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

0510414 - FGÚ 2020 RIV CH eng J - Journal Article
Máčiková, Lucie - Vyklická, Lenka - Barvík, I. - Sobolevsky, A. I. - Vlachová, Viktorie
Cytoplasmic Inter-Subunit Interface Controls Use-Dependence of Thermal Activation of TRPV3 Channel.
International Journal of Molecular Sciences. Roč. 20, č. 16 (2019), č. článku 3990. E-ISSN 1422-0067
R&D Projects: GA ČR(CZ) GA19-03777S
Institutional support: RVO:67985823
Keywords : transient receptor potential * transient receptor potential vanilloid 1 (TRPV1) * noxious heat * ankyrin repeat * nociception
OECD category: Neurosciences (including psychophysiology
Impact factor: 4.556, year: 2019
Method of publishing: Open access
https://doi.org/10.3390/ijms20163990

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 degrees 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 degrees 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.
Permanent Link: http://hdl.handle.net/11104/0300922