A tyrosine residue in TM6 of the Vanilloid Receptor TRPV1 involved in desensitization and calcium permeability of capsaicin-activated currents.
The Vanilloid Receptor TRPV1 is a non-selective cation channel with a high relative Ca(2+) permeability. TRPV1 exhibits slow desensitization, a potential mechanism regulating adaptation of peripheral sensory neurons to noxious stimuli. The predicted folding pattern of TRPV1 resembles that of voltage-gated channels. Sequence alignment of segments 6 of TRPV1 and voltage-gated Na(+) channels reveals a conserved aromatic amino acid that in Na(+) channels is involved in fast inactivation and pharmacological block. We found that replacing this tyrosine Y671 by positively charged lysine (K) completely abrogated Ca(2+)-dependent desensitization. Y671K also exhibited significant reduction in Ca(2+) permeability that was not responsible for the lack in desensitization. Substitution of Y671 with negatively charged aspartate or uncharged alanine slightly altered desensitization but left Ca(2+) permeability unchanged. Substitution of Y671 with positively charged arginine produced a phenotype similar to Y671K. We propose that residue Y671 is critical for the high relative Ca(2+) permeability of TRPV1 and participates in the structural rearrangements of the channel protein leading to Ca(2+)-dependent desensitization.
Mohapatra
Durga Prasanna
DP
Department of Anesthesiology, Friedrich-Alexander-University Erlangen-Nuremberg, 91054 Erlangen, Germany.
Wang
Sho-Ya
SY
Wang
Ging Kuo
GK
Nau
Carla
C
D000595:Amino Acid Sequence / Q000235:genetics; D000596:Amino Acids / Q000235:genetics / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics*; D002211:Capsaicin / Q000494:pharmacology; D002460:Cell Line; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008564:Membrane Potentials / Q000235:genetics; D009154:Mutation / Q000235:genetics; D009475:Neurons, Afferent / Q000378:metabolism*; D009619:Nociceptors / Q000378:metabolism*; D010146:Pain / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary / Q000235:genetics; D011522:Protons; D011955:Receptors, Drug / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D015222:Sodium Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D014443:Tyrosine / Q000378:metabolism*
D000596:Amino Acids; D011522:Protons; D011955:Receptors, Drug; D015222:Sodium Channels; D014443:Tyrosine; D002211:Capsaicin