Molecular basis for heat desensitization of TRPV1 ion channels

Lei Luo, Yunfei Wang, Bowen Li, Lizhen Xu, Peter Muiruri Kamau, Jie Zheng (), Fan Yang (), Shilong Yang () and Ren Lai ()
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Lei Luo: Kunming Institute of Zoology
Yunfei Wang: Kunming Institute of Zoology
Bowen Li: Kunming Institute of Zoology
Lizhen Xu: First Affiliated Hospital, Institute of Neuroscience, National Health Commission and Chinese Academy of Medical Sciences, Zhejiang University School of Medicine
Peter Muiruri Kamau: Kunming Institute of Zoology
Jie Zheng: University of California
Fan Yang: First Affiliated Hospital, Institute of Neuroscience, National Health Commission and Chinese Academy of Medical Sciences, Zhejiang University School of Medicine
Shilong Yang: Kunming Institute of Zoology
Ren Lai: Kunming Institute of Zoology

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract The transient receptor potential vanilloid 1 (TRPV1) ion channel is a prototypical molecular sensor for noxious heat in mammals. Its role in sustained heat response remains poorly understood, because rapid heat-induced desensitization (Dh) follows tightly heat-induced activation (Ah). To understand the physiological role and structural basis of Dh, we carried out a comparative study of TRPV1 channels in mouse (mV1) and those in platypus (pV1), which naturally lacks Dh. Here we show that a temperature-sensitive interaction between the N- and C-terminal domains of mV1 but not pV1 drives a conformational rearrangement in the pore leading to Dh. We further show that knock-in mice expressing pV1 sensed heat normally but suffered scald damages in a hot environment. Our findings suggest that Dh evolved late during evolution as a protective mechanism and a delicate balance between Ah and Dh is crucial for mammals to sense and respond to noxious heat.

Date: 2019
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DOI: 10.1038/s41467-019-09965-6

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