The Ankyrin Repeats of TRPV1 Bind Multiple Ligands and Modulate Channel Sensitivity

Polina V. Lishko, Erik Procko, Xiangshu Jin, Christopher B. Phelps, Rachelle Gaudet

Research output: Contribution to journalArticlepeer-review


TRPV1 plays a key role in nociception, as it is activated by heat, low pH, and ligands such as capsaicin, leading to a burning pain sensation. We describe the structure of the cytosolic ankyrin repeat domain (ARD) of TRPV1 and identify a multiligand-binding site important in regulating channel sensitivity within the TRPV1-ARD. The structure reveals a binding site that accommodates triphosphate nucleotides such as ATP, and biochemical studies demonstrate that calmodulin binds the same site. Electrophysiology experiments show that either ATP or PIP2 prevent desensitization to repeated applications of capsaicin, i.e., tachyphylaxis, while calmodulin plays an opposing role and is necessary for tachyphylaxis. Mutations in the TRPV1-ARD binding site eliminate tachyphylaxis. We present a model for the calcium-dependent regulation of TRPV1 via competitive interactions of ATP and calmodulin at the TRPV1-ARD-binding site and discuss its relationship to the C-terminal region previously implicated in interactions with PIP2 and calmodulin.

Original languageEnglish (US)
Pages (from-to)905-918
Number of pages14
Issue number6
StatePublished - Jun 21 2007
Externally publishedYes



ASJC Scopus subject areas

  • Neuroscience(all)


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