Transient Receptor Potential Ankyrin Type-1 Channels as a Potential Target for the Treatment of Cardiovascular Diseases

Gao, Song; Kaudimba, Keneilwe Kenny; Guo, Shanshan; Zhang, Shuang; Liu, Tiemin; Chen, Peijie; Wang, Ru

doi:10.3389/fphys.2020.00836

Cited by 17 publications

(12 citation statements)

References 174 publications

(205 reference statements)

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“…The changes require the timely movement of calcium ions through channels, including voltage-gated, ligand-mediated, and mechanosensitive calcium channels. Many of these calcium channels are referred to as TRP mediate ion channels ( Gao S. et al, 2020 ; Wen et al, 2020 ).…”

Section: Trp Channels As Potential Drug Targetsmentioning

confidence: 99%

A Review on the Role of TRP Channels and Their Potential as Drug Targets_An Insight Into the TRP Channel Drug Discovery Methodologies

Fallah¹,

Ahuja²,

Lin³

et al. 2022

Front. Pharmacol.

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Transient receptor potential (TRP) proteins are a large group of ion channels that control many physiological functions in our body. These channels are considered potential therapeutic drug targets for various diseases such as neurological disorders, cancers, cardiovascular disease, and many more. The Nobel Prize in Physiology/Medicine in the year 2021 was awarded to two scientists for the discovery of TRP and PIEZO ion channels. Improving our knowledge of technologies for their study is essential. In the present study, we reviewed the role of TRP channel types in the control of normal physiological functions as well as disease conditions. Also, we discussed the current and novel technologies that can be used to study these channels successfully. As such, Flux assays for detecting ionic flux through ion channels are among the core and widely used tools for screening drug compounds. Technologies based on these assays are available in fully automated high throughput set-ups and help detect changes in radiolabeled or non-radiolabeled ionic flux. Aurora’s Ion Channel Reader (ICR), which works based on label-free technology of flux assay, offers sensitive, accurate, and reproducible measurements to perform drug ranking matching with patch-clamp (gold standard) data. The non-radiolabeled trace-based flux assay coupled with the ICR detects changes in various ion types, including potassium, calcium, sodium, and chloride channels, by using appropriate tracer ions. This technology is now considered one of the very successful approaches for analyzing ion channel activity in modern drug discovery. It could be a successful approach for studying various ion channels and transporters, including the different members of the TRP family of ion channels.

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Section: Trp Channels As Potential Drug Targetsmentioning

confidence: 99%

A Review on the Role of TRP Channels and Their Potential as Drug Targets_An Insight Into the TRP Channel Drug Discovery Methodologies

Fallah¹,

Ahuja²,

Lin³

et al. 2022

Front. Pharmacol.

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“…Finally, increasing evidence supports a role for TRPA1 in fibrosis associated with systemic diseases [ 150 , 151 ]. Accordingly, the possibility that TRPA1 promotes fibrosis in fibrogenic skin diseases (e.g., scleroderma) or wound healing is worth investigating, due to the lack of effective therapeutic strategies in such conditions.…”

Section: Therapeutic Perspectives and Future Directionsmentioning

confidence: 99%

The Role of TRPA1 in Skin Physiology and Pathology

Maglie

Araújo

Antiga

et al. 2021

IJMS

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The transient receptor potential ankyrin 1 (TRPA1), a member of the TRP superfamily of channels, acts as ‘polymodal cellular sensor’ on primary sensory neurons where it mediates the peripheral and central processing of pain, itch, and thermal sensation. However, the TRPA1 expression extends far beyond the sensory nerves. In recent years, much attention has been paid to its expression and function in non-neuronal cell types including skin cells, such as keratinocytes, melanocytes, mast cells, dendritic cells, and endothelial cells. TRPA1 seems critically involved in a series of physiological skin functions, including formation and maintenance of physico-chemical skin barriers, skin cells, and tissue growth and differentiation. TRPA1 appears to be implicated in mechanistic processes in various immunological inflammatory diseases and cancers of the skin, such as atopic and allergic contact dermatitis, psoriasis, bullous pemphigoid, cutaneous T-cell lymphoma, and melanoma. Here, we report recent findings on the implication of TRPA1 in skin physiology and pathophysiology. The potential use of TRPA1 antagonists in the treatment of inflammatory and immunological skin disorders will be also addressed.

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“…[28][29][30] A primary clinical goal for TRPA1 modulation has been novel analgesics, 31 but developmental drugs based on TRPA1 antagonism that have reached phase II clinical trials have also been aimed at neuropathy and respiratory disorders. 32 Recent efforts have also aimed at the development of TRPA1 modulators for the treatment of cardiovascular disease 33 and chronic itch. 34 Applications in skin regeneration have even been explored.…”

Section: Trpa1 (Transient Receptor Potential Ankyrin 1 or Transient Receptor Potential Channelmentioning

confidence: 99%

Atomistic Mechanisms of Human TRPA1 Activation By Electrophile Irritants Through Molecular Dynamics Simulation and Mutual Information Analysis

Habgood

Seiferth

Zaki

et al. 2021

Preprint

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The ion channel TRPA1 is a promiscuous chemosensor, with reported response to a wide spectrum of noxious electrophilic irritants, as well as cold, heat, and mechanosensation. It is also implicated in the inception of itch and pain and has hence been investigated as a drug target for novel analgesics. The mechanism of electrophilic activation for TRPA1 is therefore of broad interest. TRPA1 structures with the pore in both open and closed states have recently been published as well as covalent binding modes for electrophile agonists. However, the detailed mechanism of coupling between electrophile binding sites and the pore remains speculative. In addition, while two different cysteine residues (C621 and C665) have been identified as critical for electrophile bonding and activation, the bound geometry has only been resolved at C621. Here, we use molecular dynamics simulations of TRPA1 in both pore-open and pore-closed states to explore the allosteric link between the electrophile binding sites and pore stability. Our simulations reveal that an open pore is structurally stable in the presence of open ‘pockets’ in the C621 / C665 region, but rapidly collapses and closes when these pockets are shut. Binding of electrophiles at either C621 or C665 provides stabilisation of the pore-open state, but molecules bound at C665 are shown to be able to rotate in and out of the pocket, allowing for immediate stabilisation of transient open states. Finally, mutual information analysis of trajectories reveals an informational path linking the electrophile binding site pocket to the pore via the voltage-sensing-like domain, giving a detailed insight into the how the pore is stabilized in the open state.

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Transient Receptor Potential Ankyrin Type-1 Channels as a Potential Target for the Treatment of Cardiovascular Diseases

Cited by 17 publications

References 174 publications

A Review on the Role of TRP Channels and Their Potential as Drug Targets_An Insight Into the TRP Channel Drug Discovery Methodologies

A Review on the Role of TRP Channels and Their Potential as Drug Targets_An Insight Into the TRP Channel Drug Discovery Methodologies

The Role of TRPA1 in Skin Physiology and Pathology

Atomistic Mechanisms of Human TRPA1 Activation By Electrophile Irritants Through Molecular Dynamics Simulation and Mutual Information Analysis

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