TRPA1 as a drug target—promise and challenges

Chen, Jun; Hackos, David H.

doi:10.1007/s00210-015-1088-3

Cited by 141 publications

(128 citation statements)

References 128 publications

(222 reference statements)

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“…Therefore, inhibition of neuronal TRPA1 and TRPV1 in OA and DDD can possibly alleviate pain symptoms. Selective agonists and antagonists of TRPA1 and TRPV1 are available and being tested as analgesics in pre-clinical and clinical trials for neuropathic and OA pain (Brito et al, 2014;Chen and Hackos, 2015;Moran et al, 2011). Challenges that may be associated with systemic use of these compounds are impaired sensing mechanisms in non-target tissues (e.g.…”

Section: Trpcmentioning

confidence: 99%

The role of transient receptor potential channels in joint diseases

Krupková

Zvick²,

Wuertz‐Kozak³

2017

eCM

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Transient receptor potential channels (TRP channels) are cation selective transmembrane receptors with diverse structures, activation mechanisms and physiological functions. TRP channels act as cellular sensors for a plethora of stimuli, including temperature, membrane voltage, oxidative stress, mechanical stimuli, pH and endogenous as well as exogenous ligands, thereby illustrating their versatility. As such, TRP channels regulate various functions in both excitable and non-excitable cells, mainly by mediating Ca 2+ homeostasis. Dysregulation of TRP channels is implicated in many pathologies, including cardiovascular diseases, muscular dystrophies and hyperalgesia. However, the importance of TRP channel expression, physiological function and regulation in chondrocytes and intervertebral disc (IVD) cells is largely unexplored. Osteoarthritis (OA) and degenerative disc disease (DDD) are chronic age-related disorders that significantly affect the quality of life by causing pain, activity limitation and disability. Furthermore, currently available therapies cannot effectively slow-down or stop progression of these diseases. Both OA and DDD are characterised by reduced tissue cellularity, enhanced inflammatory responses and molecular, structural and mechanical alterations of the extracellular matrix, hence affecting load distribution and reducing joint flexibility. However, knowledge on how chondrocytes and IVD cells sense their microenvironment and respond to its changes is still limited. In this review, we introduced six families of mammalian TRP channels, their mechanisms of activation as well as activation-driven cellular consequences. We summarised the current knowledge on TRP channel expression and activity in chondrocytes and IVD cells and the significance of TRP channels as therapeutic targets for the treatment of OA and DDD.

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Section: Trpcmentioning

confidence: 99%

The role of transient receptor potential channels in joint diseases

Krupková

Zvick²,

Wuertz‐Kozak³

2017

eCM

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“…IL8 expression was observed in the bronchial epithelial cells co-expressing TRPA1. Furthermore TRPA1 specific inhibitors from Hydra Biosciences (HC-030031) and Abbott (A-967079) (Figure 1) [48] inhibited P. aeruginosa induced transcription of IL8, IL1b, IL6 and tumor necrosis factor α (TNFα) in A549 and human cystic fibrosis cell line (CuFi-1). P. aeruginosa is a gram negative bacteria and releases lipopolysaccharide (LPS) which is a direct TRPA1 agonist and sensitizer [49].…”

Section: Role Of Trpa1 In Cystic Fibrosismentioning

confidence: 99%

Blocking TRPA1 in Respiratory Disorders: Does It Hold a Promise?

2016

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Transient Receptor Potential Ankyrin 1 (TRPA1) ion channel is expressed abundantly on the C fibers that innervate almost entire respiratory tract starting from oral cavity and oropharynx, conducting airways in the trachea, bronchi, terminal bronchioles, respiratory bronchioles and upto alveolar ducts and alveoli. Functional presence of TRPA1 on non-neuronal cells got recognized recently. TRPA1 plays a well-recognized role of “chemosensor”, detecting presence of exogenous irritants and endogenous pro-inflammatory mediators that are implicated in airway inflammation and sensory symptoms like chronic cough, asthma, chronic obstructive pulmonary disease (COPD), allergic rhinitis and cystic fibrosis. TRPA1 can remain activated chronically due to elevated levels and continued presence of such endogenous ligands and pro-inflammatory mediators. Several selective TRPA1 antagonists have been tested in animal models of respiratory disease and their performance is very promising. Although there is no TRPA1 antagonist in advanced clinical trials or approved on market yet to treat respiratory diseases, however, limited but promising evidences available so far indicate likelihood that targeting TRPA1 may present a new therapy in treatment of respiratory diseases in near future. This review will focus on in vitro, animal and human evidences that strengthen the proposed role of TRPA1 in modulation of specific airway sensory responses and also on preclinical and clinical progress of selected TRPA1 antagonists.

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“…Exogenous pungent molecules such as AITC [37], cinnamaldehyde [38] and allicin [39], and environmental irritants like acroline [40] and 4-Hydroxynonenal (4-HNE) [41] directly activate TRPA1 via interactions with ankyrin repeats (ARs) at the amino-terminal end [42]. Conversely, endogenous compounds including bradykinin [43], histamine [44] and substance-P [39] indirectly activate TRPA1 mainly through G-protein coupled receptors (GPCRs) and phospholipase C (PLC) [43,45]. At present, fundamental questions regarding endogenous activation of TRPA1 remain unaddressed.…”

Section: Discussionmentioning

confidence: 99%

“…At present, fundamental questions regarding endogenous activation of TRPA1 remain unaddressed. Recent studies have proposed potential pathways for endogenous TRPA1 activation in the peripheral nervous system and in invertebrates [39,[45][46][47]. TRPA1 is activated by direct interaction with intracellular Ca 2+ ([Ca 2+ ]i).…”

Section: Discussionmentioning

confidence: 99%

Enhanced sensory coding in mouse vibrissal and visual cortex through TRPA1

Kheradpezhouh

Tang

Mattingley

et al. 2019

Preprint

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Transient Receptor Potential Ankyrin 1 (TRPA1) is a non-selective cation channel, which is broadly expressed throughout the body. Despite its expression in the mammalian cortex, little is known about the contribution of TRPA1 to cortical function. Here we investigate the role of TRPA1 in sensory information processing by performing electrophysiological recording and 2-photon calcium imaging from two sensory areas in mice: the primary vibrissal somatosensory cortex (vS1) and the primary visual cortex (V1). In vS1, local activation of TRPA1 by its agonist AITC significantly increased the spontaneous activity of cortical neurons, their evoked response to vibrissal stimulation, and their response range, consistent with a positive gain modulation. TRPA1 inhibition with HC-030031 reversed these modulations to below initial control gains. The gain modulations were absent in TRPA1 Knockout mice. In V1, TRPA1 activation increased the gain of direction and orientation selectivity similarly to the gain modulations observed in vS1 cortex. Linear decoding analysis of V1 population activity confirmed faster and more reliable encoding of visual signals in the presence of TRPA1 activation. Overall, our findings reveal a physiological role for TRPA1 in enhancing sensory signals in the mammalian cortex.

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TRPA1 as a drug target—promise and challenges

Cited by 141 publications

References 128 publications

The role of transient receptor potential channels in joint diseases

The role of transient receptor potential channels in joint diseases

Blocking TRPA1 in Respiratory Disorders: Does It Hold a Promise?

Enhanced sensory coding in mouse vibrissal and visual cortex through TRPA1

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