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Cytoplasmic Inter-Subunit Interface Controls Use-Dependence of Thermal Activation of TRPV3 Channel

1
Department of Cellular Neurophysiology, Institute of Physiology Czech Academy of Sciences, 142 20 Prague, Czech Republic
2
Department of Physiology, Faculty of Science, Charles University, 128 00 Prague, Czech Republic
3
Division of Biomolecular Physics, Institute of Physics, Faculty of Mathematics and Physics, Charles University, 121 16 Prague, Czech Republic
4
Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY 10032, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(16), 3990; https://doi.org/10.3390/ijms20163990
Received: 23 July 2019 / Revised: 12 August 2019 / Accepted: 13 August 2019 / Published: 16 August 2019
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Abstract

The vanilloid transient receptor potential channel TRPV3 is a putative molecular thermosensor widely considered to be involved in cutaneous sensation, skin homeostasis, nociception, and pruritus. Repeated stimulation of TRPV3 by high temperatures above 50 °C progressively increases its responses and shifts the activation threshold to physiological temperatures. This use-dependence does not occur in the related heat-sensitive TRPV1 channel in which responses decrease, and the activation threshold is retained above 40 °C during activations. By combining structure-based mutagenesis, electrophysiology, and molecular modeling, we showed that chimeric replacement of the residues from the TRPV3 cytoplasmic inter-subunit interface (N251–E257) with the homologous residues of TRPV1 resulted in channels that, similarly to TRPV1, exhibited a lowered thermal threshold, were sensitized, and failed to close completely after intense stimulation. Crosslinking of this interface by the engineered disulfide bridge between substituted cysteines F259C and V385C (or, to a lesser extent, Y382C) locked the channel in an open state. On the other hand, mutation of a single residue within this region (E736) resulted in heat resistant channels. We propose that alterations in the cytoplasmic inter-subunit interface produce shifts in the channel gating equilibrium and that this domain is critical for the use-dependence of the heat sensitivity of TRPV3. View Full-Text
Keywords: transient receptor potential; transient receptor potential vanilloid 1 (TRPV1); noxious heat; ankyrin repeat; nociception transient receptor potential; transient receptor potential vanilloid 1 (TRPV1); noxious heat; ankyrin repeat; nociception
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Macikova, L.; Vyklicka, L.; Barvik, I.; Sobolevsky, A.I.; Vlachova, V. Cytoplasmic Inter-Subunit Interface Controls Use-Dependence of Thermal Activation of TRPV3 Channel. Int. J. Mol. Sci. 2019, 20, 3990.

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