Mutation in <i>TRPV3</i> causes painful focal plantar keratoderma

Peters, Franziska; Köpp, Julia; Fischer, Judith; Tantcheva‐Poór, Iliana

doi:10.1111/jdv.16498

Cited by 5 publications

(10 citation statements)

References 6 publications

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“…Gain-of-function mutations in TRPV3 were discovered in patients with Olmstedt disease 103 , 104 , erythromelalgia 104 , and painful plantar keratoderma 105 . As with TRPA1 above, many of these TRPV3 gain-of-function mutations are at the elbow connecting the S4−S5 linker and the S5 helix (Fig.…”

Section: Pain: Trp Channels As Analgesic Targetsmentioning

confidence: 99%

“…In humans, gain-of-function TRPV3 mutations (G568D and Q580P; Fig. 3b ) were described in palmoplantar keratoderma 105 , and increased TRPV3 expression was reported in post-burn pruritus 217 . Similarly, TRPV4 is overexpressed in skin biopsy samples from patients with chronic pruritus 218 , and genetic deletion of Trpv4 ameliorates itching in mouse models of chronic itch 219 .…”

Section: Dermatology and Ophthalmologymentioning

confidence: 99%

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Advances in TRP channel drug discovery: from target validation to clinical studies

Koivisto

Belvisi

Gaudet

et al. 2021

Nat Rev Drug Discov

293

171

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Transient receptor potential (TRP) channels are multifunctional signalling molecules with many roles in sensory perception and cellular physiology. Therefore, it is not surprising that TRP channels have been implicated in numerous diseases, including hereditary disorders caused by defects in genes encoding TRP channels (TRP channelopathies). Most TRP channels are located at the cell surface, which makes them generally accessible drug targets. Early drug discovery efforts to target TRP channels focused on pain, but as our knowledge of TRP channels and their role in health and disease has grown, these efforts have expanded into new clinical indications, ranging from respiratory disorders through neurological and psychiatric diseases to diabetes and cancer. In this Review, we discuss recent findings in TRP channel structural biology that can affect both drug development and clinical indications. We also discuss the clinical promise of novel TRP channel modulators, aimed at both established and emerging targets. Last, we address the challenges that these compounds may face in clinical practice, including the need for carefully targeted approaches to minimize potential side-effects due to the multifunctional roles of TRP channels.

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Section: Pain: Trp Channels As Analgesic Targetsmentioning

confidence: 99%

Section: Dermatology and Ophthalmologymentioning

confidence: 99%

Advances in TRP channel drug discovery: from target validation to clinical studies

Koivisto

Belvisi

Gaudet

et al. 2021

Nat Rev Drug Discov

293

171

View full text Add to dashboard Cite

show abstract

“…Our results revealed that citrusinine-II could cross the blood-brain barrier and therefore citrusinine-II might be involved in the regulation of the descending pain pathway. These findings suggest that citrusinine-II is a valuable candidate drug for the treatment of pruritus-related diseases and that TRPV3 channel is a promising therapeutic target for treating severe itching and pain, as clinically reported in palmoplantar keratoderma and Olmsted syndrome (Choi et al, 2018;Peters et al, 2020).…”

Section: Discussionmentioning

confidence: 68%

“…Although there is no overwhelming evidence that TRPV3 has a definite role in analgesic therapy, some reports suggest that TRPV3 channel maybe pain-related (Carreno et al, 2012;Huang & Chung, 2013;Park et al, 2016). In addition, hereditary palmoplantar keratoderma, a rare genetic disorder which is partly due to TRPV3 gain-of-function mutation, is also characterized by severe pain and debilitating itch (Peters et al, 2020). Therefore, we tested the analgesic activity of citrusinine-II on several rodent pain models in which pain was induced by formalin, acetic acid or heat.…”

Section: Citrusinine-ii Alleviates Pain Behaviour In Rodent Modelsmentioning

confidence: 99%

A plant‐derived TRPV3 inhibitor suppresses pain and itch

Han

Luo

Kamau

et al. 2021

British J Pharmacology

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Background and Purpose: Itching is the most frequent pathology in dermatology that has significant impacts on people's mental health and social life. Transient receptor potential vanilloid 3 (TRPV3) channel is a promising target for treating pruritus. However, few selecetive and potent antagonists have been reported. This study was designed to identify selective TRPV3 antagonist and elucidate its anti-pruritus pharmacology. Experimental Approach: FlexStation and calcium fluorescence imaging were conducted to track the functional compounds. Whole-cell patch clamp was used to record itch-related ion channel currents. Homologous recombination and site-directed mutagenesis were employed to construct TRPV3 channel chimeras and point mutations for exploring pharmacological mechanism. Mouse models were used for in vivo anti-pruritus assay. Key Results: An acridone alkaloid (citrusinine-II) was purified and characterized from Atalantia monophylla. It directly interacts with Y564 within S4 helix of TRPV3 to selectively inhibit the channel with a half maximal inhibitory concentration (IC 50) of 12.43 μM. Citrusinine-II showed potential efficacy to attenuate both chronic and acute itch. Intradermal administration of citrusinine-II (143 ng/skin site) nearly completely inhibited itch behaviours. It also shows significant analgesic effects. Little side effects of the compound are observed. Conclusion and Implications: By acting as a selective and potent inhibitor of TRPV3 channel, citrusinine-II shows valuable therapeutic effects in pruritus animal models Abbreviations: 2-APB, 2-aminoethoxydiphenyl borate; ASIC3, acid-sensing (proton-gated) ion channel 3; CCK8, cell counting kit-8; Nav, voltage-gated sodium channel; TRP, transient receptor potential; TRPA1, transient receptor potential ankyrin 1; TRPM8, transient receptor potential melastatin 8; TRPV1, transient receptor potential vanilloid 1; TRPV2, transient receptor potential vanilloid 2; TRPV3, transient receptor potential vanilloid 3; TRPV4, transient receptor potential vanilloid 4.

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“…As a member of TRPV subfamily similar to TRPV1, TRPV3 is suspected to have similar nociceptive sensation function to TRPV1, although this view is still controversial [ 15 , 18 , 44 ]. Most studies have supported the function of TRPV3 in nociceptive sensation.…”

Section: Physiological and Pathological Functions Of Keratinocytes-ex...mentioning

confidence: 99%

Novel Insights into the Role of Keratinocytes-Expressed TRPV3 in the Skin

et al. 2023

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TRPV3 is a non-selective cation channel that is highly expressed in keratinocytes in the skin. Traditionally, keratinocytes-expressed TRPV3 is involved in multiple physiological and pathological functions of the skin, such as itching, heat pain, and hair development. Although the underlying mechanisms by which TRPV3 functions in vivo remain obscure, recent research studies suggest that several cytokines and EGFR signaling pathways may be involved. However, there have also been other studies with opposite results that question the role of TRPV3 in heat pain. In addition, an increasing number of studies have suggested a novel role of TRPV3 in promoting skin regeneration, indicating that TRPV3 may become a new potential target for regulating skin regeneration. This paper not only reviews the role of keratinocytes-expressed TRPV3 in the physiological and pathological processes of itching, heat pain, hair development, and skin regeneration, but also reviews the relationship between TRPV3 gene mutations and skin diseases such as atopic dermatitis (AD) and Olmsted syndrome (OS). This review will lay a foundation for further developing our understanding of the mechanisms by which TRPV3 is involved in itching, heat pain, and hair development, as well as the treatments for TRPV3-related skin diseases.

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Mutation in TRPV3 causes painful focal plantar keratoderma

Cited by 5 publications

References 6 publications

Advances in TRP channel drug discovery: from target validation to clinical studies

Advances in TRP channel drug discovery: from target validation to clinical studies

A plant‐derived TRPV3 inhibitor suppresses pain and itch

Novel Insights into the Role of Keratinocytes-Expressed TRPV3 in the Skin

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