ABSTRACT
The transient receptor potential vanilloid-1 (TRPV1) ion channel is essential for sensation of thermal and chemical pain. TRPV1 activation is accompanied by Ca2+-dependent desensitization; acute desensitization reflects rapid reduction in channel activity during stimulation, whereas tachyphylaxis denotes the diminution in TRPV1 responses to repetitive stimulation. Acute desensitization has been attributed to conformational changes of the TRPV1 channel; however, the mechanisms underlying the establishment of tachyphylaxis remain to be defined. Here, we report that the degree of whole-cell TRPV1 tachyphylaxis is regulated by the strength of inducing stimulation. Using light-sheet microscopy and pH-sensitive sensor pHluorin to follow TRPV1 endocytosis and exocytosis trafficking, we provide real-time information that tachyphylaxis of different degrees concurs with TRPV1 recycling to the plasma membrane in a proportional manner. This process controls TRPV1 surface expression level thereby the whole-cell nociceptive response. We further show that activity-gated TRPV1 trafficking associates with intracellular Ca2+ signals of distinct kinetics, and recruits recycling routes mediated by synaptotagmin 1 and 7, respectively. These results suggest that activity-dependent TRPV1 recycling contributes to the establishment of tachyphylaxis.
Subject(s)
Cell Membrane/metabolism , Endocytosis , TRPV Cation Channels/metabolism , Tachyphylaxis , Animals , Calcium Signaling , Exocytosis , HEK293 Cells , Humans , Light , Protein Transport , Rats , Synaptotagmins/metabolismABSTRACT
In the originally published version of this Article, the affiliation details for Yan Wang, Yingwei Gao, Qi Deng, Yangbo Wang, Tian Zhou, Yingping Wang, Huiqing Liu, Ruining Ma, Jinke Cheng and Yong Li incorrectly omitted 'Shanghai Jiao Tong University'. This has now been corrected in both the PDF and HTML versions of the Article.' Furthermore, the Supplementary Information file originally associated with this Article inadvertently omitted Supplementary Figure 9. The error has now been fixed and the corrected version Supplementary Information PDF is available to download from the HTML version of the Article.
ABSTRACT
Although TRPV1 channels represent a key player of noxious heat sensation, the precise mechanisms for thermal hyperalgesia remain unknown. We report here that conditional knockout of deSUMOylation enzyme, SENP1, in mouse dorsal root ganglion (DRG) neurons exacerbated thermal hyperalgesia in both carrageenan- and Complete Freund's adjuvant-induced inflammation models. TRPV1 is SUMOylated at a C-terminal Lys residue (K822), which specifically enhances the channel sensitivity to stimulation by heat, but not capsaicin, protons or voltage. TRPV1 SUMOylation is decreased by SENP1 but upregulated upon peripheral inflammation. More importantly, the reduced ability of TRPV1 knockout mice to develop inflammatory thermal hyperalgesia was rescued by viral infection of lumbar 3/4 DRG neurons of wild-type TRPV1, but not its SUMOylation-deficient mutant, K822R. These data suggest that TRPV1 SUMOylation is essential for the development of inflammatory thermal hyperalgesia, through a mechanism that involves sensitization of the channel response specifically to thermal stimulation.
Subject(s)
Endopeptidases/metabolism , Ganglia, Spinal/metabolism , Inflammation , Nociception , Pain/metabolism , TRPV Cation Channels/metabolism , Animals , Calcium/metabolism , Cricetinae , Cysteine Endopeptidases , Genotype , HEK293 Cells , Hot Temperature , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mutation , Neurons/metabolism , Polymerase Chain Reaction , Protein Domains , Signal Transduction , TRPV Cation Channels/geneticsABSTRACT
Myeloid sarcoma (MS) is a rare, extramedullary malignant tumor composed of immature myeloid precursor cells and myeloblast. Most MSs occur in the subperiosteal region of the bone, with the skull, sternum, ribs, and proximal portions of the long bones being the common sites of involvement. It is thought that the MS tumor originates in the bone marrow, and traverses the Haversian canals to reach the subperiosteum. Various reports have also described the involvement of the liver, spleen, brain, heart, pharynx, uterus, vagina, skin, kidney, and other soft tissues in the formation of the tumor.
