Structural modeling and patch-clamp analysis of pain-related mutation TRPA1-N855S reveal inter-subunit salt bridges stabilizing the channel open state

Neuropharmacology
Vlastimil ZímaV Vlachová

Abstract

The ankyrin transient receptor potential channel TRPA1 is a polymodal sensor for noxious stimuli, and hence a promising target for treating chronic pain. This tetrameric six-transmembrane segment (S1-S6) channel can be activated by various pungent chemicals, such as allyl isothiocyanate or cinnamaldehyde, but also by intracellular Ca(2+) or depolarizing voltages. Within the S4-S5 linker of human TRPA1, a gain-of-function mutation, N855S, was recently found to underlie familial episodic pain syndrome, manifested by bouts of severe upper body pain, triggered by physical stress, fasting, or cold. To clarify the structural basis for this channelopathy, we derive a structural model of TRPA1 by combining homology modeling, molecular dynamics simulations, point mutagenesis and electrophysiology. In the vicinity of N855, the model reveals inter-subunit salt bridges between E854 and K868. Using the heterologous expression of recombinant wild-type and mutant TRPA1 channels in HEK293T cells, we indeed found that the charge-reversal mutants E854R and K868E exhibited dramatically reduced responses to chemical and voltage stimuli, whereas the charge-swapping mutation E854R/K868E substantially rescued their functionalities. Moreover, mutation...Continue Reading

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Citations

Apr 16, 2016·The Journal of Physiology·Félix Viana
Nov 23, 2016·Scientific Reports·Rupali GuptaMakoto Tominaga
Nov 30, 2018·Journal of Neurophysiology·Jannis E MeentsMichael J M Fischer
Jan 25, 2018·Science Signaling·Lucie ZimovaViktorie Vlachova
Nov 2, 2019·Physiological Reviews·Karel TalaveraBernd Nilius
Jul 19, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Wenying XianPeter Lipp
Dec 29, 2017·Neuroscience Bulletin·Carlene MooreWolfgang B Liedtke
May 24, 2020·Pflügers Archiv : European journal of physiology·Robbe NaertKarel Talavera
May 14, 2021·Physiological Research·V Sinica, V Vlachová

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