title: Citrus fruit and fabacea secondary metabolites potently and selectively block TRPM3.
abstract: OBJECTIVE
  The melastatin-related transient receptor potential TRPM3 is a calcium-permeable nonselective cation channel that can be activated by the neurosteroid pregnenolone sulphate (PregS) and heat. TRPM3-deficient mice show an impaired perception of noxious heat. Hence, drugs inhibiting TRPM3 possibly get in focus of analgesic therapy.
  
  
  METHODS
  Fluorometric methods were used to identify novel TRPM3-blocking compounds and to characterize their potency and selectivity to block TRPM3 but not other sensory TRP channels. Biophysical properties of the block were assessed using electrophysiological methods. Single cell calcium measurements confirmed the block of endogenously expressed TRPM3 channels in rat and mouse dorsal root ganglion (DRG) neurones.
  
  
  RESULTS
  By screening a compound library, we identified three natural compounds as potent blockers of TRPM3. Naringenin and hesperetin belong to the citrus fruit flavanones, and ononetin is a deoxybenzoin. Eriodictyol, a metabolite of naringenin and hesperetin, was still biologically active as a TRPM3 blocker. The compounds exhibited a marked specificity for recombinant TRPM3 and blocked PregS-induced [Ca(2+)]i signals in freshly isolated DRG neurones.
  
  
  CONCLUSIONS
  The data indicate that citrus fruit flavonoids are potent and selective blockers of TRPM3. Their potencies ranged from upper nanomolar to lower micromolar concentrations. Since physiological functions of TRPM3 channels are still poorly defined, the development and validation of potent and selective blockers is expected to contribute to clarifying the role of TRPM3 in vivo. Considering the involvement of TRPM3 in nociception, TRPM3 blockers may represent a novel concept for analgesic treatment.
authors.affiliation: Rudolf-Boehm-Institut für Pharmakologie und Toxikologie, Universität Leipzig, Leipzig, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Straub
authors.forename: F
authors.initials: F
authors.lastname: Mohr
authors.forename: J
authors.initials: J
authors.lastname: Stab
authors.forename: M
authors.initials: M
authors.lastname: Konrad
authors.forename: S E
authors.initials: SE
authors.lastname: Philipp
authors.forename: J
authors.initials: J
authors.lastname: Oberwinkler
authors.forename: M
authors.initials: M
authors.lastname: Schaefer
mesh_terms: D000818:Animals; D001573:Benzoin / Q000031:analogs & derivatives* / Q000302:isolation & purification / Q000494:pharmacology; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000302:isolation & purification* / Q000494:pharmacology; D020013:Calcium Signaling / Q000187:drug effects; D002957:Citrus / Q000737:chemistry*; D004353:Drug Evaluation, Preclinical; D007887:Fabaceae / Q000737:chemistry* / Q000378:metabolism; D044950:Flavanones / Q000302:isolation & purification* / Q000494:pharmacology; D005727:Ganglia, Spinal / Q000378:metabolism*; D057809:HEK293 Cells; D006569:Hesperidin / Q000302:isolation & purification / Q000494:pharmacology; D006801:Humans; D008564:Membrane Potentials; D051379:Mice; D008810:Mice, Inbred C57BL; D011284:Pregnenolone / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D064210:Secondary Metabolism; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D002121:Calcium Channel Blockers; D044950:Flavanones; D050053:TRPM Cation Channels; C533868:TRPM3 protein, mouse; C018370:pregnenolone sulfate; D011284:Pregnenolone; D006569:Hesperidin; C492807:deoxybenzoin; C005273:naringenin; D001573:Benzoin; C007619:eriodictyol; C013015:hesperetin; D002118:Calcium