Structural determinant of TRPV1 desensitization interacts with calmodulin

doi:10.1073/pnas.1337252100

Structural determinant of TRPV1 desensitization interacts with calmodulin

^*Department of Cellular and Molecular Physiology, Mie University School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan; and ^†Department of Anesthesiology, University of Tsukuba School of Medicine, Tsukuba 305-0006, Japan

Edited by Lily Y. Jan, University of California School of Medicine, San Francisco, CA (received for review December 4, 2002)

Abstract

The capsaicin receptor, TRPV1 (VR1), is a sensory neuron-specific ion channel that serves as a polymodal detector of pain-producing chemical and physical stimuli. Extracellular Ca²⁺-dependent desensitization of TRPV1 observed in patch–clamp experiments when using both heterologous expression systems and native sensory ganglia is thought to be one mechanism underlying the paradoxical effectiveness of capsaicin as an analgesic therapy. Here, we show that the Ca²⁺-binding protein calmodulin binds to a 35-aa segment in the C terminus of TRPV1, and that disruption of the calmodulin-binding segment prevents TRPV1 desensitization. Compounds that interfere with the 35-aa segment could therefore prove useful in the treatment of pain.

Footnotes

↵ ‡ To whom correspondence should be addressed. E-mail: tominaga{at}doc.medic.mie-u.ac.jp.
This paper was submitted directly (Track II) to the PNAS office.
Abbreviations: CaM, calmodulin; TRP, transient receptor potential; Δ35AA, deletion mutant of TRPV1 lacking 35 aa.