Polyamines and potassium channels: A 25-year romance
2018; Elsevier BV; Volume: 293; Issue: 48 Linguagem: Inglês
10.1074/jbc.tm118.003344
ISSN1083-351X
AutoresColin G. Nichols, Sun‐Joo Lee,
Tópico(s)Neurotransmitter Receptor Influence on Behavior
ResumoPotassium 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 (670) Google Scholar). The functional role of Kir channels depends critically on the degree of inward rectification that they exhibit. 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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 (670) Google Scholar, 13Baronas V.A. Kurata H.T. Inward rectifiers and their regulation by endogenous polyamines.Front. Physiol. 2014; 5 (25221519): 325Crossref PubMed Scopus (50) 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 (162) Google Scholar). 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Cloning and expression of an inwardly rectifying ATP-regulated potassium channel.Nature. 1993; 362 (7680431): 31-3810.1038/362031a0Crossref PubMed Scopus (853) 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 (948) 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 (670) 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. 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Physiol. 1996; 108 (8854340): 105-11310.1085/jgp.108.2.105Crossref PubMed Scopus (81) 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 (5848) 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 (1761) 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 (194) Google Scholar, 51Yang J. Jan Y.N. Jan L.Y. 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Physiol. 1973; 61 (4541078): 687-70810.1085/jgp.61.6.687Crossref PubMed Scopus (1251) 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
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