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Glucosylsphingosine evokes pruritus via activation of 5‐HT 2A receptor and TRPV4 in sensory neurons
Author(s) -
Sanjel Babina,
Kim BoHyun,
Song MyungHyun,
Carstens Earl,
Shim WonSik
Publication year - 2022
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.15733
Subject(s) - trpv4 , scratching , chemistry , ketanserin , receptor , receptor antagonist , dorsal root ganglion , knockout mouse , phospholipase c , antagonist , endocrinology , pharmacology , transient receptor potential channel , medicine , microbiology and biotechnology , sensory system , 5 ht receptor , biology , neuroscience , serotonin , biochemistry , physics , acoustics
Background and purpose Glucosylsphingosine (GS), an endogenous sphingolipid, is highly accumulated in the epidermis of patients with atopic dermatitis (AD) due to abnormal ceramide metabolism. More importantly, GS can evoke scratching behaviours. However, the precise molecular mechanism by which GS induces pruritus has been elusive. Thus, the present study aimed to elucidate the molecular signalling pathway of GS, especially at the peripheral sensory neuronal levels. Experimental approach Calcium imaging was used to investigate the responses of HEK293T cells or mouse dorsal root ganglion (DRG) neurons to application of GS. Scratching behaviour tests were also performed with wild‐type and Trpv4 knockout mice. Key results GS activated DRG neurons in a manner involving both the 5‐HT 2A receptor and TRPV4. Furthermore, GS‐induced responses were significantly suppressed by various inhibitors, including ketanserin (5‐HT 2A receptor antagonist), YM254890 (Gα q/11 inhibitor), gallein (Gβγ complex inhibitor), U73122 (phospholipase C inhibitor), bisindolylmaleimide I (PKC inhibitor) and HC067047 (TRPV4 antagonist). Moreover, DRG neurons from Trpv4 knockout mice exhibited significantly reduced responses to GS. Additionally, GS‐evoked scratching behaviours were greatly decreased by pretreatment with inhibitors of either 5‐HT 2A receptor or TRPV4. As expected, GS‐evoked scratching behaviour was also significantly decreased in Trpv4 knockout mice. Conclusion and implications Overall, the present study provides evidence for a novel molecular signalling pathway for GS‐evoked pruritus, which utilizes both 5‐HT 2A receptor and TRPV4 in mouse sensory neurons. Considering the high accumulation of GS in the epidermis of patients with AD, GS could be another pruritogen in patients with AD.