Characteristics and molecular basis of celecoxib modulation on K(v)7 potassium channels

doi:10.1111/j.1476-5381.2011.01483.x

CORC > 上海药物研究所 > 中国科学院上海药物研究所 > 神经药理学研究国际科学家工作站

	Characteristics and molecular basis of celecoxib modulation on K(v)7 potassium channels
	Du, X. N.2; Zhang, X.2; Qi, J. L.2,3; An, H. L.1; Li, J. W.1; Wan, Y. M.2; Fu, Y.3; Gao, H. X.2; Gao, Z. B.4; Zhan, Y.1
刊名	BRITISH JOURNAL OF PHARMACOLOGY
	2011-11
卷号	164 期号:6 页码:1722-1737
关键词	activation of potassium channels celecoxib HEK 293 cell K(v)7 NSAIDs retigabine SCG
ISSN号	0007-1188
DOI	10.1111/j.1476-5381.2011.01483.x
文献子类	Article
英文摘要	BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACH 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. KEY 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 IC50 value for inhibition of K(v)7.1 channels was approximately 4 mu M and the EC50 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 mu M. 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 AND IMPLICATIONS 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.
资助项目	National Natural Science Foundation of China[30730031] ; National Natural Science Foundation of China[30500112] ; 973 Program[2007CB512100] ; National Science Fund for Distinguished Young Scholars of China[30325038]
WOS关键词	SENSORY NEURONS ; K+ CHANNELS ; ACTIVATION ; ANTICONVULSANT ; INHIBITION ; RETIGABINE ; CURRENTS ; METAANALYSIS ; PHYSIOLOGY ; K(V)LQT1
WOS研究方向	Pharmacology & Pharmacy
语种	英语
出版者	WILEY-BLACKWELL
WOS记录号	WOS:000296908300015
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/278359]
专题	神经药理学研究国际科学家工作站中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Zhang, H. L.
作者单位	1.Hebei Univ Technol, Inst Biophys, Tianjin, Peoples R China; 2.Hebei Med Univ, Dept Pharmacol, Minist Educ, Key Lab Neural & Vasc Biol, Shijiazhuang 050017, Hebei, Peoples R China; 3.Hebei Med Univ, Dept New Drug Dev, Shijiazhuang 050017, Hebei, Peoples R China; 4.Chinese Acad Sci, Shanghai Inst Mat Med, Ctr Drug Discovery & Design, State Key Lab Drug Res,Shanghai Inst Biol Sci, Shanghai 200031, Peoples R China
推荐引用方式 GB/T 7714	Du, X. N.,Zhang, X.,Qi, J. L.,et al. Characteristics and molecular basis of celecoxib modulation on K(v)7 potassium channels[J]. BRITISH JOURNAL OF PHARMACOLOGY,2011,164(6):1722-1737.
APA	Du, X. N..,Zhang, X..,Qi, J. L..,An, H. L..,Li, J. W..,...&Zhang, H. L..(2011).Characteristics and molecular basis of celecoxib modulation on K(v)7 potassium channels.BRITISH JOURNAL OF PHARMACOLOGY,164(6),1722-1737.
MLA	Du, X. N.,et al."Characteristics and molecular basis of celecoxib modulation on K(v)7 potassium channels".BRITISH JOURNAL OF PHARMACOLOGY 164.6(2011):1722-1737.