Activation of TRPM3 by a potent synthetic ligand reveals a role in peptide release

作者：Held Katharina; Kichko Tatjana; De Clercq Katrien; Klaassen Hugo; Van Bree Rieta; Vanherck Jean Christophe; Marchand Arnaud; Reeh Peter W; Chaltin Patrick; Voets Thomas; Vriens Joris^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2015, 112(11): E1363-E1372.

DOI：10.1073/pnas.1419845112

• TRP channel
• TRPM3
• peptide release
• nociceptor

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 generelated 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.

• 出版日期2015-3-17