Lysophosphatidic acid-induced itch is mediated by signalling of LPA5receptor, phospholipase D and TRPA1/TRPV1.
Lysophosphatidic acid (LPA) is an itch mediator, but not a pain mediator by a cheek injection model. Dorsal root ganglion neurons directly respond to LPA depending on transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1). LPA-induced itch-related behaviours are decreased in TRPA1-knockout (KO), TRPV1KO or TRPA1TRPV1 double KO mice. TRPA1 and TRPV1 channels are activated by intracellular LPA, but not by extracellular LPA following LPA5receptor activation with an activity of Ca2+-independent phospholipase A2and phospholipase D. Intracellular LPA interaction sites of TRPA1 are KK672-673 and KR977-978 (K: lysine, R: arginine).



Intractable and continuous itch sensations often accompany diseases such as atopic dermatitis, neurogenic lesions, uremia and cholestasis. Lysophosphatidic acid (LPA) is an itch mediator found in cholestatic itch patients and it induces acute itch and pain in experimental rodent models. However, the molecular mechanism by which LPA activates peripheral sensory neurons remains unknown. In this study, we used a cheek injection method in mice to reveal that LPA induced itch-related behaviours but not pain-related behaviours. The LPA-induced itch behaviour and cellular effects were dependent on transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1), which are important for itch signal transduction. We also found that, among the six LPA receptors, the LPA5receptor had the greatest involvement in itching. Furthermore, we demonstrated that phospholipase D (PLD) plays a critical role downstream of LPA5and that LPA directly and intracellularly activates TRPA1 and TRPV1. These results suggest a unique mechanism by which cytoplasmic LPA produced de novo could activate TRPA1 and TRPV1. We conclude that LPA-induced itch is mediated by LPA5, PLD, TRPA1 and TRPV1 signalling, and thus targeting TRPA1, TRPV1 or PLD could be effective for cholestatic itch interventions.
Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, 444-8787, Japan.
Hiroki
H
Kittaka
Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, 444-8787, Japan.|Department of Physiological Science and Molecular Biology, Fukuoka Dental College, Fukuoka, 814-0193, Japan.
Kunitoshi
K
Uchida
Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, 444-8787, Japan.
Naomi
N
Fukuta
Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Okazaki, 444-8787, Japan.|Department of Physiological Sciences, School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, 444-8787, Japan.|Institute for Environmental and Gender-Specific Medicine, Juntendo University, Urayasu, 279-0021, Japan.
Makoto
0000-0003-3111-3772
M
Tominaga
D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D008246:Lysophospholipids / Q000633:toxicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010739:Phospholipase D / Q000502:physiology*; D011537:Pruritus / Q000139:chemically induced / Q000378:metabolism*; D049368:Receptors, Lysophosphatidic Acid / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels / Q000502:physiology*; D050051:Transient Receptor Potential Channels / Q000502:physiology*
C548235:LPAR5 protein, mouse; D008246:Lysophospholipids; D049368:Receptors, Lysophosphatidic Acid; D000074025:TRPA1 Cation Channel; D050916:TRPV Cation Channels; C493921:TRPV1 protein, mouse; D050051:Transient Receptor Potential Channels; C475685:Trpa1 protein, mouse; D010739:Phospholipase D; C032881:lysophosphatidic acid
TRP channels; itch; lysophosphatidic acid