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Keywords:

  • inward-rectifier K+ channel ;
  • inward rectification;
  • Kir;
  • Kir1.1 ;
  • Kir2.1 ;
  • ROMK;
  • IRK;
  • spermine;
  • polyamines;
  • KcsA

Abstract

  1. Top of page
  2. Abstract
  3. The mechanism of inward-rectification
  4. Structural determinants of inward rectification
  5. Physiological role of rectification
  6. References

Inward-rectifier potassium (Kir) channels comprise a superfamily of potassium (K+) channels with unique structural and functional properties. Expressed in virtually all types of cells they are responsible for setting the resting membrane potential, controlling the excitation threshold and secreting K+ ions. All Kir channels present an inwardly rectifying current–voltage relation, meaning that at any given driving force the inward flow of K+ ions exceeds the outward flow for the opposite driving force. This inward-rectification is due to a voltage-dependent block of the channel pore by intracellular polyamines and magnesium. The present molecular–biophysical understanding of inward-rectification and its physiological consequences is the topic of this review. In addition to polyamines, Kir channels are gated by intracellular protons, G-proteins, ATP and phospholipids depending on the respective Kir subfamily as detailed in the following review articles.

Abbreviations
Kir

inward-rectifier potassium channel

KATP

ATP-sensitive potassium channel

ROMK

renal outer medulla potassium channel

SPM

spermine

SPD

spermidine

PUT

putrescine

TM

transmembrane segment

KcsA

potassium channel of streptomyces lividans

SUR

sulfonylurea receptor

About half a decade after cloning of the first K+ channels from the Shaker locus of Drosophila melanogaster[1–3], the first two genes encoding Kir channels were isolated in 1993 by expression cloning [4,5]. These two Kir proteins termed ROMK1 (for renal outer medulla K+ channel) and IRK1 (inward rectifier K+ channel) demonstrated the prototypic structure of this type of K+ channels: they are made up of two transmembrane domains (TM1 and TM2) flanking a well-conserved pore-loop (P-loop) and large hydrophilic N- and C-termini located on the cytoplasmic side of the membrane ( Fig. 1A). This topology, first based on hydrophobicity analysis only, has recently been confirmed by the landmark effort of MacKinnon’s group that resulted in successful crystalization of KcsA [6], a structural homologue of Kir channels from Streptomyces lividans[7] ( Fig. 1B). The crystal structure showed that two-segment type K+ channels are assembled from four subunits that are symmetrically arranged around a central pore lined by TM2 and the P-loop, in good agreement with functional studies performed on cloned Kir channels [8–11]. As in all other K+ channels known, the P-loop of the two-segment type K+ channels contains the famous glycine-tyrosine-glycine (GYG) or glycine-phenylalanine-glycine (GFG) stretch [12] that establishes the channels’ filter for K+ selectivity ( Fig. 1B).

image

Figure 1. Structure and membrane topology of Kir channels. (A) Membrane topology of Kir channels as deduced from hydrophobicity analysis. (B) Structure of the bacterial two-segment K+ channel KcsA viewed from side (left panel) and top (right panel); the spheres represent K+ ions at their binding sites. (C) Dendrogram of the superfamily of Kir channels; the first members to be cloned, ROMK1 and IRK1, are highlighted.

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After isolation of the first Kir proteins, subsequent homology-based cloning procedures uncovered a series of further Kir subunits that all shared the hallmark structural properties described above and showed that Kir channels indeed form a superfamily of K+ channel proteins [13–19]. Based on sequence homology, this superfamily was divided in up to seven subfamilies (Kir1–Kir7, reviewed in [20–22]) with up to four members each ( Fig. 1C); between subfamilies the level of identity in primary sequence is ≈ 40%, while individual members within one subfamily share an identity of ≈ 60% [20–22]. Upon heterologous expression, all Kir proteins were shown to be K+ selective and to exhibit an inwardly rectifying current–voltage (IV) relation [21,22]. The latter reflects the fact that Kir channels mediate a high K+ conductance at membrane potentials negative to the K+ equilibrium potential (EK) and at a limited voltage-range positive to EK. Further depolarization of the membrane potential leads to a rapid decrease in the Kir-mediated conductance which consequently prevents outward K+ currents [23,24].

Besides common properties, the members of the various Kir subfamilies show a number of characteristics that are either unique to certain subfamilies or are only shared by a few of them. Thus, Kir1 and Kir4 channels, which are predominantly expressed in epithelia, are exquisitely sensitive to changes in intracellular pH in the physiological range. Both channel subtypes are closed down by acidification, while alkalinization results in channel opening [25]. The members of the Kir3 subfamily are expressed in a variety of tissues and cell types, among them cardiac myocytes and central neurons, and, uniquely among Kir channels, they are activated by GTP-binding proteins (G-proteins) via stimulation of G-protein-coupled receptors [13,16,26,27]. Kir6 channels display a ubiquitous expression pattern [18] and in coassembly with the sulfonylurea receptor (SUR) represent the well known ATP-sensitive K+ channels (KATP) [28–30].

The members of the Kir2 family are predominantly expressed in heart, skeletal muscle and nervous system and represent the typical ‘strong’ rectifiers found in these tissues [4]. The term ‘strong’ refers to the high voltage-dependence of rectification in these channels [24,31–33]. The nature of this voltage-dependence as well as the mechanism and physiological implication of the strong inward-rectification is reviewed in the following sections.

The mechanism of inward-rectification

  1. Top of page
  2. Abstract
  3. The mechanism of inward-rectification
  4. Structural determinants of inward rectification
  5. Physiological role of rectification
  6. References

Since the first description of inwardly rectifying currents by Katz [34], the mechanism of rectification has been subject to investigation. Armstrong [35] suggested that inward-rectification might result from a positively charged particle that blocks the ion conducting pathway from the intracellular side of the membrane. Indeed, extensive work on native inward rectifiers (from cardiomyocytes) showed that the divalent magnesium (Mg2+) caused inward-rectification by blocking the channel pore in a voltage-dependent manner [36,37]. However, in some cases inward-rectification remained even in the absence of intracellular Mg2+. Hence, the remaining voltage-dependent rectification was ascribed to a mechanism intrinsic to the channel protein and termed ‘intrinsic gating’ to distinguish it from the ‘extrinsic’ Mg2+-induced pore block [38,39].

However, it was not recognized until cloned Kir channels were available, that neither of these suggested mechanisms could fully account for the rectification observed with these channels under cellular conditions. Thus, intrinsic gating could be washed-off from excised membrane patches similar to the soluble blocker Mg2+[31,32]; furthermore Mg2+-induced rectification was significantly less voltage-dependent than that observed under cell-attached conditions, i.e. with the channels contacting the cytoplasm [24,32]. In three independent approaches, the mystery was resolved by identifying the naturally occurring intracellular polyamines, spermine (SPM) and spermidine (SPD), as the ‘rectifier substance’ of Kir channels [24,31–33]. Both polyamines are present in the cytoplasm at micromolar concentrations [40] and block outward currents through Kir channels in a steeply voltage-dependent manner ( Fig. 2A). The voltage-dependence of SPM- and SPD-mediated rectification is considerably steeper than that of Mg2+, which explains why rectification observed under native conditions is steeper than predicted by Mg2+ block alone [24]. Intriguingly, polyamines also delivered the key to understanding intrinsic gating. As illustrated in Fig. 2B, release of SPM and/or SPD from blocked channels is a time-dependent process, while Mg2+ is released instantaneously. The latter combined with the fact that the positively charged polyamines can hardly be removed from cells or patches [31,32] explains why polyamine block appeared to be an intrinsic gating process [24,33].

image

Figure 2. Strong rectification is due to voltage-dependent pore block by intracellular polyamines. (A) Upper panel, current mediated by Kir2.1 channels in response to voltage ramps; black trace represents cell-attached conditions, grey trace is the current measured after patch excision and application of 1 m m Mg2+ to the cytoplasmic side of the channels. Inset: currents at enlarged scale to show the dramatic difference between rectification under cell-attached conditions and in the presence of 1 m m Mg2+. Lower panel, rectification measured in excised patches after application of cytoplasmic lysate or 10 µm SPM. (B) Release of block by either 10 µm SPM (left panel) or 1 m m Mg2+ (right panel) induced by voltage steps from 100 mV to potentials between 100 and − 50 mV. Note that only with SPM the release displays an exponential time course. Modified from [24].

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What determines the much higher voltage-dependence of the polyamine block with respect to pore block by Mg2+? The ‘Woodhull model’ describing block of ion channels [41] assumes that voltage-dependence of the block is roughly determined by the number of charges that move during the blocking process times the distance these charges move within the electrical field (electrical distance). In agreement with such a model, the blocking potency and voltage-dependence for the various polyamines and Mg2+ indeed decreases as follows: SPM4+ (fourfold positively charged) > SPD3+ > putrescine2+ (PUT) ≈ Mg2+[24,33]. However, while the electrical distance derived from the Woodhull model for Mg2+ delivers somehow realistic values (smaller than unity) [24,42], SPM block results in ‘electrical distances’ of more than 100%, i.e. the SPM molecule would absorb more energy than offered by the transmembrane electrical field [24,32,42,43]. As a solution to this paradox it was suggested that more than one SPM molecule participates in the blocking reaction and that binding of SPM to the pore is coupled to the movement of permeant and impermeant ions [11,42–45].

Taken together, there is substantial evidence that polyamines are responsible for strong inward-rectification of Kir channels by blocking the channel pore in a voltage-dependent manner. It should be added at this point, that a similar phenomenon has recently been observed in AMPA-type glutamate receptors [46–48], where polyamines were implicated in synaptic facilitation [48,49]. Differently from Kir channels, however, SPM-mediated block of the nonselective AMPA receptors is less voltage-dependent and is released at strong depolarizations, consistent with the polyamines permeating through the channel when the driving voltage is sufficiently high [46–49].

Structural determinants of inward rectification

  1. Top of page
  2. Abstract
  3. The mechanism of inward-rectification
  4. Structural determinants of inward rectification
  5. Physiological role of rectification
  6. References

Although all Kir channels are blocked by intracellularly applied polyamines, the voltage-dependence of block differs significantly among Kir subfamilies [20–22]. While strongly rectifying Kirs are completely blocked at ≈ 50 mV positive to EK, members of the Kir1 and Kir6 subfamily conduct significant outward current even at very depolarized potentials (e.g. + 80 mV).

Sequence comparison between the prototypic weak and strong rectifiers, Kir1.1 and Kir2.1, uncovered two structural determinants in the channel molecule that govern the degree of rectification [31,50–52]. The first was a residue in TM2 ( Fig. 3A). This position is occupied by a negatively charged amino acid in all strong rectifiers, while it presents with an uncharged residue in weak rectifiers. In Kir1.1 (ROMK1), changing this residue to a negatively charged aspartate was sufficient to convert the channel into a strong rectifier ( Fig. 3B, left panels). The reverse mutation in Kir4.1 changes rectification properties from strong to weak [9], almost indistinguishable from those of Kir1.1 in the mutated channel ( Fig. 3B, right panels). The ‘phenotype’ of strong rectification thus requires a negatively charged amino acid (aspartate or glutamate) at the TM2 site suggesting electrostatic interactions between this site and the positively charged blocker molecules. This hypothesis is further substantiated by the findings that a reporter cysteine at this position can be readily modified with cysteine-reactive reagents indicating exposure to the lumen of the pore [11]. In agreement, the KcsA structure presents the homologous position as a pore lining residue [6] ( Fig. 3A). Thus, it seems very likely that negatively charged amino acids at the TM2 site stabilize binding of polyamines and Mg2+ in the pore via direct electrostatic interactions.

image

Figure 3. Structural determinants for polyamine block in Kir channels. (A) Localization of the TM2-site in the KcsA structure; only two of the four channel subunits are shown for clarity. (B) Rectification in Kir1.1 (left panel) and Kir4.1 (right panel) changes dramatically upon charging (Kir1.1(N171D) or neutralization (Kir4.1(E158N) of this site. IV relations, measured as current responses to voltage-ramps in the absence and presence of 100 µm SPM. Modified from [9].

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The second determinant for rectification was localized to the C-terminus of the Kir protein [44,53]. In contrast to Kir1 and Kir4, SPM block observed with the strong rectifier subfamilies Kir2 and Kir3 shows more complex kinetics and steady-state voltage-dependence [21,42,44]. When the TM2 residue was neutralized in Kir2.1, the resulting channels did not exhibit weak rectification as expected [21,44,52], although voltage-dependence was reduced and kinetics of block were changed. Using a chimeric approach, Yang et al. and Taglialatela et al. identified another negatively charged residue in the C-terminus of Kir2.1 (glutamate at position 224 [44,53]), which contributes to rectification. Neutralization of this amino acid in the TM2-neutralized Kir2.1 mutant results in a further decrease of SPM block, although channels are still significantly blocked by polyamines. Introduction of a negatively charged residue at this position into Kir1.1, however, did not induce any change in rectification properties with respect to wild-type, indicating a unique role of the C-terminal rectification site in the structural context of the Kir2 proteins [44,53].

A recent report by Baukrowitz et al. then added another twist to the C-terminal determinants of rectification [54]. In Kir6 channels, a C-terminal histidine was identified that interacts with SPM and controls rectification in a pH-dependent manner. Around neutral intracellular pH, the histidine is protonated and KATP channels present with weak inward-rectification, while alkalinization that deprotonates the residue results in strongly rectifying channels [54].

Taken together, the TM2 site seems to be a common structural determinant for block of the Kir channel pore by intracellular cations. In contrast, the C-terminal contribution to pore block and rectification varies between the different Kir subunits. Furthermore, for Kir2 channels additional sites must exist as channels lacking the TM2 and C-terminal sites still display significant rectification.

Physiological role of rectification

  1. Top of page
  2. Abstract
  3. The mechanism of inward-rectification
  4. Structural determinants of inward rectification
  5. Physiological role of rectification
  6. References

The major physiological role of strongly rectifying Kir channels is their impact on the resting membrane potential in excitable and nonexcitable cells, as well as the establishment of the threshold that must be exceeded by excitatory stimuli to trigger generation and propagation of action potentials [23,24].

The ability of a strongly rectifying Kir channel to set a sharp excitation threshold is illustrated with a model system consisting of a cell-attached patch containing Kir2.1 channels using the current-clamp mode of the patch clamp amplifier ( Fig. 4A). In this mode, current is applied to the patch to simulate a depolarizing current in an excitable cell while the membrane potential is measured. Injection of 10, 20 and 30 pA depolarizing currents result in only small ohmic increases of the membrane potential because up to this point the membrane potential is mostly determined by the K+ conductance in the patch. However, when the applied current is large enough to depolarize the membrane potentials (VM) to values where polyamine block becomes prominent, Kir2.1 channels close. This allows VM to depolarize further and thus promotes further channel closure. This positive feedback leads to the fast all-or-nothing breakdown of the K+ conductance and thus to the observed large depolarization ( Fig. 4A). Intriguingly, this experiment demonstrates that an effective excitation threshold can be set by Kir channels in the absence of voltage activated Na+ channels.

image

Figure 4. Strong rectifier Kir channels determine resting potential and excitation threshold. (A) Current-clamp experiment in a cell-attached patch from a Xenopus oocyte expressing Kir2.1 channels. Voltage-responses to current-pulses that are increased in steps of 10 pA from 0 to 50 pA. Note the dramatic depolarization observed upon exceeding the excitation threshold (fourth step). Modified from [24]. (B) Schematic time course of a representative neuronal action potential, phases I–IV represent rest, prethreshold, depolarization and repolarization. (C) Currents underlying the action potential: rest is determined by the Kir-mediated K+ conductance, as soon as excitation exceeds the maximal Kir-mediated outward current (excitation threshold) the membrane is depolarized by sodium currents (INa); repolarization is caused by voltage-gated (Kv) K+ channels. Curves represent typical instantaneous IV values for IKir, INa and IKV.

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Figure 4B,C depicts the function of Kir channels in a more native setting by correlating the K+ conductance mediated by Kir channels with the time-course of a typical neuronal action potential. At rest, the membrane potential is stabilized at values close to EK, due to the high K+ conductance mediated by the unblocked, i.e. open Kir channels (phase I in Fig. 4B). Excitatory stimuli trying to depolarize the membrane are mostly extinguished by instantaneous outward K+ currents resulting in a rather slow (and variable) prethreshold depolarization (phase II). This stabilizing effect is maintained as long as the depolarizing currents do not exceed the maximal outward current that can be mediated by the Kir channels. If this current maximum reflected by the inversion point at the steady-state IV (≈ 30 mV positive to EK, Fig. 4C) is exceeded, Kir channels will rapidly be blocked by polyamines and thus allow for fast depolarization of the membrane, which at this point is driven primarily by the opening of voltage activated Na+ channels and the resulting large Na+ inward currents (INa). Subsequently the action potential is terminated by Na+ channel inactivation (not shown) and opening of voltage gated K+ channels (phase IV).

Thus, Kir channels via their pore block by SPM establish an effective threshold for excitation and therefore exert a major impact on excitability in many cell types. This view is supported by recent experiments by Bianchi et al. who found that a reduction in intracellular SPM levels reduced rectification of strong rectifier Kirs and consequently led to a shift of the excitation threshold to more positive potentials [55]. Taken together, Kir channels represent an effective tool to control cellular excitation and might therefore serve as a general target for treatment of disorders in excitability. Furthermore, many Kir channels are regulated by extracellular and intracellular factors to allow adjustment of cell excitability in response to a multitude of biological stimuli. These regulatory mechanisms will be discussed in detail in the following articles.

References

  1. Top of page
  2. Abstract
  3. The mechanism of inward-rectification
  4. Structural determinants of inward rectification
  5. Physiological role of rectification
  6. References
  • 1
    Pongs, O., Kecskemethy, N., Muller, R., Krah, J.I., Baumann, A., Kiltz, H.H., Canal, I., Llamazares, S., Ferrus, A. (1988) Shaker encodes a family of putative potassium channel proteins in the nervous system of Drosophila. EMBO J. 7, 1087 1096.
  • 2
    Tempel, B.L., Jan, Y.N., Jan, L.Y. (1988) Cloning of a probable potassium channel gene from mouse brain. Nature 332, 837 839.
  • 3
    Papazian, D.M., Schwarz, T.L., Tempel, B.L., Jan, Y.N., Jan, L.Y. (1987) Cloning of genomic and complementary DNA from Shaker, a putative potassium channel gene from Drosophila. Science 237, 749 753.
  • 4
    Kubo, Y., Baldwin, T.J., Jan, Y.N., Jan, L.Y. (1993) Primary structure and functional expression of a mouse inward rectifier potassium channel. Nature 362, 127 133.
  • 5
    Ho, K., Nichols, C.G., Lederer, W.J., Lytton, J., Vassilev, P.M., Kanazirska, M.V., Hebert, S.C. (1993) Cloning and expression of an inwardly rectifying ATP-regulated potassium channel. Nature 362, 31 38.
  • 6
    Doyle, D.A., Cabral, J.M., Pfuetzner, R.A., Kuo, A., Gulbis, J.M., Cohen, S.L., Chait, B.T., MacKinnon, R. (1998) The structure of the potassium channel: molecular basis of K+ conductivity and selectivity. Science 280, 69 77.
  • 7
    Schrempf, H., Schmidt, O., Kümmerlen, R., Hinnah, S., Müller, D., Betzler, M., Seinkamp, T., Wagner, R. (1995) A prokaryotic potassium ion channel with two predicted transmembrane segments from Streptomyces lividans. EMBO J. 14, 5170 5178.
  • 8
    Yang, J., Jan, Y.N., Jan, L.Y. (1995) Determination of the subunit stoichiometry of an inwardly rectifying potassium channel. Neuron 15, 1441 1447.
  • 9
    Glowatzki, E., Fakler, G., Brändle, U., Rexhausen, U., Zenner, H.P., Ruppersberg, J.P., Fakler, B. (1995) Subunit-dependent assembly of inward-rectifier K+ channels. Proc. R. Soc. Lond. B. Biol. Sci. 261, 251 261.
  • 10
    Minor, D.L.J., Masseling, S.J., Jan, Y.N., Jan, L.Y. (1999) Transmembrane structure of an inwardly rectifying potassium channel. Cell 96, 879 891.
  • 11
    Lu, T., Nguyen, B., Zhang, X., Yang, J. (1999) Architecture of a K+ channel inner pore revealed by stoichiometric covalent modification. Neuron 22, 571 580.
  • 12
    Heginbotham, L., Lu, Z., Abramson, T., MacKinnon, R. (1994) Mutations in the K+ channel signature sequence. Biophys. J. 66, 1061 1067.
  • 13
    Kubo, Y., Reuveny, E., Slesinger, P.A., Jan, Y.N., Jan, L.Y. (1993) Primary structure and functional expression of a rat G-protein-coupled muscarinic potassium channel. Nature 364, 802 806.
  • 14
    Bond, C.T., Pessia, M., Xia, X.M., Lagrutta, A., Kavanaugh, M.P., Adelman, J.P. (1994) Cloning and expression of a family of inward rectifier potassium channels. Recept. Channel. 2, 183 191.
  • 15
    Koyama, H., Morishige, K., Takahashi, N., Zanelli, J.S., Fass, D.N., Kurachi, Y. (1994) Molecular cloning, functional expression and localization of a novel inward rectifier potassium channel in the rat brain. FEBS Lett. 341, 303 307.
  • 16
    Lesage, F., Duprat, F., Fink, M., Giullemare, E., Coppola, T., Lazdunzki, M., Hugnot, J.-P. (1994) Cloning provides evidence for a family of inward rectifier and G-protein coupled K+ channels in the brain. FEBS Lett. 353, 37 42.
  • 17
    Bond, C.T., Ämmälä, C., Ashfield, R., Blair, T.A., Gribble, F., Khan, R.N., Lee, K., Proks, P., Rowe, I.C.M., Sakura, H., Ashford, M.J., Adelman, J.P., Ashcroft, F.M. (1995) Cloning and functional expression of the cDNA encoding an inwardly-rectifying potassium channel expressed in pancreatic β-cells and in the brain. FEBS 367, 61 66.
  • 18
    Inagaki, N., Tsuura, Y., Namba, N., Msauda, K., Gonoi, T., Horie, M., Seino, Y., Mizuta, M., Seino, S. (1995) Cloning and functional characterization of a novel ATP-sensitive potassium channel ubiquitously expressed in rat tissues, including pancreatic islets, pituitary, skeletal muscle, and heart0. J. Biol. Chem. 270, 5691 5694.
  • 19
    Inagaki, N., Gonoi, T., Clement, I.V.J.P., Namba, N., Inazawa, J., Gonzales, G., Aguilar-Bryan, L., Seino, S., Bryan, J. (1995) Reconstitution of IKATP: an inward rectifier subunit plus the sulfonylurea receptor. Science 270, 1166 1169.
  • 20
    Doupnik, C.A., Davidson, N., Lester, H.A. (1995) The inward rectifier potassium channel family. Curr. Opin. Neurobiol. 5, 268 277.
  • 21
    Fakler, B. & Ruppersberg, J.P. (1996) Functional and molecular diversity classifies the family of inward rectifier K+ channels. Cell. Physiol. Biochem. 6, 195 209.
  • 22
    Nichols, C. & Lopatin, A. (1997) Inward rectifier potassium channels. Annu. Rev. Physiol. 59, 171 191.
  • 23
    Hille, B. (1992) Ionic Channels in Excitable Membranes , 2nd edn, 127 130. Sinauer Assoc. Inc., Sunderland, MA.
  • 24
    Fakler, B., Brändle, U., Glowatzki, E., Weidemann, S., Zenner, H.P., Ruppersberg, J.P. (1995) Strong voltage-dependent inward-rectification of inward rectifier K+ channels is caused by intracellular spermine. Cell 80, 149 154.
  • 25
    Schulte, U., Hahn, H., Konrad, M., Jeck, N., Derst, C., Wild, K., Weidemann, S., Ruppersberg, J.P., Fakler, B., Ludwig, J. (1999) pH gating of ROMK (K(ir)1.1) channels: control by an Arg-Lys-Arg triad disrupted in antenatal Bartter syndrome. Proc. Natl Acad. Sci. USA 96, 15298 15303.
  • 26
    Krapivinsky, G., Gordon, E.A., Wickman, K., Velimirovic, B., Krapivinsky, L., Clapham, D.E. (1995) The G-protein-gated atrial K+ channel IKACh is a heteromultimer of two inwardly rectifying K+-channel proteins . Nature 374, 135 141.
  • 27
    Dascal, N., Schreibmayer, W., Lim, N.F., Wang, W., Chavkin, C., DiMagno, L., Labarca, C., Kieffer, B.L., Gaveriaux-Ruff, C., Trollinger, D., Lester, H.A., Davison, N. (1993) Atrial G protein-activated K+ channel: expression cloning and molecular properties. Proc. Natl Acad. Sci. USA 90, 10235 10239.
  • 28
    Ashcroft, F.M. (1988) Adenosine 5′-triphosphate-sensitive potassium channels. Annu. Rev. Neurosci. 11, 97 118.
  • 29
    Nichols, C.G. & Lederer, W.J. (1991) Adenosine triphosphate-sensitive potassium channels in the cardiovascular system. Am. J. Physiol. 261, H1675 H1686.
  • 30
    Seino, S. (1999) ATP-sensitive potassium channels: a model of heteromultimeric potassium channel/receptor assemblies. Annu. Rev. Physiol. 61, 337 362.
  • 31
    Fakler, B., Brändle, U., Glowatzki, E., König, C., Bond, C., Adelman, J.P., Zenner, H.-P., Ruppersberg, J.P. (1994) A structural determinant of differential sensitivity of cloned inward rectifier channels to intracellular spermine. FEBS 356, 199 203.
  • 32
    Lopatin, A.N., Makhina, E.H., Nichols, C.G. (1994) Potassium channel block by cytoplasmic polyamines as the mechanism of intrinsic rectification. Nature 372, 366 369.
  • 33
    Ficker, E., Taglialatela, M., Wible, B.A., Henley, C.M., Brown, A.M. (1994) Spermine and spermidine as gating molecules for inward rectifier K+ channels. Science 266, 1068 1072.
  • 34
    Katz, B. (1949) Les constantes électriques de la membrane du muscle. Arch. Sci. Physiol. 51, 285 300.
  • 35
    Armstrong, C.M. (1969) Inactivation of the potassium conductance and related phenomena caused by quaternary ammonium ion injection in squid axons. J. Gen Physiol. 54, 553 575.
  • 36
    Matsuda, H. (1991) Effects of external and internal K+ ions on magnesium block of inwardly rectifying K+ channels in guinea-pig heart cells. J. Physiol. (Lond) 435, 83 99.
  • 37
    Vandenberg, C.A. (1987) Inward rectification of a potassium channel in cardiac ventricular cells depends on internal magnesium ions. Proc. Natl Acad. Sci., USA 84, 2560 2564.
  • 38
    Silver, M.R. & DeCoursey, T.E. (1990) Intrinsic gating of inward rectifier in bovine pulmonary artery endothelial cells in the presence or absence of internal Mg2+. J. Gen Physiol. 96, 109 133.
  • 39
    Ishihara, K., Mitsuiye, T., Noma, A., Takano, M. (1989) The Mg2+ block and intrinsic gating underlying inward rectification of the K+ current in guinea-pig cardiac myocytes. J. Physiol. (Lond) 419, 297 320.
  • 40
    Watanabe, S.-I., Kusama-Eguchi, K., Kobayashi, H., Igarashi, K. (1991) Estimation of Polyamine binding to macromolecules and ATP in bovine lymphocytes and rat liver. J. Biol. Chem. 266, 20803 20809.
  • 41
    Woodhull, A. (1973) Ionic blockage of sodium channels in nerve. J. Gen. Physiol. 61, 687 708.
  • 42
    Lopatin, A.N., Makhina, E.N., Nichols, C.G. (1995) The mechanism of inward rectification of potassium channels: ‘long-pore plugging’ by cytoplasmic polyamines. J. Gen. Physiol. 106, 923 955.
  • 43
    Oliver, D., Hahn, H., Antz, C., Ruppersberg, J.P., Fakler, B. (1998) Interaction of permeant and blocking ions in cloned inward-rectifier K+ channels. Biophys. J. 74, 2318 2326.
  • 44
    Yang, J., Jan, Y.N., Jan, L.Y. (1995) Control of rectification and permeation by residues in two distinct domains in an inward rectifier K+ channel. Neuron 14, 1047 1054.
  • 45
    Spassova, M. & Lu, Z. (1998) Coupled ion movement underlies rectification in an inward-rectifier K+ channel. J. Gen. Physiol. 112, 211 221.
  • 46
    Bowie, D. & Mayer, M.L. (1995) Inward rectification of both AMPA and kainate subtype glutamate receptors generated by polyamine-mediated ion channel block. Neuron 15, 453 462.
  • 47
    Bowie, D., Lange, G.D., Mayer, M.L. (1998) Activity-dependent modulation of glutamate receptors by polyamines. J. Neurosci 18, 8175 8185.
  • 48
    Koh, D.S., Burnashev, N., Jonas, P. (1995) Block of native Ca(2+)-permeable AMPA receptors in rat brain by intracellular polyamines generates double rectification. J. Physiol. (Lond) 486, 305 312 (erratum appears in J. Physiol. (Lond) 488, 843 ).
  • 49
    Rozov, A. & Burnashev, N. (1999) Polyamine-dependent facilitation of postsynaptic AMPA receptors counteracts paired-pulse depression. Nature 401, 594 598.
  • 50
    Stanfield, P.R., Davies, N.W., Shelton, P.A., Sutcliffe, M.J., Khan, I.A., Brammar, W.J., Conley, E.C. (1994) A single aspartate residue is involved in both intrinsic gating and blockade by Mg2+ of the inward rectifier, IRK1. J. Physiol. (Lond) 478, 1 6.
  • 51
    Lu, Z. & MacKinnon, R. (1994) Electrostatic tuning of Mg2+ affinity in an inward-rectifier K+ channel. Nature 371, 243 246.
  • 52
    Wible, B.A., Taglialatela, M., Ficker, E., Brown, A.M. (1994) Gating of inwardly rectifying K+ channels localized to a single negatively charged residue. Nature 371, 246 249.
  • 53
    Taglialatela, M., Ficker, E., Wible, B., Brown, A.M. (1995) C-terminus determinant for Mg2+ and polyamine block of the inward rectifier K+ channel IRK1. EMBO J. 14, 5532 5541.
  • 54
    Baukrowitz, T., Tucker, S.J., Schulte, U., Benndorf, K., Ruppersberg, J.P., Fakler, B. (1999) Inward rectification in KATP channels: a pH switch in the pore. EMBO J. 18, 847 853.
  • 55
    Bianchi, L., Roy, M.L., Taglialatela, M., Lundgren, D.W., Brown, A.M., Ficker, E. (1996) Regulation by spermine of native inward rectifier K+ channels in RBL-1 cells. J. Biol. Chem. 271, 6114 6121.