Download<\/a><\/div>\n\n\n\nPaz Duran1,2,3, Jeffri S. Retamal2,4, Marcella de Amorim Ferreira1,2,3, Kai Trevett1,3, Evan Chen1,3 and Dane D. Jensen1,2,3*
1Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY,
United States, 2Translational Research Center, College of Dentistry, New York University, New York, NY,
United States, 3NYU Pain Research Center, College of Dentistry, New York University, New York, NY,
United States, 4Department of Chemistry and Biology, University of Santiago Chile, Santiago, Chile<\/p>\n\n\n\n
G protein-coupled receptors (GPCRs) and TRPV (transient receptor potential
vanilloid) channels are crucial for signal transduction in physiological
processes, including neurotransmission, pain, and itch. Downstream effectors
of GPCR signaling can directly stimulate TRPV channels or enhance their
sensitivity to stimuli, a process known as TRPV sensitization. Traditionally,
GPCRs are activated at the cell surface by extracellular agonists, triggering
signaling cascades. Recent evidence suggests GPCRs continue to signal
from intracellular organelles. The human Mas-related G-protein coupled
receptor X1 (MrGPRX1) is a GPCR expressed in primary sensory neurons
involved in nociception and pruritus. Recent studies demonstrated how
intracellular GPCR signaling regulates neuronal activity. However, there is no
evidence characterizing MrGPRX1 trafficking or intracellular signaling. Herein,
we characterized MrGPRX1 signaling within the endosomal network and its role
in sensitizing TRPV1 channels to enhance itch signaling. Utilizing subcellular
targeted biosensors, we demonstrated MrGPRX1 can traffic and signal from
endosomes. Immunofluorescence analysis showed that MrGPRX1 internalizes
following BAM8-22 stimulation. BRET assays revealed that MrGPRX1 activation
induces G\u03b1q and \u03b2-arrestin-1 recruitment to the plasma membrane and
early endosomes. Inhibition of dynamin or clathrin blocked BAM8-22-induced
MrGPRX1 endocytosis and decreased nuclear extracellular signal-regulated
kinase (ERK) signaling. Calcium signaling confirmed that MrGPRX1-mediated
TRPV1 sensitization is mediated by protein kinase C and ERK activation.
Our findings reveal a novel role for MrGPRX1 endosomal signaling in TRPV1
sensitization. Understanding the mechanisms of MrGPRX1 signaling offers
valuable insights into differentiating between pain and itch pathways, aiding in
the development of targeted therapies for chronic pain and persistent itch.<\/p>\n\n\n\n
KEYWORDS
endosome, intracellular signaling, MrGPRs, signal transduction, transient receptor
potential channels (TRP Channels)<\/p>\n","protected":false},"excerpt":{"rendered":"
Endosomal MrGPRX1 signaling sensitizes TRPV1 to enhance itch Paz Duran1,2,3, Jeffri S. Retamal2,4, Marcella de Amorim Ferreira1,2,3, Kai Trevett1,3, Evan Chen1,3 and Dane D. Jensen1,2,3*1Department of Molecular Pathobiology, College of Dentistry, New York University, New York, NY,United States, 2Translational Research Center, College of Dentistry, New York University, New York, NY,United States, 3NYU Pain Research Center, […]<\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}},"ast-content-background-meta":{"desktop":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"tablet":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""},"mobile":{"background-color":"var(--ast-global-color-5)","background-image":"","background-repeat":"repeat","background-position":"center center","background-size":"auto","background-attachment":"scroll","background-type":"","background-media":"","overlay-type":"","overlay-color":"","overlay-opacity":"","overlay-gradient":""}}},"categories":[1],"tags":[],"_links":{"self":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/3830"}],"collection":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=3830"}],"version-history":[{"count":1,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/3830\/revisions"}],"predecessor-version":[{"id":3837,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=\/wp\/v2\/posts\/3830\/revisions\/3837"}],"wp:attachment":[{"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=3830"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=3830"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/misterx95.myds.me\/wordpress\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=3830"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}