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      Coupled Ion Movement Underlies Rectification in an Inward-Rectifier K + Channel

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          Abstract

          We studied block of the internal pore of the ROMK1 inward-rectifier K + channel by Mg 2+ and five quaternary ammoniums (tetramethylammonium, tetraethylammonium, tetrapropylammonium, tetrabutylammonium, and tetrapentylammonium). The apparent affinity of these blockers varied as a function of membrane voltage. As a consequence, the channel conducted K + current more efficiently in the inward than the outward direction; i.e., inward rectification. Although the size of some monovalent quaternary ammoniums is rather large, the zδ values (which measure voltage dependence of their binding to the pore) were near unity in symmetric 100 mM K +. Furthermore, we observed that not only the apparent affinities of the blockers themselves, but also their dependence on membrane voltage (or zδ), varied as a function of the concentration of extracellular K +. These results suggest that there is energetic coupling between the binding of blocking and permeating (K +) ions, and that the voltage dependence of channel blockade results, at least in part, from the movement of K + ions in the electrical field. A further quantitative analysis of the results explains why the complex phenomenon of inward rectification depends on both membrane voltage and the equilibrium potential for K +.

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          Most cited references42

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          Ionic Blockage of Sodium Channels in Nerve

          Increasing the hydrogen ion concentration of the bathing medium reversibly depresses the sodium permeability of voltage-clamped frog nerves. The depression depends on membrane voltage: changing from pH 7 to pH 5 causes a 60% reduction in sodium permeability at +20 mV, but only a 20% reduction at +180 mV. This voltage-dependent block of sodium channels by hydrogen ions is explained by assuming that hydrogen ions enter the open sodium channel and bind there, preventing sodium ion passage. The voltage dependence arises because the binding site is assumed to lie far enough across the membrane for bound ions to be affected by part of the potential difference across the membrane. Equations are derived for the general case where the blocking ion enters the channel from either side of the membrane. For H+ ion blockage, a simpler model, in which H+ enters the channel only from the bathing medium, is found to be sufficient. The dissociation constant of H+ ions from the channel site, 3.9 x 10-6 M (pK a 5.4), is like that of a carboxylic acid. From the voltage dependence of the block, this acid site is about one-quarter of the way across the membrane potential from the outside. In addition to blocking as described by the model, hydrogen ions also shift the responses of sodium channel "gates" to voltage, probably by altering the surface potential of the nerve. Evidence for voltage-dependent blockage by calcium ions is also presented.
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            Gated access to the pore of a voltage-dependent K+ channel.

            Voltage-activated K+ channels are integral membrane proteins that open or close a K(+)-selective pore in response to changes in transmembrane voltage. Although the S4 region of these channels has been implicated as the voltage sensor, little is known about how opening and closing of the pore is accomplished. We explored the gating process by introducing cysteines at various positions thought to lie in or near the pore of the Shaker K+ channel, and by testing their ability to be chemically modified. We found a series of positions in the S6 transmembrane region that react rapidly with water-soluble thiol reagents in the open state but not the closed state. An open-channel blocker can protect several of these cysteines, showing that they lie in the ion-conducting pore. At two of these sites, Cd2+ ions bind to the cysteines without affecting the energetics of gating; at a third site, Cd2+ binding holds the channel open. The results suggest that these channels open and close by the movement of an intracellular gate, distinct from the selectivity filter, that regulates access to the pore.
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              Interaction of Tetraethylammonium Ion Derivatives with the Potassium Channels of Giant Axons

              A number of compounds related to TEA+ (tetraethylammoniumion) were injected into squid axons and their effects on g K (the potassium conductance) were determined. In most of these ions a quaternary nitrogen is surrounded by three ethyl groups and a fourth group that is very hydrophobic. Several of the ions cause inactivation of g K, a type of ionic gating that is not normally seen in squid axon; i.e., after depolarization g K increases and then spontaneously decreases to a small fraction of its peak value even though the depolarization is maintained. Observations on the mechanism of this gating show that (a) QA (quaternary ammonium) ions only enter K+ channels that have open activation gates (the normal permeability gates). (b) The activation gates of QA-occluded channels do not close readily. (c) Hyperpolarization helps to clear QA ions from the channels. (d) Raising the external K+ concentration also helps to clear QA ions from the channels. Observations (c) and (d) strongly suggest that K+ ions traverse the membrane by way of pores, and they cannot be explained by the usual type of carrier model. The data suggest that a K+ pore has two distinct parts: a wide inner mouth that can accept a hydrated K+ ion or a TEA+-like ion, and a narrower portion that can accept a dehydrated or partially dehydrated K+ ion, but not TEA+.
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                Author and article information

                Journal
                J Gen Physiol
                The Journal of General Physiology
                The Rockefeller University Press
                0022-1295
                1540-7748
                1 August 1998
                : 112
                : 2
                : 211-221
                Affiliations
                From the Department of Physiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104
                Author notes

                Address correspondence to Dr. Zhe Lu, University of Pennsylvania, Department of Physiology, D302A Richards Building, 3700 Hamilton Walk, Philadelphia, PA 19104-6085. Fax: 215-573-5851; E-mail: zhelu@ 123456mail.med.upenn.edu

                Article
                10.1085/jgp.112.2.211
                2525747
                9689028
                517c8cc6-962f-4d22-9082-14672172af07
                Copyright @ 1998
                History
                : 27 February 1998
                : 8 March 1998
                Categories
                Article

                Anatomy & Physiology
                inward-rectifier k+ channel,rectification,ionic blocker,magnesium,tetraethylammonium

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