The current knowledge about heat nociception is mainly confined to the thermosensors including the transient receptor potential cation channel V1 expressed in the nociceptive neurons of dorsal root ganglion(DRG). Howe...The current knowledge about heat nociception is mainly confined to the thermosensors including the transient receptor potential cation channel V1 expressed in the nociceptive neurons of dorsal root ganglion(DRG). However,the loss of thermosensors only partially impairs heat nociception,suggesting the existence of undiscovered mechanisms. Using single-cell RNA sequencing and in vivo electrophysiological recording,we analyzed the transcriptome and functions of DRG neurons. At least six types of mechanoheat nociceptors were identified. However,the molecular network and mechanism responsible for heat nociception in these mechanoheat nociceptors remain to be explored. We found that fibroblast growth factor 13(FGF13) was highly expressed in five types of mechanoheat nociceptors.FGF13 is an intracellular,non-secretory protein,a member of FGF11 subfamily. We found that the loss of FGF13 in the mouse DRG neurons selectively abolished heat nociception. The noxious heat stimuli could not evoke the sustained action potential firing in small DRG neurons from FGF13-deficient mice. Furthermore,FGF13 interacted with sodium channel Na_v1.7 at the C-terminal region in a heatfacilitated manner. FGF13 increased Na_v1.7 sodium currents and maintained the membrane localization of Na_v1.7 during noxious heat stimulation,enabling the sustained firing of action potentials. Disrupting the FGF13/Na_v1.7 interaction reduced the heat-evoked action potential firing and nociceptive behavior.Thus,beyond the thermosensors,the FGF13/Na_v1.7 complex is essential for sustaining the transmission of noxious heat signals.展开更多
文摘The current knowledge about heat nociception is mainly confined to the thermosensors including the transient receptor potential cation channel V1 expressed in the nociceptive neurons of dorsal root ganglion(DRG). However,the loss of thermosensors only partially impairs heat nociception,suggesting the existence of undiscovered mechanisms. Using single-cell RNA sequencing and in vivo electrophysiological recording,we analyzed the transcriptome and functions of DRG neurons. At least six types of mechanoheat nociceptors were identified. However,the molecular network and mechanism responsible for heat nociception in these mechanoheat nociceptors remain to be explored. We found that fibroblast growth factor 13(FGF13) was highly expressed in five types of mechanoheat nociceptors.FGF13 is an intracellular,non-secretory protein,a member of FGF11 subfamily. We found that the loss of FGF13 in the mouse DRG neurons selectively abolished heat nociception. The noxious heat stimuli could not evoke the sustained action potential firing in small DRG neurons from FGF13-deficient mice. Furthermore,FGF13 interacted with sodium channel Na_v1.7 at the C-terminal region in a heatfacilitated manner. FGF13 increased Na_v1.7 sodium currents and maintained the membrane localization of Na_v1.7 during noxious heat stimulation,enabling the sustained firing of action potentials. Disrupting the FGF13/Na_v1.7 interaction reduced the heat-evoked action potential firing and nociceptive behavior.Thus,beyond the thermosensors,the FGF13/Na_v1.7 complex is essential for sustaining the transmission of noxious heat signals.
