![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Department of Physiology and Pharmacology, Sackler Faculty of Medical Sciences (A.P., N.D., R.N., Y.U., G.G., B.A.) and School of Chemistry, Faculty of Exact Sciences (D.S.), Tel Aviv University, Tel Aviv, Israel
Abstract
The voltage-dependent M-type potassium current (M-current) plays a major role in controlling brain excitability by stabilizing the membrane potential and acting as a brake for neuronal firing. The KCNQ2/Q3 heteromeric channel complex was identified as the molecular correlate of the M-current. Furthermore, the KCNQ2 and KCNQ3 channel 
subunits are mutated in families with benign familial neonatal convulsions, a neonatal form of epilepsy. Enhancement of KCNQ2/Q3 potassium currents may provide an important target for antiepileptic drug development. Here, we show that meclofenamic acid (meclofenamate) and diclofenac, two related molecules previously used as anti-inflammatory drugs, act as novel KCNQ2/Q3 channel openers. Extracellular application of meclofenamate (EC50 = 25 µM) and diclofenac (EC50 = 2.6 µM) resulted in the activation of KCNQ2/Q3 K+ currents, heterologously expressed in Chinese hamster ovary cells. Both openers activated KCNQ2/Q3 channels by causing a hyperpolarizing shift of the voltage activation curve (-23 and -15 mV, respectively) and by markedly slowing the deactivation kinetics. The effects of the drugs were stronger on KCNQ2 than on KCNQ3 channel subunits. In contrast, they did not enhance KCNQ1 K+ currents. Both openers increased KCNQ2/Q3 current amplitude at physiologically relevant potentials and led to hyperpolarization of the resting membrane potential. In cultured cortical neurons, meclofenamate and diclofenac enhanced the M-current and reduced evoked and spontaneous action potentials, whereas in vivo diclofenac exhibited an anticonvulsant activity (ED50 = 43 mg/kg). These compounds potentially constitute novel drug templates for the treatment of neuronal hyperexcitability including epilepsy, migraine, or neuropathic pain.
Received for publication September 10, 2004.
Accepted for publication December 9, 2004.
Address correspondence to: Dr. Bernard Attali, Department of Physiology and Pharmacology, Sackler Medical School, Tel Aviv University, Tel Aviv 69978, Israel. E-mail: battali{at}post.tau.ac.il
This article has been cited by other articles:
|
|
 |
|
  L. I. Brueggemann, A. R. Mackie, B. K. Mani, L. L. Cribbs, and K. L. Byron Differential Effects of Selective Cyclooxygenase-2 Inhibitors on Vascular Smooth Muscle Ion Channels May Account for Differences in Cardiovascular Risk Profiles Mol. Pharmacol., November 1, 2009; 76(5): 1053 - 1061. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Veruki and E. Hartveit Meclofenamic Acid Blocks Electrical Synapses of Retinal AII Amacrine and ON-Cone Bipolar Cells J Neurophysiol, May 1, 2009; 101(5): 2339 - 2347. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Cheng and M. C. Sanguinetti Niflumic Acid Alters Gating of HCN2 Pacemaker Channels by Interaction with the Outer Region of S4 Voltage Sensing Domains Mol. Pharmacol., May 1, 2009; 75(5): 1210 - 1221. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. R. Mackie and K. L. Byron Cardiovascular KCNQ (Kv7) Potassium Channels: Physiological Regulators and New Targets for Therapeutic Intervention Mol. Pharmacol., November 1, 2008; 74(5): 1171 - 1179. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Z. Gao, Q. Xiong, H. Sun, and M. Li Desensitization of Chemical Activation by Auxiliary Subunits: CONVERGENCE OF MOLECULAR DETERMINANTS CRITICAL FOR AUGMENTING KCNQ1 POTASSIUM CHANNELS J. Biol. Chem., August 15, 2008; 283(33): 22649 - 22658. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Schmidt, K. Taniguchi, and P. Kofuji Intrinsic and Extrinsic Light Responses in Melanopsin-Expressing Ganglion Cells During Mouse Development J Neurophysiol, July 1, 2008; 100(1): 371 - 384. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Schuetz, S. Kumar, P. Poronnik, and D. J. Adams Regulation of the voltage-gated K+ channels KCNQ2/3 and KCNQ3/5 by serum- and glucocorticoid-regulated kinase-1 Am J Physiol Cell Physiol, July 1, 2008; 295(1): C73 - C80. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Etxeberria, P. Aivar, J. A. Rodriguez-Alfaro, A. Alaimo, P. Villace, J. C. Gomez-Posada, P. Areso, and A. Villarroel Calmodulin regulates the trafficking of KCNQ2 potassium channels FASEB J, April 1, 2008; 22(4): 1135 - 1143. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Fernandez, J. Sargent, F. B. Sachse, and M. C. Sanguinetti Structural Basis for Ether-a-go-go-Related Gene K+ Channel Subtype-Dependent Activation by Niflumic Acid Mol. Pharmacol., April 1, 2008; 73(4): 1159 - 1167. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. C. Hernandez, O. Zaika, G. P. Tolstykh, and M. S. Shapiro Regulation of neural KCNQ channels: signalling pathways, structural motifs and functional implications J. Physiol., April 1, 2008; 586(7): 1811 - 1821. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. D. Wickenden, J. L. Krajewski, B. London, P. K. Wagoner, W. A. Wilson, S. Clark, R. Roeloffs, G. McNaughton-Smith, and G. C. Rigdon N-(6-Chloro-pyridin-3-yl)-3,4-difluoro-benzamide (ICA-27243): A Novel, Selective KCNQ2/Q3 Potassium Channel Activator Mol. Pharmacol., March 1, 2008; 73(3): 977 - 986. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Q. Xiong, H. Sun, Y. Zhang, F. Nan, and M. Li Combinatorial augmentation of voltage-gated KCNQ potassium channels by chemical openers PNAS, February 26, 2008; 105(8): 3128 - 3133. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. Zaika, G. P. Tolstykh, D. B. Jaffe, and M. S. Shapiro Inositol Triphosphate-Mediated Ca2+ Signals Direct Purinergic P2Y Receptor Regulation of Neuronal Ion Channels J. Neurosci., August 15, 2007; 27(33): 8914 - 8926. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Peretz, A. Sheinin, C. Yue, N. Degani-Katzav, G. Gibor, R. Nachman, A. Gopin, E. Tam, D. Shabat, Y. Yaari, et al. Pre- and Postsynaptic Activation of M-Channels By a Novel Opener Dampens Neuronal Firing and Transmitter Release J Neurophysiol, January 1, 2007; 97(1): 283 - 295. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. P. Schools, M. Zhou, and H. K. Kimelberg Development of Gap Junctions in Hippocampal Astrocytes: Evidence That Whole Cell Electrophysiological Phenotype Is an Intrinsic Property of the Individual Cell J Neurophysiol, September 1, 2006; 96(3): 1383 - 1392. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. J. Canning, D. G. Farmer, and N. Mori Mechanistic studies of acid-evoked coughing in anesthetized guinea pigs Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2006; 291(2): R454 - R463. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. F. Otto, Y. Yang, W. N. Frankel, H. S. White, and K. S. Wilcox A Spontaneous Mutation Involving Kcnq2 (Kv7.2) Reduces M-Current Density and Spike Frequency Adaptation in Mouse CA1 Neurons J. Neurosci., February 15, 2006; 26(7): 2053 - 2059. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. V. Soldovieri, P. Castaldo, L. Iodice, F. Miceli, V. Barrese, G. Bellini, E. M. del Giudice, A. Pascotto, S. Bonatti, L. Annunziato, et al. Decreased Subunit Stability as a Novel Mechanism for Potassium Current Impairment by a KCNQ2 C Terminus Mutation Causing Benign Familial Neonatal Convulsions J. Biol. Chem., January 6, 2006; 281(1): 418 - 428. [Abstract] [Full Text] [PDF]
|
|
 |
 |
 |
|
 |
 |
 |
