Characteristics of Brain Kv1 Channels Tailored to Mimic Native Counterparts by Tandem Linkage of α Subunits

Akhtar, S.; Shamotienko, Oleg; Papakosta, Marianthi; Ali, Farooq H.; Dolly, J. Oliver

doi:10.1074/jbc.m109698200

Cited by 36 publications

(33 citation statements)

References 37 publications

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“…Given the expression gradient for Kv1.1 but not Kv1.2 in NM (Fukui and Ohmori, 2004) it is tempting to speculate that a similar gradient exists in MNTB neurons. If so, I KLVA channels in medial neurons may contain higher proportions of Kv1.1 subunits, and hence activate at more negative potentials (Hopkins et al, 1994;Akhtar et al, 2002) consistent with our observation that I KLVA channels in medial neurons activated at t4-5 mV more negative potentials than in lateral neurons (Fig. 3).…”

Section: Channel Stoichiometrysupporting

confidence: 85%

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Systematic variation of potassium current amplitudes across the tonotopic axis of the rat medial nucleus of the trapezoid body

Brew

Forsythe

2005

Hearing Research

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Section: Channel Stoichiometrysupporting

confidence: 85%

“…with the most negatively activating channels formed by Kv1.1 homomers (Akhtar et al, 2002). We therefore decided to test whether the voltage-dependence of G KLVA varied across the tonotopic axis of MNTB.…”

Section: Resultsmentioning

confidence: 99%

Systematic variation of potassium current amplitudes across the tonotopic axis of the rat medial nucleus of the trapezoid body

Brew

Forsythe

2005

Hearing Research

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“…Concurrently, both current thresholds (72.5% decrease with DTX K ; 22.8% decrease with TsTX-Kα; P<0.05) and 50% refractory time were notably reduced, albeit the latter reached statistical significance only in DTX K treated samples (61.3±7.1%, n = 5 vs. 13.2±3.1%, n = 6; p = 0.01 and p>0.05, respectively). The quantitatively different effects of these blockers was unexpected given that the presence of a single toxin-sensitive subunit renders hetero-tetrameric channels susceptible to toxins [33], and suggests that enhanced K + conductance in demyelinated axons could be mediated largely, but not exclusively, through K V 1.1 homo-tetrameric channels.…”

Section: Resultsmentioning

confidence: 99%

Disruption of Myelin Leads to Ectopic Expression of KV1.1 Channels with Abnormal Conductivity of Optic Nerve Axons in a Cuprizone-Induced Model of Demyelination

et al. 2014

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The molecular determinants of abnormal propagation of action potentials along axons and ectopic conductance in demyelinating diseases of the central nervous system, like multiple sclerosis (MS), are poorly defined. Widespread interruption of myelin occurs in several mouse models of demyelination, rendering them useful for research. Herein, considerable myelin loss is shown in the optic nerves of cuprizone-treated demyelinating mice. Immuno-fluorescence confocal analysis of the expression and distribution of voltage-activated K+ channels (KV1.1 and 1.2 α subunits) revealed their spread from typical juxta-paranodal (JXP) sites to nodes in demyelinated axons, albeit with a disproportionate increase in the level of KV1.1 subunit. Functionally, in contrast to monophasic compound action potentials (CAPs) recorded in controls, responses derived from optic nerves of cuprizone-treated mice displayed initial synchronous waveform followed by a dispersed component. Partial restoration of CAPs by broad spectrum (4-aminopyridine) or KV1.1-subunit selective (dendrotoxin K) blockers of K+ currents suggest enhanced KV1.1-mediated conductance in the demyelinated optic nerve. Biophysical profiling of K+ currents mediated by recombinant channels comprised of different KV1.1 and 1.2 stoichiometries revealed that the enrichment of KV1 channels KV1.1 subunit endows a decrease in the voltage threshold and accelerates the activation kinetics. Together with the morphometric data, these findings provide important clues to a molecular basis for temporal dispersion of CAPs and reduced excitability of demyelinated optic nerves, which could be of potential relevance to the patho-physiology of MS and related disorders.

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“…This dramatic loss of affinity underlines the crucial interaction of these mutated residues with the toxin. Since it was reported that DTX K only needs one K V 1.1 subunit to cause inhibition of the potassium current through wild type heteromultimeric channels [26], we investigated also if DTX K could block the triple mutant. Concentration response curves were constructed for both K V 1.1 wild type and triple mutant channels ( fig.…”

Section: Electrophysiological Experimentsmentioning

confidence: 99%

A bifunctional sea anemone peptide with Kunitz type protease and potassium channel inhibiting properties

Peigneur¹,

Billen²,

Derua³

et al. 2011

Biochemical Pharmacology

104

101

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Page 1 of 22A c c e p t e d M a n u s c r i p t Abstract Sea anemone venom is a known source of interesting bioactive compounds, including peptide toxins which are invaluable tools for studying structure and function of voltage-gated potassium channels. APEKTx1 is a novel peptide isolated from the sea anemone Anthopleura elegantissima, containing 63 amino acids cross-linked by 3 disulfide bridges. Sequence alignment reveals that APEKTx1 is a new member of the type 2 sea anemone peptides targeting voltage-gated potassium channels (K V 's), which also include the kalicludines from Anemonia sulcata. Similar to the kalicludines, APEKTx1 shares structural homology with both the basic pancreatic trypsin inhibitor (BPTI), a very potent Kunitz-type protease inhibitor, and dendrotoxins which are powerful blockers of voltage-gated potassium channels. In this study, APEKTx1 has been subjected to a screening on a wide range of 23 ion channels expressed in Xenopus leavis oocytes: 13 cloned voltage-gated potassium channels (K V 1.1-K V 1.6, K V 1.1 triple mutant, K V 2.1, K V 3.1, K V 4.2, K V 4.3, hERG, the insect channel Shaker IR), 2 cloned hyperpolarization-activated cyclic nucleotidesensitive cation non-selective channels (HCN1 and HCN2) and 8 cloned voltage-gated sodium channels (Na V 1.2-Na V 1.8 and the insect channel DmNa V 1). Our data shows that APEKTx1 selectively blocks K V 1.1 channels in a very potent manner with an IC 50 value of 0.9 nM. Furthermore, we compared the trypsin inhibitory activity of this toxin with BPTI. APEKTx1 inhibits trypsin with a dissociation constant of 124 nM. In conclusion, this study demonstrates that APEKTx1 has the unique feature to combine the dual functionality of a potent and selective blocker of K V 1.1 channels with that of a competitive inhibitor of trypsin.Keywords Anthopleura elegantissima · K V channel inhibitor · sea anemone toxin · protease inhibitor ·

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Characteristics of Brain Kv1 Channels Tailored to Mimic Native Counterparts by Tandem Linkage of α Subunits

Cited by 36 publications

References 37 publications

Systematic variation of potassium current amplitudes across the tonotopic axis of the rat medial nucleus of the trapezoid body

Systematic variation of potassium current amplitudes across the tonotopic axis of the rat medial nucleus of the trapezoid body

Disruption of Myelin Leads to Ectopic Expression of KV1.1 Channels with Abnormal Conductivity of Optic Nerve Axons in a Cuprizone-Induced Model of Demyelination

A bifunctional sea anemone peptide with Kunitz type protease and potassium channel inhibiting properties

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