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• W2896257816 abstract "Potassium channels that exhibit the property of inward rectification (Kir channels) are present in most cells. Cloning of the first Kir channel genes 25 years ago led to recognition that inward rectification is a consequence of voltage-dependent block by cytoplasmic polyamines, which are also ubiquitously present in animal cells. Upon cellular depolarization, these polycationic metabolites enter the Kir channel pore from the intracellular side, blocking the movement of K+ ions through the channel. As a consequence, high K+ conductance at rest can provide very stable negative resting potentials, but polyamine-mediated blockade at depolarized potentials ensures, for instance, the long plateau phase of the cardiac action potential, an essential feature for a stable cardiac rhythm. Despite much investigation of the polyamine block, where exactly polyamines get to within the Kir channel pore and how the steep voltage dependence arises remain unclear. This Minireview will summarize current understanding of the relevance and molecular mechanisms of polyamine block and offer some ideas to try to help resolve the fundamental issue of the voltage dependence of polyamine block. Potassium channels that exhibit the property of inward rectification (Kir channels) are present in most cells. Cloning of the first Kir channel genes 25 years ago led to recognition that inward rectification is a consequence of voltage-dependent block by cytoplasmic polyamines, which are also ubiquitously present in animal cells. Upon cellular depolarization, these polycationic metabolites enter the Kir channel pore from the intracellular side, blocking the movement of K+ ions through the channel. As a consequence, high K+ conductance at rest can provide very stable negative resting potentials, but polyamine-mediated blockade at depolarized potentials ensures, for instance, the long plateau phase of the cardiac action potential, an essential feature for a stable cardiac rhythm. Despite much investigation of the polyamine block, where exactly polyamines get to within the Kir channel pore and how the steep voltage dependence arises remain unclear. This Minireview will summarize current understanding of the relevance and molecular mechanisms of polyamine block and offer some ideas to try to help resolve the fundamental issue of the voltage dependence of polyamine block. Voltage-dependent changes in the conductance of K+, Na+, and Ca2+ channels underlie the electrical signals or action potentials that are essential to all excitable processes, and indeed to life itself (1Hille B. Ionic Channels of Excitable Membranes. Sinauer Associates, Sunderland, MA1992Google Scholar). Physiologically, intracellular [K+] is ∼140 mm, whereas extracellular [K+] is only ∼4 mm. As a consequence, K+-selective conductances normally reverse at negative voltages and exhibit larger outward currents (at voltages positive to the reversal potential) than inward currents (at voltages negative to reversal) as illustrated in Fig. 1A. “Inward” or “anomalous” rectification refers to the phenomenon whereby K+ conductance is paradoxically reduced at positive potentials. It is a prominent feature of one major subfamily of K+ channels, the so-called “inward rectifier” (Kir) channels that are present in almost all cells (2Nichols C.G. Lopatin A.N. Inward rectifier potassium channels.Annu. Rev. Physiol. 1997; 59 (9074760): 171-19110.1146/annurev.physiol.59.1.171Crossref PubMed Scopus (660) Google Scholar). The functional role of Kir channels depends critically on the degree of inward rectification that they exhibit. Classical strong inward rectification, first described in skeletal muscle (3Katz B. Les constantes electriques de la membrane du muscle.Arch. Sci. Physiol. 1949; 2: 285-299Google Scholar), is a property of a key current (IK1) in cardiac myocytes, as well as in glial cells and neurons in the central nervous system (4Nakajima Y. Nakajima S. Inoue M. Pertussis toxin-insensitive G protein mediates substance P-induced inhibition of potassium channels in brain neurons.Proc. Natl. Acad. Sci. U.S.A. 1988; 85 (2453066): 3643-364710.1073/pnas.85.10.3643Crossref PubMed Scopus (91) Google Scholar5Hestrin S. The properties and function of inward rectification in rod photoreceptors of the tiger salamander.J. Physiol. 1987; 390 (2450992): 319-33310.1113/jphysiol.1987.sp016703Crossref PubMed Scopus (103) Google Scholar, 6Newman E.A. Inward-rectifying potassium channels in retinal glial (Muller) cells.J. 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In contrast to classical inward rectifiers, renal Kir channels (9Giebisch G. Hunter M. Kawahara K. Apical potassium channels in Amphiuma diluting segment: effect of barium.J. Physiol. 1990; 420 (2324987): 313-32310.1113/jphysiol.1990.sp017914Crossref PubMed Scopus (11) Google Scholar) and ATP-sensitive K+ (KATP) channels, present in multiple cell types (10Nichols C.G. KATP channels as molecular sensors of cellular metabolism.Nature. 2006; 440 (16554807): 471-47610.1038/nature04711Crossref Scopus (664) Google Scholar), display only “weak” rectification and allow substantial outward current to flow at positive potentials. Between the two extremes, potassium channels showing intermediate rectification properties, many of these channels being strongly dependent on ligand activation, often through G-proteins or other second messenger systems, are particularly prominent in the brain (2Nichols C.G. Lopatin A.N. Inward rectifier potassium channels.Annu. Rev. Physiol. 1997; 59 (9074760): 171-19110.1146/annurev.physiol.59.1.171Crossref PubMed Scopus (660) Google Scholar). Cloning of the first Kir channel genes in 1993 (11Kubo Y. Reuveny E. Slesinger P.A. Jan Y.N. Jan L.Y. Primary structure and functional expression of a rat G-protein-coupled muscarinic potassium channel.Nature. 1993; 364 (8355805): 802-80610.1038/364802a0Crossref PubMed Scopus (545) Google Scholar, 12Ho K. Nichols C.G. Lederer W.J. Lytton J. Vassilev P.M. Kanazirska M.V. Hebert S.C. Cloning and expression of an inwardly rectifying ATP-regulated potassium channel.Nature. 1993; 362 (7680431): 31-3810.1038/362031a0Crossref PubMed Scopus (833) Google Scholar) led to the elucidation of the structural components of each of the major types of inward rectifier channels, as well as the molecular basis of inward rectification. This Minireview represents a personal review of this 25-year effort, highlighting the remaining unknowns. For further insights, the reader is recommended to other detailed reviews (2Nichols C.G. Lopatin A.N. Inward rectifier potassium channels.Annu. Rev. Physiol. 1997; 59 (9074760): 171-19110.1146/annurev.physiol.59.1.171Crossref PubMed Scopus (660) Google Scholar, 13Baronas V.A. Kurata H.T. Inward rectifiers and their regulation by endogenous polyamines.Front. Physiol. 2014; 5 (25221519): 325Crossref PubMed Scopus (40) Google Scholar, 14Lu Z. Mechanism of rectification in inward-rectifier K+ channels.Annu. Rev. Physiol. 2004; 66 (14977398): 103-12910.1146/annurev.physiol.66.032102.150822Crossref PubMed Scopus (156) Google Scholar). Over the last 15 years, high-resolution crystal structures of bacterial and eukaryotic Kir channels have revealed a highly conserved architecture: Kir channels are generated by tetrameric arrangements of identical or similar Kir subunits, each of which comprises a transmembrane domain (TMD) 2The abbreviations used are: TMDtransmembrane domainCNGcyclic nucleotide-gatedEKpotassium reversal potential. and a large cytoplasmic domain (Fig. 1B) (15Nishida M. MacKinnon R. Structural basis of inward rectification: cytoplasmic pore of the G protein-gated inward rectifier GIRK1 at 1.8 A resolution.Cell. 2002; 111 (12507423): 957-96510.1016/S0092-8674(02)01227-8Abstract Full Text Full Text PDF PubMed Scopus (341) Google Scholar, 16Kuo A. Gulbis J.M. Antcliff J.F. Rahman T. Lowe E.D. Zimmer J. Cuthbertson J. Ashcroft F.M. Ezaki T. Doyle D.A. Crystal structure of the potassium channel KirBac1.1 in the closed state.Science. 2003; 300 (12738871): 1922-192610.1126/science.1085028Crossref PubMed Scopus (736) Google Scholar17Nishida M. Cadene M. Chait B.T. MacKinnon R. Crystal structure of a Kir3.1-prokaryotic Kir channel chimera.EMBO J. 2007; 26 (17703190): 4005-401510.1038/sj.emboj.7601828Crossref PubMed Scopus (257) Google Scholar). The TMD is conserved in overall structure throughout the potassium channel family (18Doyle D.A. Morais Cabral J. Pfuetzner R.A. Kuo A. Gulbis J.M. Cohen S.L. Chait B.T. MacKinnon R. The structure of the potassium channel: molecular basis of K+ conduction and selectivity.Science. 1998; 280 (9525859): 69-7710.1126/science.280.5360.69Crossref PubMed Scopus (5732) Google Scholar) and includes two membrane-spanning α-helices (the outer and inner helices, termed M1 and M2, respectively) (19Tao X. Avalos J.L. Chen J. MacKinnon R. Crystal structure of the eukaryotic strong inward-rectifier K+ channel Kir2.2 at 3.1 A resolution.Science. 2009; 326 (20019282): 1668-167410.1126/science.1180310Crossref PubMed Scopus (270) Google Scholar, 20Hansen S.B. Tao X. MacKinnon R. Structural basis of PIP2 activation of the classical inward rectifier K+ channel Kir2.2.Nature. 2011; 477 (21874019): 495-49810.1038/nature10370Crossref PubMed Scopus (436) Google Scholar), connected by an extracellular turret region, a short pore helix, and the ion selectivity filter. The selectivity filter (Fig. 1B, SF) at the outer end of the channel generates the narrowest part of the pore that contains four selective binding sites for K+ ions. Below the selectivity filter, the inner M2 helices line the “inner cavity” continuation of the pore. Below that, the cytoplasmic (Kir) domain, unique to Kir channels and consisting primarily of multiple β-sheets, lines a long extension of the pore (the cytoplasmic pore) below the transmembrane region through which permeant ions and blockers must pass (Fig. 1B). Although the cytoplasmic pore region is generally quite wide (Fig. 1B), and ions are likely to be fully hydrated within it, there is a narrowing at what is termed the “G-loop,” potentially an additional location of channel gating (21Pegan S. Arrabit C. Zhou W. Kwiatkowski W. Collins A. Slesinger P.A. Choe S. Cytoplasmic domain structures of Kir2.1 and Kir3.1 show sites for modulating gating and rectification.Nat. Neurosci. 2005; 8 (15723059): 279-28710.1038/nn1411Crossref PubMed Scopus (254) Google Scholar, 22Whorton M.R. MacKinnon R. Crystal structure of the mammalian GIRK2 K+ channel and gating regulation by G proteins, PIP2, and sodium.Cell. 2011; 147 (21962516): 199-20810.1016/j.cell.2011.07.046Abstract Full Text Full Text PDF PubMed Scopus (333) Google Scholar). transmembrane domain cyclic nucleotide-gated potassium reversal potential. We have a clear picture of the physically distinct processes that underlie voltage-dependent transitions of the depolarization-activated Kv, Na+, and Ca2+ channels. Following activation, current declines, a process referred to as “inactivation,” which involves blocking of the pore by a positively charged cytoplasmic “ball” domain that gains access to its binding site after the channel has opened (23Hoshi T. Zagotta W.N. Aldrich R.W. Biophysical and molecular mechanisms of Shaker potassium channel inactivation.Science. 1990; 250 (2122519): 533-53810.1126/science.2122519Crossref PubMed Scopus (1276) Google Scholar, 24Zhou M. Morais-Cabral J.H. Mann S. MacKinnon R. Potassium channel receptor site for the inactivation gate and quaternary amine inhibitors.Nature. 2001; 411 (11395760): 657-66110.1038/35079500Crossref PubMed Scopus (493) Google Scholar). Parallels between the voltage-dependent inactivation of Kv channels and rectification of Kir channels first led Armstrong (25Armstrong C.M. Inactivation of the potassium conductance and related phenomena caused by quaternary ammonium ion injection in squid axons.J. Gen. Physiol. 1969; 54 (5346528): 553-57510.1085/jgp.54.5.553Crossref PubMed Scopus (303) Google Scholar) to hypothesize that inward rectification might also arise from a fundamentally similar process, i.e. that inward rectification might result from a positively charged substance blocking the channel in a voltage-dependent manner, from the internal side of the membrane. Mg2+ and Na+ ions were subsequently shown to cause such effects in weak inward rectifier KATP channels (26Ciani S. Ribalet B. Ion permeation and rectification in ATP-sensitive channels from insulin-secreting cells (RINm5F): effects of K+, Na+ and Mg2+.J. Membr. Biol. 1988; 103 (2846847): 171-18010.1007/BF01870947Crossref PubMed Scopus (23) Google Scholar, 27Nichols C.G. Ho K. Hebert S. Mg2+-dependent inward rectification of ROMK1 potassium channels expressed in Xenopus oocytes.J. Physiol. 1994; 476 (8057249): 399-40910.1113/jphysiol.1994.sp020141Crossref PubMed Scopus (76) Google Scholar) and in cardiac inward rectifier channels (28Vandenberg C.A. Inward rectification of a potassium channel in cardiac ventricular cells depends on internal magnesium ions.Proc. Natl. Acad. Sci. U.S.A. 1987; 84 (2436236): 2560-256410.1073/pnas.84.8.2560Crossref PubMed Scopus (405) Google Scholar), but a seemingly intrinsic and much more steeply voltage-dependent process was clearly a dominant cause of strong inward rectification in IK1 and other strong inward rectifier channels (29Matsuda H. Saigusa A. Irisawa H. Ohmic conductance through the inwardly rectifying K channel and blocking by internal Mg2+.Nature. 1987; 325 (2433601): 156-15910.1038/325156a0Crossref PubMed Scopus (481) Google Scholar, 30Matsuda H. Matsuura H. Noma A. Triple-barrel structure of inwardly rectifying K+ channels revealed by Cs+ and Rb+ block in guinea-pig heart cells.J. Physiol. 1989; 413 (2600845): 139-15710.1113/jphysiol.1989.sp017646Crossref PubMed Scopus (59) Google Scholar31Oliva C. Cohen I.S. Pennefather P. The mechanism of rectification of iK1 in canine Purkinje myocytes.J. Gen. Physiol. 1990; 96 (1698915): 299-31810.1085/jgp.96.2.299Crossref PubMed Scopus (41) Google Scholar). The first members of the Kir channel subfamily were cloned in 1993, Kir1.1 (12Ho K. Nichols C.G. Lederer W.J. Lytton J. Vassilev P.M. Kanazirska M.V. Hebert S.C. Cloning and expression of an inwardly rectifying ATP-regulated potassium channel.Nature. 1993; 362 (7680431): 31-3810.1038/362031a0Crossref PubMed Scopus (833) Google Scholar) and Kir2.1 (32Kubo Y. Baldwin T.J. Jan Y.N. Jan L.Y. Primary structure and functional expression of a mouse inward rectifier potassium channel.Nature. 1993; 362 (7680768): 127-13310.1038/362127a0Crossref PubMed Scopus (937) Google Scholar). This was rapidly followed by cloning of multiple additional representatives of ultimately all seven Kir subfamilies (2Nichols C.G. Lopatin A.N. Inward rectifier potassium channels.Annu. Rev. Physiol. 1997; 59 (9074760): 171-19110.1146/annurev.physiol.59.1.171Crossref PubMed Scopus (660) Google Scholar). The availability of cloned Kir channels in the Kir2 subfamily (which encodes the classical cardiac inward rectifier (33Panama B.K. McLerie M. Lopatin A.N. Heterogeneity of IK1 in the mouse heart.Am. J. Physiol. Heart Circ. Physiol. 2007; 293 (17890431): H3558-H356710.1152/ajpheart.00419.2007Crossref PubMed Scopus (24) Google Scholar, 34Panama B.K. Lopatin A.N. Differential polyamine sensitivity in inwardly rectifying Kir2 potassium channels.J. Physiol. 2006; 571 (16373386): 287-30210.1113/jphysiol.2005.097741Crossref PubMed Scopus (31) Google Scholar)) permitted high-level expression in endogenous system, and facilitated the discovery of polyamines as the agents of strong inward rectification (35Lopatin A.N. Makhina E.N. Nichols C.G. Potassium channel block by cytoplasmic polyamines as the mechanism of intrinsic rectification.Nature. 1994; 372 (7969496): 366-36910.1038/372366a0Crossref PubMed Scopus (740) Google Scholar, 36Ficker E. Taglialatela M. Wible B.A. Henley C.M. Brown A.M. Spermine and spermidine as gating molecules for inward rectifier K+ channels.Science. 1994; 266 (7973666): 1068-107210.1126/science.7973666Crossref PubMed Scopus (469) Google Scholar37Fakler B. Brändle U. Bond C. Glowatzki E. König C. Adelman J.P. Zenner H.P. Ruppersberg J.P. A structural determinant of differential sensitivity of cloned inward rectifier K+ channels to intracellular spermine.FEBS Lett. 1994; 356 (7805837): 199-20310.1016/0014-5793(94)01258-XCrossref PubMed Scopus (130) Google Scholar). In macro-patch experiments on strong inward rectifier channels expressed in Xenopus oocytes, we first showed that rectification gradually disappears after patch excision into divalent ion-free solutions (35Lopatin A.N. Makhina E.N. Nichols C.G. Potassium channel block by cytoplasmic polyamines as the mechanism of intrinsic rectification.Nature. 1994; 372 (7969496): 366-36910.1038/372366a0Crossref PubMed Scopus (740) Google Scholar), as earlier reported in cardiac IK1 channels (38Matsuda H. Open-state substructure of inwardly rectifying potassium channels revealed by magnesium block in guinea-pig heart cells.J. Physiol. 1988; 397 (2457698): 237-25810.1113/jphysiol.1988.sp016998Crossref PubMed Scopus (179) Google Scholar). Strikingly, however, strong rectification was restored by placing excised membrane patches close to the surface of the oocyte, suggesting that soluble intrinsic factors released from the oocyte might be the cause of the rectification. Size- and charge-exclusion chromatography (35Lopatin A.N. Makhina E.N. Nichols C.G. Potassium channel block by cytoplasmic polyamines as the mechanism of intrinsic rectification.Nature. 1994; 372 (7969496): 366-36910.1038/372366a0Crossref PubMed Scopus (740) Google Scholar) indicated that the active agents were small polycationic organic amines, and HPLC confirmed that the naturally occurring polyamines (spermine, spermidine, and putrescine) are indeed released from the oocyte (35Lopatin A.N. Makhina E.N. Nichols C.G. Potassium channel block by cytoplasmic polyamines as the mechanism of intrinsic rectification.Nature. 1994; 372 (7969496): 366-36910.1038/372366a0Crossref PubMed Scopus (740) Google Scholar) (subsequently demonstrated to be through connexin hemi-channels (39Enkvetchakul D. Ebihara L. Nichols C.G. Polyamine flux in Xenopus oocytes through hemi-gap junctional channels.J. Physiol. 2003; 553 (12963797): 95-10010.1113/jphysiol.2003.047910Crossref PubMed Scopus (15) Google Scholar)). Critically, application of micromolar levels of these polyamines to inside-out membrane patches is sufficient to restore all the essential features of classical inward rectification (Fig. 2A) (35Lopatin A.N. Makhina E.N. Nichols C.G. Potassium channel block by cytoplasmic polyamines as the mechanism of intrinsic rectification.Nature. 1994; 372 (7969496): 366-36910.1038/372366a0Crossref PubMed Scopus (740) Google Scholar, 36Ficker E. Taglialatela M. Wible B.A. Henley C.M. Brown A.M. Spermine and spermidine as gating molecules for inward rectifier K+ channels.Science. 1994; 266 (7973666): 1068-107210.1126/science.7973666Crossref PubMed Scopus (469) Google Scholar, 40Lopatin A.N. Makhina E.N. Nichols C.G. The mechanism of inward rectification of potassium channels: “long-pore plugging” by cytoplasmic polyamines.J. Gen. Physiol. 1995; 106 (8648298): 923-95510.1085/jgp.106.5.923Crossref PubMed Scopus (190) Google Scholar, 41Fakler B. Brändle U. Glowatzki E. Weidemann S. Zenner H.P. Ruppersberg J.P. Strong voltage-dependent inward rectification of inward rectifier K+ channels is caused by intracellular spermine.Cell. 1995; 80 (7813010): 149-15410.1016/0092-8674(95)90459-XAbstract Full Text PDF PubMed Scopus (315) Google Scholar). The voltage dependence of the spermine and spermidine block is markedly steeper than Mg2+ block (35Lopatin A.N. Makhina E.N. Nichols C.G. 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Heterooligomeric assembly of inward-rectifier K+ channels from subunits of different subfamilies: Kir2.1 (IRK1) and Kir4.1 (BIR10).Pflugers Arch. 1996; 433 (9019734): 77-8310.1007/s004240050251Crossref PubMed Scopus (39) Google Scholar, 47Kucheryavykh Y.V. Pearson W.L. Kurata H.T. Eaton M.J. Skatchkov S.N. Nichols C.G. Polyamine permeation and rectification of Kir4.1 channels.Channels. 2007; 1 (18690029): 172-17810.4161/chan.4389Crossref PubMed Scopus (19) Google Scholar) subfamily members that exhibit strong rectification physiologically. Members of the Kir1 and Kir6 subfamilies exhibit only shallow inward rectification, shown to be a consequence of only weakly voltage-dependent and low potency (millimolar sensitivity) block by Mg2+ and polyamines (27Nichols C.G. Ho K. Hebert S. Mg2+-dependent inward rectification of ROMK1 potassium channels expressed in Xenopus oocytes.J. 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The steepness of the voltage dependence of polyamine block increases roughly in direct equivalence to the charge on the polyamine itself, from +2 (putrescine2+) to +3 (spermidine3+) to +4 (spermine4+) (35Lopatin A.N. Makhina E.N. Nichols C.G. Potassium channel block by cytoplasmic polyamines as the mechanism of intrinsic rectification.Nature. 1994; 372 (7969496): 366-36910.1038/372366a0Crossref PubMed Scopus (740) Google Scholar, 36Ficker E. Taglialatela M. Wible B.A. Henley C.M. Brown A.M. Spermine and spermidine as gating molecules for inward rectifier K+ channels.Science. 1994; 266 (7973666): 1068-107210.1126/science.7973666Crossref PubMed Scopus (469) Google Scholar), although it can be even higher. External potassium ions relieve polyamine-dependent rectification by increasing the apparent polyamine off-rate (43Lopatin A.N. Nichols C.G. [K+] dependence of polyamine-induced rectification in inward rectifier potassium channels (IRK1, Kir2.1).J. Gen. Physiol. 1996; 108 (8854340): 105-11310.1085/jgp.108.2.105Crossref PubMed Scopus (78) Google Scholar), as expected for a channel blocker that interacts with permeant ions within the pore. As a linear molecule, spermine is very long (almost 20 Å long), compared with a K+ ion, but of similar diameter (∼3 Å). It was an obvious possibility that, in blocking Kir channels, spermine lies along the pore axis, binding at multiple sites that would otherwise be occupied by K+ ions. Our original conception was that the polyamine would enter deeply into the pore, entering what we now recognize as the selectivity filter, which is otherwise occupied by two or more K+ ions (18Doyle D.A. Morais Cabral J. Pfuetzner R.A. Kuo A. Gulbis J.M. Cohen S.L. Chait B.T. MacKinnon R. The structure of the potassium channel: molecular basis of K+ conduction and selectivity.Science. 1998; 280 (9525859): 69-7710.1126/science.280.5360.69Crossref PubMed Scopus (5732) Google Scholar, 50Zhou Y. Morais-Cabral J.H. Kaufman A. MacKinnon R. Chemistry of ion coordination and hydration revealed by a K+ channel-Fab complex at 2.0 A resolution.Nature. 2001; 414 (11689936): 43-4810.1038/35102009Crossref PubMed Scopus (1731) Google Scholar), thereby achieving the necessary voltage dependence by moving essentially all four spermine charges through the electric field–what we termed “long-pore plugging” (Fig. 2B). Close inspection revealed that spermine block of Kir2 subfamily channels also includes a shallow voltage-dependent component at more negative voltages (Fig. 2A), which suggested a second blocking component, perhaps within the cytoplasmic pore (Fig. 2B) (40Lopatin A.N. Makhina E.N. Nichols C.G. The mechanism of inward rectification of potassium channels: “long-pore plugging” by cytoplasmic polyamines.J. Gen. Physiol. 1995; 106 (8648298): 923-95510.1085/jgp.106.5.923Crossref PubMed Scopus (190) Google Scholar, 51Yang J. Jan Y.N. Jan L.Y. Control of rectification and permeation by residues in two distinct domains in an inward rectifier K+ channel.Neuron. 1995; 14 (7748552): 1047-105410.1016/0896-6273(95)90343-7Abstract Full Text PDF PubMed Scopus (272) Google Scholar). We originally proposed two concentration-dependent binding reactions (i.e. two polyamines independently entering the channel pore), and a voltage-dependent transition deep within the electric field to account for the steep voltage-dependent component of spermine-induced rectification (40Lopatin A.N. Makhina E.N. Nichols C.G. The mechanism of inward rectification of potassium channels: “long-pore plugging” by cytoplasmic polyamines.J. Gen. Physiol. 1995; 106 (8648298): 923-95510.1085/jgp.106.5.923Crossref PubMed Scopus (190) Google Scholar). In this earliest conception, based on the original pore-blocking model of Woodhull (52Woodhull A.M. Ionic blockage of sodium channels in nerve.J. Gen. Physiol. 1973; 61 (4541078): 687-70810.1085/jgp.61.6.687Crossref PubMed Scopus (1232) Google Scholar), the voltage-dependent block results from the movement of the charged blocker itself into the electric field; interactions of the blocking particle with permeant ions are ignored. If the channel was blocked by only one spermine molecule, but the entering spermine molecule had to sweep out permeant ions to reach its binding site, excess charge movement could result, as first pointed out by Ruppersberg et al. (53Ruppersberg P.J. Kitzing E.V. Schoepfer R. The mechanism of magnesium block of NMDA receptors.Neurosciences. 1994; 6: 87-9610.1006/smns.1994.1012Google Scholar), and hence the voltage dependence of the block at a selectivity filter site could be underestimated. The Kir channel permeation pathway has now been elucidated in exquisite detail (Fig. 1B), and many mutations that affect polyamine blocking have been identified (Fig. 1A). Aspartate 172, located in the M2 region of Kir2.1, was the first residue implicated in the classical inward rectification of these channels. Subsequent mutational analyses showed that this" @default.
• W2896257816 created "2018-10-26" @default.
• W2896257816 creator A5012403281 @default.
• W2896257816 creator A5088002796 @default.
• W2896257816 date "2018-11-01" @default.
• W2896257816 modified "2023-09-27" @default.
• W2896257816 title "Polyamines and potassium channels: A 25-year romance" @default.
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