Journal
FASEB JOURNAL
Volume 22, Issue 9, Pages 3298-3309Publisher
FEDERATION AMER SOC EXP BIOL
DOI: 10.1096/fj.08-107425
Keywords
structure-function; thermoreceptor; functional coupling; nociceptor; sensory transduction; oligomerization
Categories
Funding
- Spanish Ministry of Education and Science (MEC) [SAF2006-2580, BFU2005-03986]
- Fundacion Ramon Areces
- Generalitat Valenciana [GV-ACOMP06/202, GV05/076]
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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 inter-subunit interactions within the TRP box play an important role in TRPV1 gating.
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