title: Characteristics and molecular basis of celecoxib modulation on K(v)7 potassium channels.
abstract: OBJECTIVE
  Celecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor used for the treatment of pain and inflammation. Emerging and accumulating evidence suggests that celecoxib can affect cellular targets other than COX, such as ion channels. In this study, we characterized the effects of celecoxib on K(v)7 K(+) channels and compared its effects with the well-established K(v)7 channel opener retigabine.
  
  
  METHODS
  A perforated whole-cell patch technique was used to record K(v)7currents expressed in HEK 293 cells and M-type currents from rat superior cervical ganglion neurons.
  
  
  RESULTS
  Celecoxib enhanced K(v)7.2-7.4, K(v)7.2/7.3 and K(v)7.3/7.5 currents but inhibited K(v)7.1 and K(v)7.1/KCNE1 currents and these effects were concentration dependent. The IC(50) value for inhibition of K(v)7.1 channels was approximately 4 µM and the EC(50) values for activation of K(v)7.2-7.4, K(v)7.2/K(v)7.3 and K(v)7.3/K(v)7.5 channels were approximately 2-5 µM. The effects of celecoxib were manifested by increasing current amplitudes, shifting the voltage-dependent activation curve in a more negative direction and slowing the deactivation of K(v)7 currents. 2,5-Dimethyl-celecoxib, a celecoxib analogue devoid of COX inhibition activity, has similar but greater effects on K(v)7currents. K(v)7.2(A235T) and K(v) 7.2(W236L) mutant channels, which have greatly attenuated responses to retigabine, showed a reversed response to celecoxib, from activation to inhibition.
  
  
  CONCLUSIONS
  These results suggest that K(v)7 channels are targets of celecoxib action and provide new mechanistic evidence for understanding the effects of celecoxib. They also provide a new approach to developing K(v)7 modulators and for studying the structure-function relationship of K(v)7 channels.
authors.affiliation: The Key Laboratory of Neural and Vascular Biology, Ministry of Education, Department of Pharmacology, Shijiazhuang, China.
authors.forename: X N
authors.initials: XN
authors.lastname: Du
authors.forename: X
authors.initials: X
authors.lastname: Zhang
authors.forename: J L
authors.initials: JL
authors.lastname: Qi
authors.forename: H L
authors.initials: HL
authors.lastname: An
authors.forename: J W
authors.initials: JW
authors.lastname: Li
authors.forename: Y M
authors.initials: YM
authors.lastname: Wan
authors.forename: Y
authors.initials: Y
authors.lastname: Fu
authors.forename: H X
authors.initials: HX
authors.lastname: Gao
authors.forename: Z B
authors.initials: ZB
authors.lastname: Gao
authors.forename: Y
authors.initials: Y
authors.lastname: Zhan
authors.forename: H L
authors.initials: HL
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002219:Carbamates / Q000494:pharmacology; D000068579:Celecoxib; D002478:Cells, Cultured; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D051656:KCNQ Potassium Channels / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D010655:Phenylenediamines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013449:Sulfonamides / Q000494:pharmacology*; D017783:Superior Cervical Ganglion / Q000502:physiology*; D014162:Transfection
chemical_list: C506698:2,5-dimethylcelecoxib; D002219:Carbamates; D052246:Cyclooxygenase 2 Inhibitors; D051656:KCNQ Potassium Channels; D010655:Phenylenediamines; D011720:Pyrazoles; D013449:Sulfonamides; C101866:ezogabine; D000068579:Celecoxib