Structural determinant of TRPV1 desensitization interacts with calmodulin.
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.
Numazaki
Mitsuko
M
Department of Cellular and Molecular Physiology, Mie University School of Medicine, Edobashi 2-174, Tsu, Mie 514-8507, Japan.
Tominaga
Tomoko
T
Takeuchi
Kumiko
K
Murayama
Namie
N
Toyooka
Hidenori
H
Tominaga
Makoto
M
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism*; D002211:Capsaicin / Q000494:pharmacology; D002460:Cell Line; D004594:Electrophysiology; D015723:Gene Library; D005982:Glutathione Transferase / Q000378:metabolism; D006801:Humans; D016297:Mutagenesis, Site-Directed; D018408:Patch-Clamp Techniques; D011233:Precipitin Tests; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D011955:Receptors, Drug / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism
D002147:Calmodulin; D011955:Receptors, Drug; D011993:Recombinant Fusion Proteins; D005982:Glutathione Transferase; D002211:Capsaicin; D002118:Calcium