TRPA1: a molecular view

The transient receptor potential ankyrin 1 (TRPA1) ion channel is expressed in pain-sensing neurons and other tissues and has become a major target in the development of novel pharmaceuticals. A remarkable feature of the channel is its long list of activators, many of which we are exposed to in daily life. Many of these agonists induce pain and inflammation, making TRPA1 a major target for anti-inflammatory and analgesic therapies. Studies in human patients and in experimental animals have confirmed an important role for TRPA1 in a number of pain conditions. Over the recent years, much progress has been made in elucidating the molecular structure of TRPA1 and in discovering binding sites and modulatory sites of the channel. Because the list of published mutations and important molecular sites is steadily growing and because it has become difficult to see the forest for the trees, this review aims at summarizing the current knowledge about TRPA1, with a special focus on the molecular structure and the known binding or gating sites of the channel.

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Ciliary Genes in Renal Cystic Diseases

Cells ◽

10.3390/cells9040907 ◽

2020 ◽

Vol 9 (4) ◽

pp. 907 ◽

Cited By ~ 2

Author(s):

Anna Adamiok-Ostrowska ◽

Agnieszka Piekiełko-Witkowska

Keyword(s):

Transient Receptor Potential ◽

Current Knowledge ◽

Apical Cell ◽

Receptor Potential ◽

Renal Diseases ◽

Special Focus ◽

Type I ◽

Altered Expression ◽

Transient Receptor ◽

The Impact

Cilia are microtubule-based organelles, protruding from the apical cell surface and anchoring to the cytoskeleton. Primary (nonmotile) cilia of the kidney act as mechanosensors of nephron cells, responding to fluid movements by triggering signal transduction. The impaired functioning of primary cilia leads to formation of cysts which in turn contribute to development of diverse renal diseases, including kidney ciliopathies and renal cancer. Here, we review current knowledge on the role of ciliary genes in kidney ciliopathies and renal cell carcinoma (RCC). Special focus is given on the impact of mutations and altered expression of ciliary genes (e.g., encoding polycystins, nephrocystins, Bardet-Biedl syndrome (BBS) proteins, ALS1, Oral-facial-digital syndrome 1 (OFD1) and others) in polycystic kidney disease and nephronophthisis, as well as rare genetic disorders, including syndromes of Joubert, Meckel-Gruber, Bardet-Biedl, Senior-Loken, Alström, Orofaciodigital syndrome type I and cranioectodermal dysplasia. We also show that RCC and classic kidney ciliopathies share commonly disturbed genes affecting cilia function, including VHL (von Hippel-Lindau tumor suppressor), PKD1 (polycystin 1, transient receptor potential channel interacting) and PKD2 (polycystin 2, transient receptor potential cation channel). Finally, we discuss the significance of ciliary genes as diagnostic and prognostic markers, as well as therapeutic targets in ciliopathies and cancer.

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Mammalian Transient Receptor Potential TRPA1 Channels: From Structure to Disease

Physiological Reviews ◽

10.1152/physrev.00005.2019 ◽

2020 ◽

Vol 100 (2) ◽

pp. 725-803 ◽

Cited By ~ 26

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.

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TRPV1: Structure, Endogenous Agonists, and Mechanisms

International Journal of Molecular Sciences ◽

10.3390/ijms21103421 ◽

2020 ◽

Vol 21 (10) ◽

pp. 3421 ◽

Cited By ~ 2

Author(s):

Miguel Benítez-Angeles ◽

Sara Luz Morales-Lázaro ◽

Emmanuel Juárez-González ◽

Tamara Rosenbaum

Keyword(s):

Ion Channel ◽

Binding Sites ◽

Transient Receptor Potential ◽

Receptor Potential ◽

Transient Receptor Potential Vanilloid ◽

Trpv1 Channel ◽

Field Of Study ◽

Transient Receptor ◽

Shed Light ◽

Made In

The Transient Receptor Potential Vanilloid 1 (TRPV1) channel is a polymodal protein with functions widely linked to the generation of pain. Several agonists of exogenous and endogenous nature have been described for this ion channel. Nonetheless, detailed mechanisms and description of binding sites have been resolved only for a few endogenous agonists. This review focuses on summarizing discoveries made in this particular field of study and highlighting the fact that studying the molecular details of activation of the channel by different agonists can shed light on biophysical traits that had not been previously demonstrated.

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Molecular Basis of TRPA1 Regulation in Nociceptive Neurons. A Review

Physiological Research ◽

10.33549/physiolres.933553 ◽

2017 ◽

pp. 425-439 ◽

Cited By ~ 23

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.

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TRPing on Cell Swelling - TRPV4 Senses It

Frontiers in Immunology ◽

10.3389/fimmu.2021.730982 ◽

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.

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TRP Channels as Drug Targets to Relieve Itch

Pharmaceuticals ◽

10.3390/ph11040100 ◽

2018 ◽

Vol 11 (4) ◽

pp. 100 ◽

Cited By ~ 23

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.

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

Biochemical Society Transactions ◽

10.1042/bst0350086 ◽

2007 ◽

Vol 35 (1) ◽

pp. 86-88 ◽

Cited By ~ 23

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.

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Assembly domains in TRP channels

Biochemical Society Transactions ◽

10.1042/bst0350084 ◽

2007 ◽

Vol 35 (1) ◽

pp. 84-85 ◽

Cited By ~ 27

Author(s):

R. Schindl ◽

C. Romanin

Keyword(s):

Ion Channels ◽

Transient Receptor Potential ◽

Trp Channels ◽

Current Knowledge ◽

Large Family ◽

Receptor Potential ◽

Trp Channel ◽

Channel Formation ◽

Transient Receptor ◽

Sensory Functions

The large family of mammalian TRP (transient receptor potential) ion channels encompasses diverse sensory functions. TRP proteins consist of six transmembrane domains, with a pore–loop motif between the fifth and sixth domains and cytosolic N- and C-termini. The intracellular strands not only interact with various proteins and lipids, but also include essential multimerization regions. This review summarizes the current knowledge of the intrinsic assembly domains that assure tetrameric TRP channel formation.

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TRP Channels in Human Prostate

The Scientific World JOURNAL ◽

10.1100/tsw.2010.149 ◽

2010 ◽

Vol 10 ◽

pp. 1597-1611 ◽

Cited By ~ 23

Author(s):

Carl Van Haute ◽

Dirk De Ridder ◽

Bernd Nilius

Keyword(s):

Prostate Cancer ◽

Transient Receptor Potential ◽

Trp Channels ◽

Current Knowledge ◽

Receptor Potential ◽

Human Prostate ◽

Prostate Carcinogenesis ◽

Potential Impact ◽

Transient Receptor ◽

Prostate Diseases

This review gives an overview of morphological and functional characteristics in the human prostate. It will focus on the current knowledge about transient receptor potential (TRP) channels expressed in the human prostate, and their putative role in normal physiology and prostate carcinogenesis. Controversial data regarding the expression pattern and the potential impact of TRP channels in prostate function, and their involvement in prostate cancer and other prostate diseases, will be discussed.

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