Molecular basis for heat desensitization of TRPV1 ion channels

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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.

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Luo, L., Wang, Y., Li, B., Xu, L., Kamau, P. M., Zheng, J., … Lai, R. (2019). Molecular basis for heat desensitization of TRPV1 ion channels. Nature Communications, 10(1). https://doi.org/10.1038/s41467-019-09965-6

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