title: Facilitation of TRPV4 by TRPV1 is required for itch transmission in some sensory neuron populations.
abstract: The transient receptor potential channels (TRPs) respond to chemical irritants and temperature. TRPV1 responds to the itch-inducing endogenous signal histamine, and TRPA1 responds to the itch-inducing chemical chloroquine. We showed that, in sensory neurons, TRPV4 is important for both chloroquine- and histamine-induced itch and that TRPV1 has a role in chloroquine-induced itch. Chloroquine-induced scratching was reduced in mice in which TRPV1 was knocked down or pharmacologically inhibited. Both TRPV4 and TRPV1 were present in some sensory neurons. Pharmacological blockade of either TRPV4 or TRPV1 significantly attenuated the Ca(2+) response of sensory neurons exposed to histamine or chloroquine. Knockout of Trpv1 impaired Ca(2+) responses and reduced scratching behavior evoked by a TRPV4 agonist, whereas knockout of Trpv4 did not alter TRPV1-mediated capsaicin responses. Electrophysiological analysis of human embryonic kidney (HEK) 293 cells coexpressing TRPV4 and TRPV1 revealed that the presence of both channels enhanced the activation kinetics of TRPV4 but not of TRPV1. Biochemical and biophysical studies suggested a close proximity between TRPV4 and TRPV1 in dorsal root ganglion neurons and in cultured cells. Thus, our studies identified TRPV4 as a channel that contributes to both histamine- and chloroquine-induced itch and indicated that the function of TRPV4 in itch signaling involves TRPV1-mediated facilitation. TRP facilitation through the formation of heteromeric complexes could be a prevalent mechanism by which the vast array of somatosensory information is encoded in sensory neurons.
authors.affiliation: Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Seungil
authors.initials: S
authors.lastname: Kim
authors.affiliation: Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Devin M
authors.initials: DM
authors.lastname: Barry
authors.affiliation: Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Xian-Yu
authors.initials: XY
authors.lastname: Liu
authors.affiliation: Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Shijin
authors.initials: S
authors.lastname: Yin
authors.affiliation: Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Admire
authors.initials: A
authors.lastname: Munanairi
authors.affiliation: Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.
authors.forename: Qing-Tao
authors.initials: QT
authors.lastname: Meng
authors.affiliation: Institute of Cancer Stem Cell, Dalian Medical University, Dalian 116044, P.R. China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cheng
authors.affiliation: Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Anesthesiology, Nanhai Hospital of Southern Medical University, Foshan 528000, P.R. China.
authors.forename: Ping
authors.initials: P
authors.lastname: Mo
authors.affiliation: Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Wan
authors.affiliation: Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Shen-Bin
authors.initials: SB
authors.lastname: Liu
authors.affiliation: Department of Chemistry and Biochemistry, University of Toledo, Toledo, OH 43606, USA.
authors.forename: Kasun
authors.initials: K
authors.lastname: Ratnayake
authors.affiliation: Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Zhong-Qiu
authors.initials: ZQ
authors.lastname: Zhao
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Narasimhan
authors.initials: N
authors.lastname: Gautam
authors.affiliation: Department of Physiology and Membrane Biology, University of California School of Medicine, Davis, CA 95616, USA.
authors.forename: Jie
authors.initials: J
authors.lastname: Zheng
authors.affiliation: Department of Chemistry and Biochemistry, University of Toledo, Toledo, OH 43606, USA.
authors.forename: W K Ajith
authors.initials: WK
authors.lastname: Karunarathne
authors.affiliation: Center for the Study of Itch, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Anesthesiology, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110, USA. Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO 63110, USA. chenz@wustl.edu.
authors.forename: Zhou-Feng
authors.initials: ZF
authors.lastname: Chen
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D005727:Ganglia, Spinal / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011537:Pruritus / Q000235:genetics / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D050916:TRPV Cation Channels; C494482:TRPV1 protein, human; C493921:TRPV1 protein, mouse; C416986:TRPV4 protein, human; C486576:Trpv4 protein, mouse