title: Transient receptor potential M3 channels are ionotropic steroid receptors in pancreatic beta cells.
abstract: Transient receptor potential (TRP) cation channels are renowned for their ability to sense diverse chemical stimuli. Still, for many members of this large and heterogeneous protein family it is unclear how their activity is regulated and whether they are influenced by endogenous substances. On the other hand, steroidal compounds are increasingly recognized to have rapid effects on membrane surface receptors that often have not been identified at the molecular level. We show here that TRPM3, a divalent-permeable cation channel, is rapidly and reversibly activated by extracellular pregnenolone sulphate, a neuroactive steroid. We show that pregnenolone sulphate activates endogenous TRPM3 channels in insulin-producing beta cells. Application of pregnenolone sulphate led to a rapid calcium influx and enhanced insulin secretion from pancreatic islets. Our results establish that TRPM3 is an essential component of an ionotropic steroid receptor enabling unanticipated crosstalk between steroidal and insulin-signalling endocrine systems.
authors.affiliation: Emmy Noether Research Group Toxikologie, Universität des Saarlandes, D-66421 Homburg, Germany.
authors.forename: Thomas F J
authors.initials: TF
authors.lastname: Wagner
authors.forename: Sabine
authors.initials: S
authors.lastname: Loch
authors.forename: Sachar
authors.initials: S
authors.lastname: Lambert
authors.forename: Isabelle
authors.initials: I
authors.lastname: Straub
authors.forename: Stefanie
authors.initials: S
authors.lastname: Mannebach
authors.forename: Ilka
authors.initials: I
authors.lastname: Mathar
authors.forename: Martina
authors.initials: M
authors.lastname: Düfer
authors.forename: Annette
authors.initials: A
authors.lastname: Lis
authors.forename: Veit
authors.initials: V
authors.lastname: Flockerzi
authors.forename: Stephan E
authors.initials: SE
authors.lastname: Philipp
authors.forename: Johannes
authors.initials: J
authors.lastname: Oberwinkler
mesh_terms: D000818:Animals; D055592:Biophysical Phenomena / Q000187:drug effects; D020013:Calcium Signaling / Q000187:drug effects; D002414:Cations, Monovalent / Q000494:pharmacology; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; 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; D051379:Mice; D009543:Nifedipine / Q000494:pharmacology; D010539:Permeability / Q000187:drug effects; D011284:Pregnenolone / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D011987:Receptors, Steroid / Q000378:metabolism*; D050053:TRPM Cation Channels / Q000378:metabolism*
chemical_list: D002414:Cations, Monovalent; D007328:Insulin; D034741:RNA, Small Interfering; D011987:Receptors, Steroid; D050053:TRPM Cation Channels; C533868:TRPM3 protein, mouse; C533867:TRPM3 protein, rat; C018370:pregnenolone sulfate; D011284:Pregnenolone; D009543:Nifedipine