Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Mol Pharmacol
2009 May 01;755:1210-21. doi: 10.1124/mol.108.054437.
Show Gene links
Show Anatomy links
Niflumic acid alters gating of HCN2 pacemaker channels by interaction with the outer region of S4 voltage sensing domains.
Cheng L
,
Sanguinetti MC
.
???displayArticle.abstract???
Niflumic acid, 2-[[3-(trifluoromethyl)phenyl]amino]pyridine-3-carboxylic acid (NFA), is a nonsteroidal anti-inflammatory drug that also blocks or modifies the gating of many ion channels. Here, we investigated the effects of NFA on hyperpolarization-activated cyclic nucleotide-gated cation (HCN) pacemaker channels expressed in X. laevis oocytes using site-directed mutagenesis and the two-electrode voltage-clamp technique. Extracellular NFA acted rapidly and caused a slowing of activation and deactivation and a hyperpolarizing shift in the voltage dependence of HCN2 channel activation (-24.5 +/- 1.2 mV at 1 mM). Slowed channel gating and reduction of current magnitude was marked in oocytes treated with NFA, while clamped at 0 mV but minimal in oocytes clamped at -100 mV, indicating the drug preferentially interacts with channels in the closed state. NFA at 0.1 to 3 mM shifted the half-point for channel activation in a concentration-dependent manner, with an EC(50) of 0.54 +/- 0.068 mM and a predicted maximum shift of -38 mV. NFA at 1 mM also reduced maximum HCN2 conductance by approximately 20%, presumably by direct block of the pore. The rapid onset and state-dependence of NFA-induced changes in channel gating suggests an interaction with the extracellular region of the S4 transmembrane helix, the primary voltage-sensing domain of HCN2. Neutralization (by mutation to Gln) of any three of the outer four basic charged residues in S4, but not single mutations, abrogated the NFA-induced shift in channel activation. We conclude that NFA alters HCN2 gating by interacting with the extracellular end of the S4 voltage sensor domains.
Accili,
Inhibition of the hyperpolarization-activated current (if) of rabbit SA node myocytes by niflumic acid.
1996, Pubmed
Accili,
Inhibition of the hyperpolarization-activated current (if) of rabbit SA node myocytes by niflumic acid.
1996,
Pubmed
Bell,
Changes in local S4 environment provide a voltage-sensing mechanism for mammalian hyperpolarization-activated HCN channels.
2004,
Pubmed
,
Xenbase
Bucchi,
Current-dependent block of rabbit sino-atrial node I(f) channels by ivabradine.
2002,
Pubmed
Busch,
Positive regulation by chloride channel blockers of IsK channels expressed in Xenopus oocytes.
1994,
Pubmed
,
Xenbase
Chen,
The S4-S5 linker couples voltage sensing and activation of pacemaker channels.
2001,
Pubmed
,
Xenbase
Chen,
Functional roles of charged residues in the putative voltage sensor of the HCN2 pacemaker channel.
2000,
Pubmed
,
Xenbase
Eskandari,
Inhibition of gap junction hemichannels by chloride channel blockers.
2002,
Pubmed
,
Xenbase
Goldin,
Expression of ion channels by injection of mRNA into Xenopus oocytes.
1991,
Pubmed
,
Xenbase
Jabeen,
Non-steroidal anti-inflammatory drugs as potent inhibitors of phospholipase A2: structure of the complex of phospholipase A2 with niflumic acid at 2.5 Angstroms resolution.
2005,
Pubmed
Lee,
Inhibition of hKv2.1, a major human neuronal voltage-gated K+ channel, by meclofenamic acid.
1999,
Pubmed
Liantonio,
Molecular switch for CLC-K Cl- channel block/activation: optimal pharmacophoric requirements towards high-affinity ligands.
2008,
Pubmed
,
Xenbase
Liantonio,
Activation and inhibition of kidney CLC-K chloride channels by fenamates.
2006,
Pubmed
,
Xenbase
Malykhina,
Fenamate-induced enhancement of heterologously expressed HERG currents in Xenopus oocytes.
2002,
Pubmed
,
Xenbase
Monnet,
Effects of heart rate reduction with ivabradine on exercise-induced myocardial ischemia and stunning.
2001,
Pubmed
Männikkö,
Voltage-sensing mechanism is conserved among ion channels gated by opposite voltages.
2002,
Pubmed
,
Xenbase
Ottolia,
Potentiation of large conductance KCa channels by niflumic, flufenamic, and mefenamic acids.
1994,
Pubmed
Peretz,
Meclofenamic acid and diclofenac, novel templates of KCNQ2/Q3 potassium channel openers, depress cortical neuron activity and exhibit anticonvulsant properties.
2005,
Pubmed
Picollo,
Mechanism of interaction of niflumic acid with heterologously expressed kidney CLC-K chloride channels.
2007,
Pubmed
,
Xenbase
Satoh,
Niflumic acid reduces the hyperpolarization-activated current (I(h)) in rod photoreceptor cells.
2001,
Pubmed
Scott-Ward,
Direct block of the cystic fibrosis transmembrane conductance regulator Cl(-) channel by niflumic acid.
2004,
Pubmed
Sesti,
Hyperpolarization moves S4 sensors inward to open MVP, a methanococcal voltage-gated potassium channel.
2003,
Pubmed
Shin,
Blocker state dependence and trapping in hyperpolarization-activated cation channels: evidence for an intracellular activation gate.
2001,
Pubmed
Sinkkonen,
Receptor subtype-dependent positive and negative modulation of GABA(A) receptor function by niflumic acid, a nonsteroidal anti-inflammatory drug.
2003,
Pubmed
,
Xenbase
Stühmer,
Electrophysiological recording from Xenopus oocytes.
1992,
Pubmed
,
Xenbase
Vaca,
Mutations in the S4 domain of a pacemaker channel alter its voltage dependence.
2000,
Pubmed
Vemana,
S4 movement in a mammalian HCN channel.
2004,
Pubmed
,
Xenbase
Vilaine,
Anti-ischemic effects of ivabradine, a selective heart rate-reducing agent, in exercise-induced myocardial ischemia in pigs.
2003,
Pubmed
Vilaine,
The discovery of the selective I(f) current inhibitor ivabradine. A new therapeutic approach to ischemic heart disease.
2006,
Pubmed
Wang,
Unexpected and differential effects of Cl- channel blockers on the Kv4.3 and Kv4.2 K+ channels. Implications for the study of the I(to2) current.
1997,
Pubmed
,
Xenbase
White,
Niflumic and flufenamic acids are potent reversible blockers of Ca2(+)-activated Cl- channels in Xenopus oocytes.
1990,
Pubmed
,
Xenbase