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Published on: December 31, 2013
Calpain cleaves the distal carboxyl terminus of TRPV1 and modulates its tachyphylaxis
Jin-Yan Jiang1,2, Xiao-Chen Wang3, Jing Yang4
1Department of Neurobiology, School of Basic Medical Sciences and Neuroscience Research Institute, Peking University, 38 Xueyuan Road, 100191, Beijing, China.
Background:
Transient receptor potential vanilloid-1 (TRPV1) plays a critical role in noxious heat sensation in physiological conditions and pain hypersensitivity in pathological pain. Capsaicin, a classic TRPV1 agonist, is used to relieve pain partially through induction of TRPV1 desensitization. Multiple mechanisms have been proposed to contribute to TRPV1 desensitization. However, the limiting factors or antagonistic mechanisms of TRPV1 desensitization remain poorly understood.
Results:
Stimulation of TRPV1 by capsaicin (1 µM) activates calpain without causing obvious cellular injury. Calpain cleaves rTRPV1 at the G819/S820 site located in the distal carboxyl terminus. The truncated mutant, TRPV1 Δ820, shows reduced plasma membrane localization partially due to impaired subunit assembly. Notably, TRPV1 Δ820 shows increased resistance to tachyphylaxis as induced by repetitive capsaicin stimulation, whereas calpain-1 knockdown slightly enhances TRPV1 tachyphylaxis. In vivo delivery of TRPV1 Δ820 rescued the pain behavioral deficits in nociceptive pain models of Tprv1-/- mice, but not in inflammatory pain models.
Conclusions:
Calpain is activated following the activation of TRPV1 and cleaves its distal carboxyl terminus. This reduces the plasma membrane localization of TRPV1 while enhancing its resistance to receptor tachyphylaxis. This study revealed a constraining mechanism for TRPV1 desensitization, which maintains the receptor function in an appropriate range.
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