2012
DOI: 10.1038/nsmb.2473
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The voltage-dependent gate in MthK potassium channels is located at the selectivity filter

Abstract: Understanding how ion channels open and close their pores is crucial for understanding their physiological roles. We used intracellular quaternary ammonium blockers to locate the voltage-dependent gate in MthK potassium channels from Methanobacterium thermoautotrophicum with electrophysiology and X-ray crystallography. Blockers bind in an aqueous cavity between two putative gates, an intracellular gate and the selectivity filter. Thus, these blockers directly probe gate location: an intracellular gate will pre… Show more

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Cited by 63 publications
(119 citation statements)
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“…With net luminal-to-cytosolic cation flux, the affinity with which flecainide is bound in the cytosolic vestibule is insufficient to prevent it being displaced by interactions with permeant cations-a phenomenon first reported by Armstrong in K + channels 19 and recently explored in more detail. 20,21 This, together with the observations that no blocking site for flecainide exists at the luminal face of RyR2 and that flecainide has no effect on RyR2 gating, demonstrates why flecainide cannot inhibit the physiologically relevant movement of cations through this channel.…”
Section: Discussionmentioning
confidence: 99%
See 1 more Smart Citation
“…With net luminal-to-cytosolic cation flux, the affinity with which flecainide is bound in the cytosolic vestibule is insufficient to prevent it being displaced by interactions with permeant cations-a phenomenon first reported by Armstrong in K + channels 19 and recently explored in more detail. 20,21 This, together with the observations that no blocking site for flecainide exists at the luminal face of RyR2 and that flecainide has no effect on RyR2 gating, demonstrates why flecainide cannot inhibit the physiologically relevant movement of cations through this channel.…”
Section: Discussionmentioning
confidence: 99%
“…[19][20][21] A direct influence of voltage on flecainide would require the blocker to be positioned within the voltage drop across the membrane (ie, within the selectivity filter). It is inconceivable that a molecule as large as flecainide could interact at a site within the selectivity filter of RyR2, and not fully occlude the pore (a residual current of ≈20% persists with flecainide bound (Figure 1C)).…”
Section: Cytosolic Flecainide Does Not Block the Luminalto-cytosolic mentioning
confidence: 99%
“…The observation that inactivation occurs in strongly depolarized MthK channels without added Ca 2+ or Sr 2+ (Fig. 3) suggests that inactivation does not correspond to discrete events of Ca 2+ blockade (18,23). However, it could also be argued that low levels of Ca 2+ present in these solutions might lead to discrete events of Ca 2+ blockade, which become more frequent at depolarized voltages.…”
Section: Rapid Blockade Of Mthk Channels By Cytoplasmic Divalent Catimentioning
confidence: 94%
“…In previous experiments, MthK channels activated by Ca 2+ were found to spend increased time in a nonconducting or inactivated state with increasing depolarization (18,23). However, with Cd 2+ activation, entry into the inactivated state occurs at more depolarizing voltages compared with gating in the presence of Ca 2+ (Fig.…”
Section: Rapid Blockade Of Mthk Channels By Cytoplasmic Divalent Catimentioning
confidence: 99%
“…The conducting state of the selectivity filter, a narrow region of the K + channel pore that can discriminate between K + and other physiologically abundant ions, is stabilized through interactions with K + [108, 164, 165]. Through these and other interactions, the selectivity filter may itself act as a molecular gate to open and close the channel [163, 164, 171, 172]. …”
Section: Key Questions Subject To Interdisciplinary Study In Ion Tmentioning
confidence: 99%