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Identification of molecular determinants of channel gating in the transient receptor potential box of vanilloid receptor I

Pierluigi Valente^*,1, Nuria García-Sanz^*,1, Ana Gomis, Asia Fernández-Carvajal^*, Gregorio Fernández-Ballester^*, Félix Viana, Carlos Belmonte and Antonio Ferrer-Montiel^*,2

^* Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Elche, Alicante, Spain; and

Instituto de Neurociencias de Alicante, Universidad Miguel Hernández-Consejo Superior de Investigaciones Científicas, San Juan de Alicante, Alicante, Spain

²Correspondence: Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Av. de la Universidad s/n, 03202 Elche, Alicante, Spain. E-mail: aferrer{at}umh.es

Transient receptor potential vanilloid receptor subtype I (TRPV1) is an ion channel gated by physical and chemical stimuli that belongs to the TRPV protein family. TRPV receptors contain a highly conserved, 6-mer segment near the channel gate, known as the TRP box, whose function remains unknown. Here, we performed an alanine scanning mutagenesis of the TRP box of TRPV1 (IWKLQR) and found that mutation of this motif affected channel gating by raising the free energy of channel activation. Functional characterization of TRPV1 mutants showed that substitution of I696, W697, and R701 by alanine severely affected voltage- and heat-dependent activation and notably reduced the capsaicin responsiveness and tachyphylaxia, while mutation of K698, L699, and Q700 had minor effects. In addition, mutation of I696 to alanine promoted a strong outward rectification at negative membrane potentials, and slowed the kinetics of channel activation. Taken together, our findings suggest that modification of I696, W697, and R701 to alanine altered channel function by affecting events downstream of the initial stimuli-sensing step and imply that intersubunit interactions within the TRP box play an important role in TRPV1 gating.—Valente, P., García-Sanz, N., Gomis, A., Fernández-Carvajal, A., Fernández-Ballester, G., Viana, F., Belmonte, C., and Ferrer-Montiel, A. Identification of molecular determinants of channel gating in the transient receptor potential box of vanilloid receptor I.

Key Words: structure-function • thermoreceptor • functional coupling • nociceptor • sensory transduction • oligomerization

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