Activation of TRPM3 by a potent synthetic ligand reveals a role in peptide release.
Transient receptor potential (TRP) cation channel subfamily M member 3 (TRPM3), a member of the TRP channel superfamily, was recently identified as a nociceptor channel in the somatosensory system, where it is involved in the detection of noxious heat; however, owing to the lack of potent and selective agonists, little is known about other potential physiological consequences of the opening of TRPM3. Here we identify and characterize a synthetic TRPM3 activator, CIM0216, whose potency and apparent affinity greatly exceeds that of the canonical TRPM3 agonist, pregnenolone sulfate (PS). In particular, a single application of CIM0216 causes opening of both the central calcium-conducting pore and the alternative cation permeation pathway in a membrane-delimited manner. CIM0216 evoked robust calcium influx in TRPM3-expressing somatosensory neurons, and intradermal injection of the compound induced a TRPM3-dependent nocifensive behavior. Moreover, CIM0216 elicited the release of the peptides calcitonin gene-related peptide (CGRP) from sensory nerve terminals and insulin from isolated pancreatic islets in a TRPM3-dependent manner. These experiments identify CIM0216 as a powerful tool for use in investigating the physiological roles of TRPM3, and indicate that TRPM3 activation in sensory nerve endings can contribute to neurogenic inflammation.
Laboratory of Obstetrics and Experimental Gynecology and Laboratory of Ion Channel Research and Transient Receptor Potential Research Platform Leuven, Catholic University of Leuven, B-3000 Leuven, Belgium;
Katharina
K
Held
Institute of Physiology and Pathophysiology, University of Erlangen-Nuremberg, D-91054 Erlangen, Germany; and.
Tatjana
T
Kichko
Laboratory of Obstetrics and Experimental Gynecology and.
Katrien
K
De Clercq
Center for Innovation and Stimulation of Drug Discovery Leuven and.
Hugo
H
Klaassen
Laboratory of Obstetrics and Experimental Gynecology and.
Rieta
R
Van Bree
Center for Innovation and Stimulation of Drug Discovery Leuven and.
Jean-Christophe
JC
Vanherck
Center for Innovation and Stimulation of Drug Discovery Leuven and.
Arnaud
A
Marchand
Institute of Physiology and Pathophysiology, University of Erlangen-Nuremberg, D-91054 Erlangen, Germany; and.
Peter W
PW
Reeh
Center for Innovation and Stimulation of Drug Discovery Leuven and Center for Drug Design and Discovery, Bio-Incubator 2, B-3001 Heverlee, Belgium.
Patrick
P
Chaltin
Laboratory of Ion Channel Research and Transient Receptor Potential Research Platform Leuven, Catholic University of Leuven, B-3000 Leuven, Belgium;
Thomas
T
Voets
Laboratory of Obstetrics and Experimental Gynecology and Joris.Vriens@med.kuleuven.be.
Joris
J
Vriens
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002463:Cell Membrane Permeability / Q000187:drug effects; D057809:HEK293 Cells; D006358:Hot Temperature; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D015640:Ion Channel Gating / Q000187:drug effects; D008024:Ligands; D008810:Mice, Inbred C57BL; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism; D009479:Neuropeptides / Q000378:metabolism*; D059225:Nociception / Q000187:drug effects; D010146:Pain / Q000473:pathology / Q000503:physiopathology; D011284:Pregnenolone / Q000494:pharmacology; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000378:metabolism; D050053:TRPM Cation Channels / Q000819:agonists / Q000378:metabolism*; D014162:Transfection
D007328:Insulin; D008024:Ligands; D009479:Neuropeptides; D011804:Quinolines; D050053:TRPM Cation Channels; C533868:TRPM3 protein, mouse; C018370:pregnenolone sulfate; D011284:Pregnenolone; D002118:Calcium
TRP channel; TRPM3; nociceptor; peptide release