Abstract
The multimodal sensory channel transient receptor potential vanilloid-3 (TRPV3) is expressed in epidermal keratinocytes and implicated in chronic pruritus, allergy, and inflammation-related skin disorders. Gain-of-function mutations of TRPV3 cause hair growth disorders in mice and Olmsted syndrome in humans. Nevertheless, whether and how TRPV3 could be therapeutically targeted remains to be elucidated. We here report that mouse and human TRPV3 channel is targeted by the clinical medication dyclonine that exerts a potent inhibitory effect. Accordingly, dyclonine rescued cell death caused by gain-of-function TRPV3 mutations and suppressed pruritus symptoms in vivo in mouse model. At the single-channel level, dyclonine inhibited TRPV3 open probability but not the unitary conductance. By molecular simulations and mutagenesis, we further uncovered key residues in TRPV3 pore region that could toggle the inhibitory efficiency of dyclonine. The functional and mechanistic insights obtained on dyclonine-TRPV3 interaction will help to conceive therapeutics for skin inflammation.
Highlights
Transient receptor potential (TRP) channels belong to a family of calcium-permeable and nonselective cation channels, essential for body sensory processing and local inflammatory development (Clapham, 2003)
Here, using a multidisciplinary approach combining electrophysiology, genetic engineering and ultrafast local temperature control, we show that mouse and human transient receptor potential vanilloid-3 (TRPV3) channel was potently suppressed by dyclonine
Because TRPV3 channels exhibit sensitizing properties upon repeated stimulation (Chung, Lee, Mizuno, Suzuki, & Caterina, 2004a), we examined the effect of dyclonine after the response had stabilized following repetitive application of 2-aminoethoxydiphenyl borate (2-APB) (Figure 1A)
Summary
Transient receptor potential (TRP) channels belong to a family of calcium-permeable and nonselective cation channels, essential for body sensory processing and local inflammatory development (Clapham, 2003). Using a multidisciplinary approach combining electrophysiology, genetic engineering and ultrafast local temperature control, we show that mouse and human TRPV3 channel was potently suppressed by dyclonine. It dose-dependently inhibited TRPV3 currents in a voltage-independent manner and rescued cell death caused by TRPV3 gain-of-function mutation. We identified molecular residues that were capable of either eliminating or enhancing the inhibitory effect of dyclonine These data demonstrate the effective inhibition of TRPV3 channel by dyclonine, supplementing a molecular mechanism for its clinical effects and raising its potential to ameliorate TRPV3-associated disorders
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