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Titolo:
Inactivation gating and 4-AP sensitivity in human brain Kv1.4 potassium channel
Autore:
Judge, SIV; Monteiro, MJ; Yeh, JZ; Bever, CT;
Indirizzi:
Univ Maryland, Sch Med, Dept Neurol, Baltimore, MD 21201 USA Univ Maryland Baltimore MD USA 21201 Dept Neurol, Baltimore, MD 21201 USA VA Maryland Hlth Care Syst, Res Serv, Baltimore, MD USA VA Maryland Hlth Care Syst Baltimore MD USA Res Serv, Baltimore, MD USA VA Maryland Hlth Care Syst, Serv Neurol, Baltimore, MD USA VA Maryland Hlth Care Syst Baltimore MD USA rv Neurol, Baltimore, MD USA Univ21201land, Maryland Biotechnol Inst, Ctr Med Biotechnol, Baltimore, MDUniv Maryland Baltimore MD USA 21201 t, Ctr Med Biotechnol, Baltimore, MD Northwestern Univ, Sch Med, Dept Biol Chem & Mol Pharmacol, Chicago, IL USA Northwestern Univ Chicago IL USA l Chem & Mol Pharmacol, Chicago, IL USA
Titolo Testata:
BRAIN RESEARCH
fascicolo: 1-2, volume: 831, anno: 1999,
pagine: 43 - 54
SICI:
0006-8993(19990612)831:1-2<43:IGA4SI>2.0.ZU;2-1
Fonte:
ISI
Lingua:
ENG
Soggetto:
SPINAL-CORD INJURY; IMPROVES CLINICAL SIGNS; MAMMALIAN NERVE-FIBERS; GATED K+ CHANNELS; MULTIPLE-SCLEROSIS; 4-AMINOPYRIDINE ACTION; FUNCTIONAL EXPRESSION; AMINOPYRIDINE BLOCK; DOUBLE-BLIND; INNER MOUTH;
Keywords:
4-aminopyridine; Kv1.3 potassium channel; fast inactivation gate; L4 heptad leucine; mutagenesis; N-terminus deletion;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
58
Recensione:
Indirizzi per estratti:
Indirizzo: Judge, SIV Univre,ryland, Sch Med, Dept Neurol, BRB 12-040,655 W BaltimoreSt, Baltimo Univ Maryland BRB 12-040,655 W Baltimore St Baltimore MD USA 21201
Citazione:
S.I.V. Judge et al., "Inactivation gating and 4-AP sensitivity in human brain Kv1.4 potassium channel", BRAIN RES, 831(1-2), 1999, pp. 43-54

Abstract

Voltage-gated K+ channels vary in sensitivity to block by 4-aminopyridine (4-AP) over a 1000-fold range. Most K+ channel phenotypes with leucine at the fourth position (L4) in the leucine heptad repeat region. spanning the S4-S5 linker, exhibit low 4-AP sensitivity, while channels with phenylalanine exhibit high sensitivity. Mutational analysis on delayed rectifier type K channels demonstrate increased 4-AP sensitivity upon mutation of the L4 heptad leucine to phenylalanine. This mutation can also influence inactivation gating, which is known to compete with 4-AP in rapidly inactivating A-type K+ channels. Here, in a rapidly inactivating human brain Kv1.4 channel, we demonstrate a 400-fold increase in 4-AP sensitivity following substitution of L4 with phenylalanine. Accompanying this mutation is a slowing of inactivation, an acceleration of deactivation, and depolarizing shifts in the voltage dependence of activation and steady-state inactivation. To test therelative role of fast inactivation in modulating 4-AP block, N-terminal deletions of thr: fast inactivation gate were carried out in both channels. These deletions produced no change in 4-AP sensitivity in the mutant channeland approximately a six-fold increase in the wild type channel. These results support the view that changes at L4 which increase 4-AP sensitivity arelargely due to 4-AP binding and may, in part, arise from alterations in channel conformation. Primarily, this study demonstrates that the fast inactivation gate is not a critical determinant of 4-AP sensitivity in Kv1.4 channels. (C) 1999 Elsevier Science B.V. All rights reserved.

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Documento generato il 06/12/20 alle ore 00:03:49