{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T03:09:51Z","timestamp":1777432191715,"version":"3.51.4"},"reference-count":67,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T00:00:00Z","timestamp":1765324800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Physiol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>This study aimed to investigate the role of Tmem45b, a gene expressed in itch-associated Dorsal root ganglion (DRG) neurons, in the regulation of itch sensation.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The expression of Tmem45b was examined in DRG neurons. These neurons included Nppb-, Mrgpra3-, and Mrgprd-positive subtypes, which are known to mediate itch. Behavioral response to various pruritogens including \u03b2-alanine, chloroquine, histamine, serotonin, and N-met-LTC4 were assessed on Mrgprd-cre::Tmem45b\n                      <jats:sup>flox\/flox<\/jats:sup>\n                      conditional knockout (cKO) mice. Chronic itch was evaluated using both atopic dermatitis-like and dry skin-like mouse models. To investigate intracellular calcium dynamics, calcium imaging was performed on dissociated DRG neurons. Additionally, bulk RNA-seq was conducted on DRG from Tmem45b cKO mice to assess transcriptomic changes. Serca1 expression and the calcium storage capacity of the endoplasmic reticulum (ER) were analyzed following Tmem45b deletion.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Tmem45b was found to be expressed in itch-associated DRG neurons. In Tmem45b cKO mice, scratching behavior was reduced in response to \u03b2-alanine but increased in response to chloroquine. Notably, chronic itch was alleviated in Tmem45b-deficient mice. Calcium imaging revealed that Tmem45b cKO impaired calcium responses to \u03b2-alanine and allyl isothiocyanate, but not to chloroquine. Mechanistically, Tmem45b deficiency led to a significant downregulation of Serca1, reducing ER calcium storage capacity. Pharmacological inhibition of Serca1 in DRG neurons similarly suppressed intracellular calcium release in response to \u03b2-alanine and chloroquine.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Tmem45b plays a critical role in nonhistaminergic itch by regulating ER calcium homeostasis through Serca1. Its deficiency reduces itch behavior and impairs calcium signaling in DRG neurons, suggesting that Tmem45b is a potential therapeutic target for chronic itch.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphys.2025.1708686","type":"journal-article","created":{"date-parts":[[2025,12,10]],"date-time":"2025-12-10T05:26:18Z","timestamp":1765344378000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Tmem45b modulates itch via endoplasmic reticulum calcium regulation"],"prefix":"10.3389","volume":"16","author":[{"given":"Sa-shuang","family":"Wang","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chen","family":"Liang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruo-lin","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ze-lin","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Peng-yu","family":"Ren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bin","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan-juan","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li","family":"Fu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Li-zu","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wu-ping","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chang-lin","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,12,10]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"3726","DOI":"10.1038\/s41467-019-11646-3","article-title":"IP(3) receptor isoforms differently regulate ER-mitochondrial contacts and local calcium transfer","volume":"10","author":"Bartok","year":"2019","journal-title":"Nat. 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