many other chemically unrelated compounds whose only common feature seems to be their ability to partition in the plasma membrane. TRPA1 has been reported to be activated by cold, heat, and mechanical stimuli, and its function is modulated by multiple factors, including Ca2+, trace metals, pH, and reactive oxygen, nitrogen, and carbonyl species. TRPA1 is involved in acute and chronic pain as well as inflammation, plays key roles in the pathophysiology of nearly all organ systems, and is an attractive target for the treatment of related diseases. Here we review the current knowledge about the mammalian TRPA1 channel, linking its unique structure, widely tuned sensory properties, and complex regulation to its roles in multiple pathophysiological conditions.

scholarly journals The transient receptor potential, TRP4, cation channel is a novel member of the family of calmodulin binding proteins

2001 ◽  
Vol 355 (3) ◽  
pp. 663-670 ◽  
Author(s):  
Claudia TROST ◽  
Christiane BERGS ◽  
Nina HIMMERKUS ◽  
Veit FLOCKERZI
Keyword(s):  
Amino Acid ◽  
Ion Channels ◽  
Transient Receptor Potential ◽  
Direct Interaction ◽  
Receptor Potential ◽  
Amino Acid Residues ◽  
Glutathione S Transferase ◽  
Calmodulin Binding ◽  
Transient Receptor

The mammalian gene products, transient receptor potential (trp)1 to trp7, are related to the Drosophila TRP and TRP-like ion channels, and are candidate proteins underlying agonist-activated Ca2+-permeable ion channels. Recently, the TRP4 protein has been shown to be part of native store-operated Ca2+-permeable channels. These channels, most likely, are composed of other proteins in addition to TRP4. In the present paper we report the direct interaction of TRP4 and calmodulin (CaM) by: (1) retention of in vitro translated TRP4 and of TRP4 protein solubilized from bovine adrenal cortex by CaM–Sepharose in the presence of Ca2+, and (2) TRP4–glutathione S-transferase pull-down experiments. Two domains of TRP4, amino acid residues 688–759 and 786–848, were identified as being able to interact with CaM. The binding of CaM to both domains occurred only in the presence of Ca2+ concentrations above 10µM, with half maximal binding occurring at 16.6µM (domain 1) and 27.9µM Ca2+ (domain 2). Synthetic peptides, encompassing the two putative CaM binding sites within these domains and covering amino acid residues 694–728 and 829–853, interacted directly with dansyl–CaM with apparent Kd values of 94–189nM. These results indicate that TRP4/Ca2+-CaM are parts of a signalling complex involved in agonist-induced Ca2+ entry.

scholarly journals The unsilent majority–TRPV1 drives “spontaneous” transmission of unmyelinated primary afferents within cardiorespiratory NTS

2012 ◽  
Vol 303 (12) ◽  
pp. R1207-R1216 ◽  
Author(s):  
Michael C. Andresen ◽  
Mackenzie E. Hofmann ◽  
Jessica A. Fawley
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Visceral Afferents ◽  
Transient Receptor Potential Vanilloid ◽  
Control Mechanisms ◽  
Solitary Tract ◽  
Organ Systems ◽  
Asynchronous Release ◽  
Transient Receptor ◽  
Afferent Terminals

Cranial primary afferent sensory neurons figure importantly in homeostatic control of visceral organ systems. Of the two broad classes of visceral afferents, the role of unmyelinated or C-type class remains poorly understood. This review contrasts key aspects of peripheral discharge properties of C-fiber afferents and their glutamate transmission mechanisms within the solitary tract nucleus (NTS). During normal prevailing conditions, most information arrives at the NTS through myelinated A-type nerves. However, most of visceral afferent axons (75–90%) in NTS are unmyelinated, C-type axons. Centrally, C-type solitary tract (ST) afferent terminals have presynaptic transient receptor potential vanilloid type 1 (TRPV1) receptors. Capsaicin activation of TRPV1 blocks phasic or synchronous release of glutamate but facilitates release of glutamate from a separate pool of vesicles. This TRPV1-operated pool of vesicles is active at normal temperatures and is responsible for actively driving a 10-fold higher release of glutamate at TRPV1 compared with TRPV1− terminals even in the absence of afferent action potentials. This novel TRPV1 mechanism is responsible for an additional asynchronous release of glutamate that is not present in myelinated terminals. The NTS is rich with presynaptic G protein-coupled receptors, and the implications of TRPV1-operated glutamate offer unique targets for signaling in C-type sensory afferent terminals from neuropeptides, inflammatory mediators, lipid metabolites, cytokines, and cannabinoids. From a homeostatic view, this combination could have broad implications for integration in chronic pathological disturbances in which the numeric dominance of C-type endings and TRPV1 would broadly disturb multisystem control mechanisms.

scholarly journals Molecular Basis of TRPA1 Regulation in Nociceptive Neurons. A Review

2017 ◽  
pp. 425-439 ◽  
Author(s):  
A. KÁDKOVÁ ◽  
V. SYNYTSYA ◽  
J. KRUSEK ◽  
L. ZÍMOVÁ ◽  
V. VLACHOVÁ
Keyword(s):  
Molecular Basis ◽  
Transient Receptor Potential ◽  
Current Knowledge ◽  
Sensory Nerve ◽  
Receptor Potential ◽  
Nociceptive Response ◽  
Nociceptive Neurons ◽  
Physiological Relevance ◽  
Wide Range ◽  
Transient Receptor

Transient receptor potential A1 (TRPA1) is an excitatory ion channel that functions as a cellular sensor, detecting a wide range of proalgesic agents such as environmental irritants and endogenous products of inflammation and oxidative stress. Topical application of TRPA1 agonists produces an acute nociceptive response through peripheral release of neuropeptides, purines and other transmitters from activated sensory nerve endings. This, in turn, further regulates TRPA1 activity downstream of G-protein and phospholipase C-coupled signaling cascades. Despite the important physiological relevance of such regulation leading to nociceptor sensitization and consequent pain hypersensitivity, the specific domains through which TRPA1 undergoes post-translational modifications that affect its activation properties are yet to be determined at a molecular level. This review aims at providing an account of our current knowledge on molecular basis of regulation by neuronal inflammatory signaling pathways that converge on the TRPA1 channel protein and through modification of its specific residues influence the extent to which this channel may contribute to pain.

scholarly journals TRPing on Cell Swelling - TRPV4 Senses It

2021 ◽  
Vol 12 ◽  
Author(s):  
Trine L. Toft-Bertelsen ◽  
Nanna MacAulay
Keyword(s):  
Cell Volume ◽  
Transient Receptor Potential ◽  
Current Knowledge ◽  
Receptor Potential ◽  
Cell Swelling ◽  
Transient Receptor Potential Vanilloid ◽  
Volume Changes ◽  
Channel Activation ◽  
Volume Increase ◽  
Transient Receptor

The transient receptor potential vanilloid 4 channel (TRPV4) is a non-selective cation channel that is widely expressed and activated by a range of stimuli. Amongst these stimuli, changes in cell volume feature as a prominent regulator of TRPV4 activity with cell swelling leading to channel activation. In experimental settings based on abrupt introduction of large osmotic gradients, TRPV4 activation requires co-expression of an aquaporin (AQP) to facilitate such cell swelling. However, TRPV4 readily responds to cell volume increase irrespectively of the molecular mechanism underlying the cell swelling and can, as such, be considered a sensor of increased cell volume. In this review, we will discuss the proposed events underlying the molecular coupling from cell swelling to channel activation and present the evidence of direct versus indirect swelling-activation of TRPV4. With this summary of the current knowledge of TRPV4 and its ability to sense cell volume changes, we hope to stimulate further experimental efforts in this area of research to clarify TRPV4’s role in physiology and pathophysiology.

scholarly journals TRP Channels as Drug Targets to Relieve Itch

2018 ◽  
Vol 11 (4) ◽  
pp. 100 ◽  
Author(s):  
Zili Xie ◽  
Hongzhen Hu
Keyword(s):  
Drug Targets ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Current Knowledge ◽  
Receptor Potential ◽  
Protective Role ◽  
Chronic Itch ◽  
Transient Receptor

Although acute itch has a protective role by removing irritants to avoid further damage, chronic itch is debilitating, significantly impacting quality of life. Over the past two decades, a considerable amount of stimulating research has been carried out to delineate mechanisms of itch at the molecular, cellular, and circuit levels. There is growing evidence that transient receptor potential (TRP) channels play important roles in itch signaling. The purpose of this review is to summarize our current knowledge about the role of TRP channels in the generation of itch under both physiological and pathological conditions, thereby identifying them as potential drug targets for effective anti-itch therapies.

Subunit interaction in channel assembly and functional regulation of transient receptor potential melastatin (TRPM) channels

2007 ◽  
Vol 35 (1) ◽  
pp. 86-88 ◽  
Author(s):  
L.-H. Jiang
Keyword(s):  
Transient Receptor Potential ◽  
Current Knowledge ◽  
Receptor Potential ◽  
Subunit Interaction ◽  
Transient Receptor Potential Melastatin ◽  
Functional Regulation ◽  
Transient Receptor ◽  
Channel Assembly ◽  
Translational Mechanisms ◽  
Trpm Channels

Functional TRPM (transient receptor potential melastatin) ion channels are multimers, thought to be tetramers. Subunit interaction is the prerequisite step in channel assembly, and the specificity of subunit interaction is crucial in assembling channels with distinct functional properties. In addition, expression of short non-functional subunits and their interaction with full-length subunits serve as one of the post-translational mechanisms regulating the channel activity. This paper aims to provide an overview of the current knowledge of TRPM subunit interactions and their roles in assembly and functional regulation of the TRPM channels.

scholarly journals Polycystin-2 Is Required for Chondrocyte Mechanotransduction and Traffics to the Primary Cilium in Response to Mechanical Stimulation

2021 ◽  
Vol 22 (9) ◽  
pp. 4313
Author(s):  
Clare L. Thompson ◽  
Megan McFie ◽  
J. Paul Chapple ◽  
Philip Beales ◽  
Martin M. Knight
Keyword(s):  
Gene Expression ◽  
Mechanical Stimulation ◽  
Primary Cilia ◽  
Transient Receptor Potential ◽  
Intraflagellar Transport ◽  
Receptor Potential ◽  
Mechanical Stimuli ◽  
Matrix Gene ◽  
Transient Receptor ◽  
Ciliary Localization

Primary cilia and associated intraflagellar transport are essential for skeletal development, joint homeostasis, and the response to mechanical stimuli, although the mechanisms remain unclear. Polycystin-2 (PC2) is a member of the transient receptor potential polycystic (TRPP) family of cation channels, and together with Polycystin-1 (PC1), it has been implicated in cilia-mediated mechanotransduction in epithelial cells. The current study investigates the effect of mechanical stimulation on the localization of ciliary polycystins in chondrocytes and tests the hypothesis that they are required in chondrocyte mechanosignaling. Isolated chondrocytes were subjected to mechanical stimulation in the form of uniaxial cyclic tensile strain (CTS) in order to examine the effects on PC2 ciliary localization and matrix gene expression. In the absence of strain, PC2 localizes to the chondrocyte ciliary membrane and neither PC1 nor PC2 are required for ciliogenesis. Cartilage matrix gene expression (Acan, Col2a) is increased in response to 10% CTS. This response is inhibited by siRNA-mediated loss of PC1 or PC2 expression. PC2 ciliary localization requires PC1 and is increased in response to CTS. Increased PC2 cilia trafficking is dependent on the activation of transient receptor potential cation channel subfamily V member 4 (TRPV4) activation. Together, these findings demonstrate for the first time that polycystins are required for chondrocyte mechanotransduction and highlight the mechanosensitive cilia trafficking of PC2 as an important component of cilia-mediated mechanotransduction.

scholarly journals Potential Implications of Mammalian Transient Receptor Potential Melastatin 7 in the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: A Review

2021 ◽  
Vol 18 (20) ◽  
pp. 10708
Author(s):  
Stanley Du Preez ◽  
Helene Cabanas ◽  
Donald Staines ◽  
Sonya Marshall-Gradisnik
Keyword(s):  
Chronic Fatigue Syndrome ◽  
Molecular Mechanisms ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Chronic Fatigue ◽  
Myalgic Encephalomyelitis ◽  
Potential Candidate ◽  
Fatigue Syndrome ◽  
Organ Systems ◽  
Transient Receptor

The transient receptor potential (TRP) superfamily of ion channels is involved in the molecular mechanisms that mediate neuroimmune interactions and activities. Recent advancements in neuroimmunology have identified a role for TRP cation channels in several neuroimmune disorders including amyotropic lateral sclerosis, multiple sclerosis, and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). ME/CFS is a debilitating disorder with an obscure aetiology, hence considerable examination of its pathobiology is warranted. Dysregulation of TRP melastatin (TRPM) subfamily members and calcium signalling processes are implicated in the neurological, immunological, cardiovascular, and metabolic impairments inherent in ME/CFS. In this review, we present TRPM7 as a potential candidate in the pathomechanism of ME/CFS, as TRPM7 is increasingly recognized as a key mediator of physiological and pathophysiological mechanisms affecting neurological, immunological, cardiovascular, and metabolic processes. A focused examination of the biochemistry of TRPM7, the role of this protein in the aforementioned systems, and the potential of TRPM7 as a molecular mechanism in the pathophysiology of ME/CFS will be discussed in this review. TRPM7 is a compelling candidate to examine in the pathobiology of ME/CFS as TRPM7 fulfils several key roles in multiple organ systems, and there is a paucity of literature reporting on its role in ME/CFS.

scholarly journals Antioxidative and Analgesic Effects of Naringin through Selective Inhibition of Transient Receptor Potential Vanilloid Member 1

Antioxidants ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 64
Author(s):  
Sanung Eom ◽  
Bo-Bae Lee ◽  
Shinhui Lee ◽  
Youngseo Park ◽  
Hye Duck Yeom ◽  
...  
Keyword(s):  
Neuropathic Pain ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Selective Inhibition ◽  
Transient Receptor Potential Vanilloid ◽  
Amino Acid Residues ◽  
Suppression Effect ◽  
Analgesic Effects ◽  
Inward Currents ◽  
Transient Receptor

Transient receptor potential vanilloid member 1 (TRPV1) is activated in response to capsaicin, protons, temperature, and free reactive oxygen species (ROS) released from inflammatory molecules after exposure to harmful stimuli. The expression level of TRPV1 is elevated in the dorsal root ganglion, and its activation through capsaicin and ROS mediates neuropathic pain in mice. Its expression is high in peripheral and central nervous systems. Although pain is a response evolved for survival, many studies have been conducted to develop analgesics, but no clear results have been reported. Here, we found that naringin selectively inhibited capsaicin-stimulated inward currents in Xenopus oocytes using a two-electrode voltage clamp. The results of this study showed that naringin has an IC50 value of 33.3 μM on TRPV1. The amino acid residues D471 and N628 of TRPV1 were involved in its binding to naringin. Our study bridged the gap between the pain suppression effect of TRPV1 and the preventive effect of naringin on neuropathic pain and oxidation. Naringin had the same characteristics as a model selective antagonist, which is claimed to be ideal for the development of analgesics targeting TRPV1. Thus, this study suggests the applicability of naringin as a novel analgesic candidate through antioxidative and analgesic effects of naringin.

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