title: Local anesthetic lidocaine inhibits TRPM7 current and TRPM7-mediated zinc toxicity.
abstract: BACKGROUND
  Previous study demonstrated that overstimulation of TRPM7 substantially contributes to zinc-mediated neuronal toxicity. Inhibition of TRPM7 activity and TRPM7-mediated intracellular Zn(2+) accumulation may represent a promising strategy in the treatment of stroke.
  
  
  OBJECTIVE
  To investigate whether local anesthetics lidocaine could inhibit TRPM7 channel and TRPM7-mediated zinc toxicity.
  
  
  METHODS
  Whole-cell patch-clamp technique was used to investigate the effect of local anesthetics on TRPM7 currents in cultured mouse cortical neurons and TRPM7-overexpressed HEK293 cells. Fluorescent Zn(2+) imaging technique was used to study the effect of lidocaine on TRPM7-mediated intracellular Zn(2+) accumulation. TRPM7-mediated zinc toxicity in neurons was used to evaluate the neuroprotective effect of lidocaine.
  
  
  RESULTS
  (1) Lidocaine dose dependently inhibits TRPM7-like currents, with an IC50 of 11.55 and 11.06 mM in cultured mouse cortical neurons and TRPM7-overexpressed HEK293 cells, respectively; (2) Lidocaine inhibits TRPM7 currents in a use/frequency-dependent manner; (3) Lidocaine inhibits TRPM7-mediated intracellular Zn(2+) accumulation in both cortical neurons and TRPM7-overexpressed HEK293 cells; (4) TRPM7-mediated Zn(2+) toxicity is ameliorated by lidocaine in cortical neurons; (5) QX-314 has a similar inhibitory effect as lidocaine on TRPM7 currents when applied extracellularly; (6) Procaine also shows potent inhibitory effect on the TRPM7 currents in cortical neurons.
  
  
  CONCLUSIONS
  Our data provide the first evidence that local anesthetic lidocaine inhibits TRPM7 channel and TRPM7-mediated zinc toxicity.
authors.affiliation: Neuroscience Institute, Morehouse School of Medicine, Atlanta, GA, USA.
authors.forename: Tian-Dong
authors.initials: TD
authors.lastname: Leng
authors.forename: Jun
authors.initials: J
authors.lastname: Lin
authors.forename: Hua-Wei
authors.initials: HW
authors.lastname: Sun
authors.forename: Zhao
authors.initials: Z
authors.lastname: Zeng
authors.forename: Zaven
authors.initials: Z
authors.lastname: O'Bryant
authors.forename: Koichi
authors.initials: K
authors.lastname: Inoue
authors.forename: Zhi-Gang
authors.initials: ZG
authors.lastname: Xiong
mesh_terms: D000779:Anesthetics, Local / Q000737:chemistry / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D057809:HEK293 Cells; D006801:Humans; D042541:Intracellular Space / Q000378:metabolism; D007477:Ions / Q000378:metabolism / Q000633:toxicity; D008012:Lidocaine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011343:Procaine / Q000737:chemistry / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050053:TRPM Cation Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015032:Zinc / Q000378:metabolism / Q000633:toxicity*
chemical_list: D000779:Anesthetics, Local; D007477:Ions; D018696:Neuroprotective Agents; D050053:TRPM Cation Channels; C012647:QX-314; D011343:Procaine; D008012:Lidocaine; C421903:Trpm7 protein, mouse; D017346:Protein Serine-Threonine Kinases; C486583:TRPM7 protein, human; D015032:Zinc
keywords: Anesthetics; Lidocaine; Stroke; TRPM7; Zinc