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

• Published in: Neuron (Cambridge, Mass.) Vol. 54; no. 6; pp. 905 - 918
• Main Authors: Lishko, Polina V., Procko, Erik, Jin, Xiangshu, Phelps, Christopher B., Gaudet, Rachelle
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 21.06.2007; Elsevier Limited
• Subjects: Adenosine Triphosphate - pharmacokinetics; Adenosine Triphosphate - pharmacology; Analgesics, Non-Narcotic - pharmacology; Animals; Ankyrin Repeat; Binding Sites - drug effects; Capsaicin - pharmacology; Cell Line, Transformed; Chromatography; Cloning, Molecular - methods; Fingers & toes; Humans; Insecta - cytology; Ion Channel Gating; Ligands; Membrane Potentials - drug effects; Membrane Potentials - physiology; Models, Biological; Models, Molecular; MOLNEURO; Mutagenesis, Site-Directed; Pain; Patch-Clamp Techniques; Protein Binding - drug effects; Protein Binding - physiology; Protein Structure, Tertiary; PROTEINS; Rats; Receptors, Drug - drug effects; Receptors, Drug - physiology; SIGNALING; Transfection; TRPV Cation Channels - chemistry; TRPV Cation Channels - genetics; PROTEINS; MOLNEURO; SIGNALING
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2007.05.027

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 PIP 2 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 PIP 2 and calmodulin.