This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nichols, C.G. Articles by Lopatin, A.N. Search for Related Content PubMed PubMed Citation Articles by Nichols, C.G. Articles by Lopatin, A.N.

(Circulation Research. 1996;78:1-7.)
© 1996 American Heart Association, Inc.

Articles

Inward Rectification and Implications for Cardiac Excitability

C.G. Nichols, E.N. Makhina, W.L. Pearson, Q. Sha, A.N. Lopatin

From the Department of Cell Biology and Physiology, Washington University School of Medicine, St Louis, Mo.

	Abstract

Top Abstract Functional Diversity of... Structural Diversity of... Mechanisms of Inward... Modeling Polyamine Action: `Long... Structural Requirements for... Implications for Cardiac... Conclusions References

 
Abstract Since the cloning of the first inwardly rectifying K⁺ channel in 1993, a family of related clones has been isolated, with many members being expressed in the heart. Exogenous expression of different clones has demonstrated that between them they encode channels with the essential functional properties of classic inward rectifier channels, ATP-sensitive K⁺ channels, and muscarinic receptor–activated inward rectifier channels. High-level expression of cloned channels has led to the discovery that classic strong inward, or anomalous, rectification is caused by very steeply voltage-dependent block of the channel by polyamines, with an additional contribution by Mg²⁺ ions. Knowledge of the primary structures of inward rectifying channels and the ability to mutate them have led to the determination of many of the structural requirements of inward rectification. The implications of these advances for basic understanding and pharmacological manipulation of cardiac excitability may be significant. For example, cellular concentrations of polyamines are altered under different conditions and can be manipulated pharmacologically. Simulations predict that changes in polyamine concentrations or changes in the relative proportions of each polyamine species could have profound effects on cardiac excitability.

Key Words: K⁺ channels • inward rectifier channels • polyamines • spermine-spermidine-putrescine cloning • mutation

	Functional Diversity of K+ Channels: The Role of Inward Rectification

Top Abstract Functional Diversity of... Structural Diversity of... Mechanisms of Inward... Modeling Polyamine Action: `Long... Structural Requirements for... Implications for Cardiac... Conclusions References

 
Many different K⁺ channels are involved in cardiac electrical activity.^{1 2} Various Kv channels determine the shape of the action potential. In addition to Kv channels, cardiac cells also contain K⁺ channels (Kir channels) that are open at very negative potentials but show a reduced conductance at positive membrane potentials. This phenomenon, termed inward rectification, has also been termed anomalous rectification (Fig 1A), because it is opposite the "normal" outward rectification that is seen in delayed rectifier K⁺ channels. Work over the past 30 years has described three main types of Kir channel currents in cardiac tissue: (1) I_K1, the classic inward rectifier current (I_K1 is present in atrial and ventricular myocytes and shows "strong" inward rectification; essentially no current flows through these channels at potentials positive to -40 mV),³ (2) I_K,ATP, the ATP-sensitive K⁺ current (the K_ATP channel, which is found in ventricular, atrial, and nodal cells, displays "weak" rectification, allowing substantial outward current to flow at positive potentials),⁴ and (3) I_K,ACh, the muscarinic receptor–activated K⁺ channel (I_K,ACh is a strong inward rectifier found predominantly in atrial tissue).⁵ This channel is opened by G-protein activation subsequent to muscarinic receptor activation and underlies the vagal slowing of the heart rate. The degree of rectification exhibited by Kir channels is fundamental to their respective roles. For example, because the K_ATP channel rectification is weak, K_ATP channel activation causes marked shortening of the action potential, reducing voltage-dependent Ca²⁺ entry and hence conserving ATP in conditions of metabolic stress.⁴ The strong inward rectification of I_K1 on the other hand, means that very little current flows through this channel during the action potential, even though it is the dominant conductance at the resting potential.³ Thus, although I_K1 is essential for maintaining a stable resting potential, it may play a lesser role in determining action potential shape.

View larger version (22K): [in this window] [in a new window]   Figure 1. A, Idealized current-voltage relation of strong and weak Kir channels. Both conduct significantly at diastolic potentials, but strong inward rectifiers pass little or no current at action potential plateau potentials. B, Schematic diagram of proposed pore-blocking mechanisms causing inward rectification. Blocking ions enter the pore from the inside, and binding can be relieved by K+ ions entering the pore from the outside. Although the effective valence (Z) of Mg2+ block is consistent with one Mg2+ ion permeating 50% of the voltage field, polyamines may enter more deeply; experimental data suggest that more than one polyamine molecule actually enters the field, giving a Z value of >4 as the block approaches saturation (*). C, Schematic diagram of polyamine structure and outline of synthetic pathway in animal cells. Amines are shown in white; methyl groups are shown in black. All amines are charged at neutral pH.

In the past 3 years, a large number of cDNAs encoding pore-forming subunits of Kir channels have been cloned and have led to great strides in our understanding of the mechanisms and structural requirements of inward rectification. The purpose of this article is to summarize recent progress with cloned Kir channels in understanding the fundamental mechanisms and structural features responsible for inward rectification and to consider potential implications of these findings for understanding cardiac physiology, pharmacology, and pathology. It is not possible to comprehensively reference all the work pertaining to this subject in this space. For more complete recent reviews on I_K1 channels and their role in cardiac excitability, the reader is referred to References 1 through 6.

	Structural Diversity of K+ Channels: The New Inward Rectifier Family

Top Abstract Functional Diversity of... Structural Diversity of... Mechanisms of Inward... Modeling Polyamine Action: `Long... Structural Requirements for... Implications for Cardiac... Conclusions References

 
A large number of cardiac Kv channels have now been cloned and expressed in exogenous cells.² The proposed transmembrane topology of Kv channel subunits consists of cytoplasmic N and C termini, six transmembrane domains, and a conserved hydrophobic P or H5 loop between the fifth and sixth transmembrane domains. Four subunits are believed to be required to form a functional channel, and activation (channel opening) is steeply dependent on membrane depolarization. In 1993, members of a new K⁺ channel family (Kir1.1* [ROMK1], Kir2.1 [IRK1], and Kir3.1 [GIRK1]) were cloned. When expressed in Xenopus oocytes, these channels encode Kir channels.^{8 9 10} Like Kv channels,¹¹ these Kir channels are assumed to form as homotetramers or heterotetramers. Unlike Kv channels, however, they are proposed to have only two transmembrane domains within each subunit^{8 9} (Fig 2B), although they retain the H5 loop that is responsible for K⁺ selectivity in Kv channels.¹² Kir1.1⁸ encodes a weak inward rectifier, whereas Kir2.1⁹ and related channels (Fig 2A) encode strong inward rectifiers. Kir3.1^{10 13} and related channels¹⁴ are G protein–activated strong inward rectifiers and may underlie I_K,ACh in the heart.

View larger version (21K): [in this window] [in a new window]   Figure 2. A, Phylogenetic tree of the Kir channel family. Unbalanced branch cladogram generated by MEGALIGN software (DNAStar Inc). The scale indicates residue substitutions from ancestral channel. Members of the same subfamily (eg, Kir3.1 to 3.4) are 50% to 70% identical; members of different subfamilies (eg, Kir2.1 and Kir1.1) are 40% identical. Clones reported from heart are highlighted in bold. B, Schematic diagram of the proposed topology of Kir channels, and the approximate positions of negative-charged residues that have been shown to be involved in high affinity Mg2+ and polyamine block.

Fig 2A illustrates the phylogeny of the Kir channel family. All three members of the Kir2 subfamily are expressed in the heart and are likely to encode I_K1 channels,^{15 16 17 18} primarily because the time- and voltage-dependent rectification of the expressed channels is virtually indistinguishable from native i_K1 channels.^{19 20} Defining the molecular components of the K_ACh and K_ATP channels has been less straightforward. When Kir1.1 (ROMK1) was cloned,⁸ the rectification properties were similar to those of endogenous K_ATP channels. It seemed likely that related clones from the heart would encode the cardiac K_ATP channel. However, no closely related clone has been obtained from cardiac sources, and the homomeric channel does not show appropriate ATP sensitivity.⁸ When Kir3.1 (GIRK1/KGA) was cloned, it was shown to encode a G protein–activated inward rectifier, with the necessary properties to underlie I_K,ACh.^{9 13} Related clones (Kir3.2 and Kir3.3) were isolated from brain tissue,¹⁴ although these have not been reported in cardiac tissue. Ashford et al²¹ cloned a cDNA (rcKATP in Reference 21) from cardiac tissue that also reportedly encoded a K_ATP channel. This cDNA is a member of the Kir3 family (Kir3.4), and Krapivinsky et al²² have recently provided compelling evidence that Kir3.4 subunits coassemble with Kir3.1 (GIRK1) to form the cardiac muscarinic receptor–activated I_K,ACh and that they do not form K_ATP channels in monomeric expression. Another three subfamilies of Kir channels have been discovered, two of them in brain (Kir4 and Kir5²³ ) and one in heart and other tissues. The first member of this last class²⁴ is also proposed to encode a K_ATP channel (uKATP1 in Reference 24), but expression data are currently very limited. According to the unified nomenclature, this channel should be classed Kir6.1. Thus, there is now strong evidence for the molecular components of I_K1 and I_K,ACh, although the molecular components of I_K,ATP are not conclusively demonstrated at the time of the writing of the present article (July 1995).

Parenthetically, it should be noted that Kv channels also show weak inward rectification caused primarily by Mg²⁺ or Na⁺ block.²⁵ A recently cloned Kv channel shows a relatively high degree of inward rectification.^{26 27} This channel (HERG) is likely to be a constituent of the human delayed rectifier (I_Kr), and mutations in this gene are probably responsible for certain inherited forms of long QT syndrome. HERG may rectify by mechanisms similar to those described below for Kir channels, although at the time of the writing of this article, no mechanistic information is available.

	Mechanisms of Inward Rectification: New Insights From Cloned Kir Channels

Top Abstract Functional Diversity of... Structural Diversity of... Mechanisms of Inward... Modeling Polyamine Action: `Long... Structural Requirements for... Implications for Cardiac... Conclusions References

 
On the basis of experiments examining the channel pore-blocking actions of tertiary ammonium derivatives, Armstrong²⁸ proposed that inward rectification might result from a positively charged substance at the internal side of the membrane blocking the pore in a voltage-dependent manner. Subsequent work on native channels demonstrated that in some cases at least, this hypothesis is essentially correct. Inward rectification of weak Kir channels (eg, K_ATP) is due to block by internal cations, particularly Mg²⁺.²⁹ Binding of a single Mg²⁺ ion that occludes the channel pore can explain the observed rectification. It has also been demonstrated that intracellular Mg²⁺ can cause inward rectification in strong Kir channels, such as I_K1.^{30 31 32} Mg²⁺ block of I_K1 actually reveals two subconductance levels in addition to the fully open channel,³³ and this has been taken as evidence for a triple-pore arrangement. Such behavior has not been reported for cloned Kir channels.

In addition to block by cytoplasmic Mg²⁺ ions, an apparently intrinsic voltage dependence of the open probability also causes inward rectification in I_K1 and other strong Kir channel currents.^{30 31 32} Both Mg²⁺-dependent and intrinsic rectification depend strongly on [K⁺]_o; increasing [K⁺]_o increases the apparent K_m for Mg²⁺ binding, the so-called knockoff effect that is qualitatively explained by K⁺ ion binding at external sites interacting with Mg²⁺ binding sites deeper inside a multi-ion pore.²⁹ Intrinsic rectification has been modeled by assuming an activation "gate" with first-order kinetics, wherein the opening and closing rates are also dependent on [K⁺]_o, but the physical basis for such empirical descriptions remained unexplained.

A major impetus for cloning the constituent components of Kir channels was the opportunity to explore in detail the mechanistic and structural basis of inward rectification. The depolarization-induced opening of Kv channels involves interaction of the positively charged S4 domain with the membrane field. Such a mechanism for hyperpolarization-induced opening (intrinsic gating) of Kir channels could be excluded, since there was no similarly charged yet predominantly hydrophobic structure in cloned Kir channels.^{8 9 10} In patch-clamp experiments with cloned Kir2 channels, we confirmed the earlier observation of Matsuda,³³ who reported that intrinsic gating of I_K1 disappears after patch excision. Moreover, rectification of Kir2.3 channels was subsequently fully restored by placing excised membrane patches within 100 µm of the surface of Xenopus oocytes or other cells.³⁴ This experiment provided direct evidence that intrinsic rectification involves soluble intrinsic rectifying factors. Biochemical purification revealed that intrinsic rectifying factors are low molecular weight (<700) compounds containing positively charged amine groups,³⁴ suggesting that intrinsic rectifying factors might correspond to one or more of the polyamines in the metabolic pathway from ornithine to spermine.³⁴ High-performance liquid chromatographic analysis of active fractions confirmed that the naturally occurring polyamines (spermine, spermidine, and putrescine, Fig 1C) were indeed present. Application of these polyamines to inside-out patches containing Kir2 channels restores all the essential features of intrinsic rectification.^{34 35 36 37} When applied to inside-out membrane patches, micromolar spermine and spermidine cause steeply voltage-dependent reversible rectification of Kir2 channels, with less dramatic effects of putrescine and cadaverine. Spermine and spermidine are respectively 100-fold and 10-fold more potent blockers of Kir2 channels than is putrescine or Mg²⁺. Spermine and spermidine block are also considerably steeper than Mg²⁺ block,^{34 35 36 37} explaining how inward rectification in endogenous strong inward rectifiers is steeper than that predicted by Mg²⁺ block alone. The voltage dependence of spermine and spermidine unblock matches the time constants of channel activation in cell-attached patches.³⁶ Polyamines are present in almost all known cells, are reported to be essential for normal and neoplastic cell growth, and may have a role as stabilizing moieties for DNA.³⁸ Nanomolar to micromolar concentrations of free polyamines would be required to reproduce the degree of rectification seen in native cells, and induction of inward rectification may be the most potent property of cytoplasmic polyamines. Total cellular concentrations of these polyamines (10 to 10 000 µmol/L³⁸ ) are clearly sufficient to cause very strong rectification, although free cytoplasmic concentrations are not measurable with certainty.

Kir1.1 (ROMK1) and delayed rectifier Kv2.1 (DRK1) channels both show only weak inward rectification. Whereas Kir2 channels have high sensitivity to both Mg²⁺ and polyamines, Kir1.1 and Kv2.1 channels both have shallowly voltage-dependent millimolar sensitivity to block by Mg²⁺ and polyamines.^{34 35 39 40 41} Thus, high polyamine sensitivity is seen only with strong Kir channels and parallels sensitivity to block by Mg²⁺. Mutational analyses (see below) further suggest that Mg²⁺ and polyamines may in fact share the same binding sites within Kir channels. Although no direct proof is yet available that polyamines cause intrinsic rectification in native I_K1, Yamada and Kurachi⁴² have recently demonstrated that polyamines can induce the strong inward rectification observed in cardiac I_K,ACh, and it is likely that polyamine block will be a universal mechanism of strong inward rectification.

	Modeling Polyamine Action: `Long-Pore Plugging' of the Kir Channel

Top Abstract Functional Diversity of... Structural Diversity of... Mechanisms of Inward... Modeling Polyamine Action: `Long... Structural Requirements for... Implications for Cardiac... Conclusions References

 
Although the evidence for polyamine induction of inward rectification is now substantial,^{34 35 36 37 41 42 43} the details of the mechanism are still incomplete. Given that Mg²⁺ and other metal cation blockers are effectively spherical charge sources, with diameters similar to those of the permeant ion, it is intuitively easy to see how such ions could occupy permeant ion binding sites within the pore and block the channel by virtue of long residence times in the binding sites. The spermine molecule is almost 20 Å long, with a very different shape than K⁺ ions (Fig 1C), but the evidence is solidifying that the polyamines also act as pore-blocking particles (Fig 1B). The steepness of the voltage dependence of channel block by polyamines increases as the charge on the polyamine increases.^{34 35} Mutations that alter Mg²⁺ block sensitivity also affect polyamine blocking affinity.^{41 43} External K⁺ ions can substantially relieve polyamine block, apparently by increasing the polyamine off rate (authors' unpublished data, 1995), as expected for a channel blocker that interacts with permeant ions within the pore. On the basis of the structure of spermine and spermidine (Fig 1C), we have suggested that the long pore of the Kir channel is plugged by polyamines entering deeply and linearly into the membrane field within the channel pore.³⁶ The simplest kinetic scheme that accounts for the available experimental data requires two concentration-dependent binding reactions (ie, two polyamines independently entering the channel pore) and a voltage-dependent transition deep within the voltage field (that may reflect repulsion between the two polyamines). Such a model³⁶ takes into account the linear structure of the natural polyamines and electrostatic repulsion between two molecules inside the pore. Yang et al⁴³ have examined steady state polyamine block of Kir2.1 channels over a wide concentration range. Their data also suggest that at least two polyamines bind within the channel with different affinities, in broad agreement with the above predictions.

	Structural Requirements for Inward Rectification

Top Abstract Functional Diversity of... Structural Diversity of... Mechanisms of Inward... Modeling Polyamine Action: `Long... Structural Requirements for... Implications for Cardiac... Conclusions References

 
For members of the Kv channel family, the H5 or P loop appears to line the channel pore and determines the pore properties of these channels. For example, it has been demonstrated that external and internal tetraethylammonium blocking sites, as well as single-channel conductance and selectivity, are primarily determined by the H5 sequences.^{12 44} However, an additional role of the S6 region and the presumed cytoplasmic region beyond S6 in determining internal tetraethylammonium and Mg²⁺ sensitivity of Kv channels has also been reported.⁴⁵ The availability of both weak and strong Kir clones provided the opportunity to define the structural requirements of inward rectification. The presence of a conserved H5 region (containing the signature K⁺ channel sequence [-GYG-]) placed these channels in the same K⁺ channel superfamily as Kv channels. It initially seemed likely that Mg²⁺ binding sites in Kir channels would reside in the conserved H5 region, but to date there have been no reports of altered pore properties from mutations within this region. Stanfield et al⁴⁶ have demonstrated that a glutamate residue in the second transmembrane domain (M2, corresponding to S6 in Kv channels) of Kir2.1 (IRK1) is at least partially responsible for Mg²⁺ binding. The equivalent residue is neutral in Kir1.1 (Kir1.1-expressed currents exhibit much shallower rectification and Mg²⁺ blocking affinity^{39 40} ), and neutralization of this residue in Kir2.1 reduced Mg²⁺ block and rectification. In addition to Mg²⁺ block, subsequent mutational analyses have shown that this residue also partially determines polyamine blocking affinity.^{34 41 43 47} Neutralization of this residue in the strong inward rectifier Kir4.1 (BIR10) causes a reduction in Mg²⁺ and spermine block affinity of five orders of magnitude.⁴¹

Using chimeras between weakly rectifying Kir1.1 (ROMK1) and strongly rectifying Kir2.1 (IRK1), Taglialatela et al⁴⁸ reported experiments pointing to the C-terminal region beyond M2 as containing the necessary structural elements for high-affinity Mg²⁺ block. This region contains many negative charges and conserved stretches of significant hydrophobicity and could form part of the inner lining of the pore and contribute to binding of polyamines and Mg²⁺. Recently Yang et al⁴³ reported that E224 (in the C-terminal region of Kir2.1) is a major determinant of high Mg²⁺ and polyamine sensitivity and that dual neutralization of the negative charges in M2 (D172N) and in the C-terminal region (E224G) reduced polyamine and Mg²⁺ sensitivity almost to the level of Kir1.1 (ROMK1). At this juncture, it seems a reasonable hypothesis that D172 and E224 (in Kir2.1) contribute to the formation of at least two separate polyamine binding sites that correlate with binding sites predicted in modeling studies.³⁶

	Implications for Cardiac Cellular Electrical Activity

Top Abstract Functional Diversity of... Structural Diversity of... Mechanisms of Inward... Modeling Polyamine Action: `Long... Structural Requirements for... Implications for Cardiac... Conclusions References

 
The implications of polyamine-induced rectification for cardiac excitability and potential therapeutic directions may be significant. As a general concept, increasing levels of polyamines will increase the degree of inward rectification and hence increase excitability. At the present time, there have been no reports examining polyamine-induced inward rectification in cardiac cells, although the next couple of years are likely to see much effort in this direction. As a preliminary to such studies, we have simulated the consequences of alterations of polyamine levels in a model of the cardiac action potential (Fig 3). The formulation of I_K1 in the OXSOFT heart programs¹ (OXSOFT Heart Computer Manual, version 4.4, Oxsoft Ltd) is of an instantaneous rectification described by a simple Boltzmann function. This formulation does not reproduce the time dependence that is observed in reality, and only general conclusions can be drawn. Changes in the half-activation voltage of rectification (eg, a leftward shift simulating the effects of increased polyamine levels) cause small deviations of the late repolarization trajectory. Changes in the steepness of rectification (eg, increases from Z=1.1 to 3.1, simulating shifts in polyamine pools from low- to high-valence species) cause effects on the plateau and on repolarization. Rather striking effects on simulated Purkinje fiber firing rate are observed for similar changes in steepness: Increasing the effective valence from 2 to 3 increases the firing rate from 30/min to 70/min (Fig 3C). Purkinje fiber activity might therefore underlie ventricular arrhythmias in conditions of elevated polyamine concentrations. Cardiac hypertrophy is associated with both enhanced cellular excitability and elevated polyamine levels.^{49 50}

View larger version (17K): [in this window] [in a new window]   Figure 3. Simulations of cardiac action potentials with different IK1 properties. A, Guinea pig ventricular action potentials computed with shifts in the rectification midpoint from an equilibrium potential (Ek) of +31 mV to simulate increased (left shift) or decreased (right shift) polyamine concentrations. V1/2 indicates half-activation voltage. B, Guinea pig ventricular action potentials computed with changes in the steepness of rectification (from an effective valence [Z] of 2.1) to simulate shifts in the relative pools of polyamines, either increasing (higher Z) or decreasing (lower Z) the relative proportion of higher valence polyamines. C, Spontaneous electrical activity of Purkinje fibers computed with normal steepness of rectification (Z=2) and with increased steepness (Z=3), simulating an increase in the relative proportion of higher valence polyamines. All simulations were made with the OXSOFT heart program, varying only the stated parameters, without changing the published formulations.

Many antiarrhythmic strategies revolve around increasing or decreasing K⁺ channel conductance. In the former category, the selective activation of K_ATP channels using the broad class of drugs referred to as K⁺ channel openers originally promised to be a very effective means of stabilizing the resting potential as well as shortening the action potential and minimizing ATP consumption during ischemia. Such channel openers work by effectively antagonizing the voltage-independent gating action of ATP and thus activate these channels over the whole physiological voltage range.⁷ Under certain experimental conditions, these drugs provide an effective ischemic protectant and do reduce some types of arrhythmias.⁵¹ However, because of their marked action potential shortening effects, these drugs may be proarrhythmic by shortening the refractory period in ventricular muscle. The ideal ventricular antiarrhythmic agent might be a drug that opens K⁺ channels at the resting potential but not at the peak of the action potential, ie, one that stabilizes the resting potential without shortening action potential duration. We may now speculate that any drug that can lower the cytoplasmic polyamine concentration should have such an action. Lowering the polyamine concentration would cause a voltage-dependent increase in K⁺ conductance, with maximal effects around the resting potential. Conversely, agents that raise the polyamine concentration will reduce the I_K1 conductance and in turn prolong the action potential duration (Fig 3), an effect similar to that obtained by blocking I_Kr by class III antiarrhythmic drugs.⁵² Since polyamine levels are generally tightly regulated and appear to be essential for normal growth, it may be a long shot to attempt to manipulate polyamine levels in order to regulate excitability. However, polyamine levels inside cells do change and can be altered pharmacologically by using analogue inhibitors of the synthetic enzymes (ornithine decarboxylase [ODC] and S-adenosyl methionine decarboxylase [SAMDC], Fig 1C).³⁸ Perhaps one of the most promising analogues to consider is methylglyoxal bis-(guanylhydrazone) (MGBG), which blocks SAMDC, leading to a shift in the polyamine pool from spermine and spermidine to putrescine. More potent, or tissue targeted, derivatives of such compounds might, by an effect similar to that shown in Fig 3 (ie, reduction in effective charge of the polyamine pool), prove antiarrhythmic.

	Conclusions

Top Abstract Functional Diversity of... Structural Diversity of... Mechanisms of Inward... Modeling Polyamine Action: `Long... Structural Requirements for... Implications for Cardiac... Conclusions References

 
The last 3 years have been remarkably productive in advancing our understanding of the structural and mechanistic basis of inward rectification. The results suggest that polyamines, with an additional contribution by Mg²⁺ ions, cause classic strong inward, or anomalous, rectification by a steeply voltage-dependent plugging of the channel pore and that relief of this plugging at negative voltages is the "activation" process in strong Kir channels. Cellular concentrations of polyamines, and hence the degree of rectification of K⁺ channels, can be regulated, thus providing cardiac cells with a novel means of modulating their own excitability and providing a potential window of opportunity for the design of novel pharmaceutical agents to manipulate excitability through the cardiac inward rectifier.

	Selected Abbreviations and Acronyms

 

IK,ACh = acetylcholine-sensitive K+ current IK,ATP = ATP-sensitive K+ current IK1 = inward rectifier K+ current IKr = rapidly activating component of delayed rectifier K+ current KATP channel = ATP-sensitive K+ channel Kir channel = inward rectifier K+ channel Kv channel = depolarization-activated K+ channel

	Acknowledgments

 
Our own experimental work has been supported by the National Institutes of Health (grants HL-45742 and HL-54171 to Dr Nichols), the American Heart Association (Missouri Affiliate fellowship to Dr Lopatin, Established Investigatorship to Dr Nichols), the Juvenile Diabetes Foundation (grant-in-aid to Dr Nichols), the McDonnell Foundation (fellowship to Dr Makhina), and a Cardiovascular Training Grant in Molecular Biology and Pharmacology at Washington University (fellowship to Dr Pearson). We are grateful to Dianne Barry for a critical reading of the manuscript and for providing us with a prepublication copy of her article.

	Footnotes

 
Reprint requests to Dr Colin G. Nichols, Department of Cell Biology and Physiology, Washington University School of Medicine, 660 S Euclid Ave, St Louis, MO 63110. E-mail cnichols@cellbio.wustl.edu.

¹ Chandy and Gutman⁷ have suggested a unifying nomenclature for cloned members of this K⁺ channel family that we will use throughout this review. Where it may ease the transition to this common usage, we will include original names in brackets.

Received August 2, 1995; accepted September 19, 1995.

	References

Top Abstract Functional Diversity of... Structural Diversity of... Mechanisms of Inward... Modeling Polyamine Action: `Long... Structural Requirements for... Implications for Cardiac... Conclusions References

 
1. Noble D. Ionic mechanisms in cardiac electrical activity. In: Zipes DP, Jalife J, eds. Cardiovascular Electrophysiology. Philadelphia, Pa: WB Saunders Co; 1995:chap 29.

2. Barry DM, Nerbonne JM. Myocardial potassium channels: electrophysiological and molecular diversity. Annu Rev Physiol. 1995. In press.

3. Vandenberg CA. Cardiac inward rectifier potassium channel. In: Spooner PM, Brown AM, eds. Ion Channels in the Cardiovascular System. New York, NY: Futura Publishing Co; 1995:chap 8.

4. Nichols CG, Lederer WJ. ATP-sensitive potassium channels in the cardiovascular system. Am J Physiol. 1991;261:H1675-H1686. [Abstract/Free Full Text]

5. Kurachi Y, Tung RT, Ito H, Nakajima T. G protein activation of cardiac muscarinic K⁺ channels. Prog Neurobiol.. 1992;39:229-246. [Medline] [Order article via Infotrieve]

6. Matsuda H. Magnesium gating of the inwardly rectifying K⁺ channel. Annu Rev Physiol. 1991;53:289-298. [Medline] [Order article via Infotrieve]

7. Chandy KG, Gutman GA. Nomenclature for mammalian potassium channel genes. Trends Pharmacol Sci. 1993;14:434. [Medline] [Order article via Infotrieve]

8. Ho K, Nichols CG, Lederer WJ, Lytton J, Vassilev PM, Kanazirska MV, Hebert SC. Cloning and expression of an inwardly rectifying ATP-regulated potassium channel. Nature. 1993;362:31-38. [Medline] [Order article via Infotrieve]

9. Kubo Y, Baldwin TJ, Jan YN, Jan LY. Primary structure and functional expression of a mouse inward rectifier potassium channel. Nature. 1993;362:127-133. [Medline] [Order article via Infotrieve]

10. Kubo Y, Reuveny E, Slesinger PA, Jan YN, Jan LY. Primary structure and functional expression of a rat G-protein coupled muscarinic potassium channel. Nature. 1993;364:802-806. [Medline] [Order article via Infotrieve]

11. MacKinnon R. Determination of the subunit stoichiometry of a voltage-activated potassium channel. Nature. 1991;350:232-235. [Medline] [Order article via Infotrieve]

12. Heginbotham L, Abramson T, MacKinnon R. A functional connection between the pores of distantly related ion channels as revealed by mutant K⁺ channels. Science. 1992;258:1152-1155. [Abstract/Free Full Text]

13. Dascal N, Schreibmayer W, Lim NF, Wang W, Chavkin C, DiMagno L, Labarca C, Kieffer BL, Gaveriaux-Ruff C, Trollinger D. Atrial G protein-activated K⁺ channel: expression cloning and molecular properties. Proc Natl Acad Sci U S A. 1993;90:10235-10239. [Abstract/Free Full Text]

14. Lesage F, Duprat F, Fink M, Guillemare E, Coppola T, Lazdunski M, Hugnot JP. Cloning provides evidence for a family of inward rectifier and G-protein coupled K⁺ channels in the brain. FEBS Lett. 1994;353:37-42. [Medline] [Order article via Infotrieve]

15. Ishii K, Yamagashi T, Taira N. Cloning and functional expression of a cardiac inward rectifier K⁺ channel. FEBS Lett. 1994;338:107-111. [Medline] [Order article via Infotrieve]

16. Perier F, Radeke CM, Vandenberg CA. Primary structure and characterization of a small-conductance inwardly rectifying potassium channel from human hippocampus. Proc Natl Acad Sci U S A. 1994;91:6240-6244. [Abstract/Free Full Text]

17. Raab-Graham KF, Radeke CM, Vandenberg CA. Molecular cloning and expression of a human heart inward rectifier potassium channel. Neuroreport. 1994;5:2501-2505. [Medline] [Order article via Infotrieve]

18. Wible BA, De Biasi M, Majumder K, Taglialatela M, Brown AM. Cloning and functional expression of an inwardly rectifying K⁺ channel from human atrium. Circ Res. 1995;76:343-350. [Abstract/Free Full Text]

19. Ishihara K, Mitsuiye T, Noma A, Takano M. The Mg²⁺ block and intrinsic gating of underlying inward rectification of the K⁺ current in guinea-pig cardiac myocytes. J Physiol (Lond). 1989;419:297-320. [Abstract/Free Full Text]

20. Kurachi Y. Voltage-dependent activation of the inward-rectifier potassium channel in the ventricular cell membrane of guinea-pig heart. J Physiol (Lond). 1985;366:365-385. [Abstract/Free Full Text]

21. Ashford ML, Bond CT, Blair TA, Adelman JP. Cloning and functional expression of a rat heart KATP channel. Nature. 1994;370:456-459. [Medline] [Order article via Infotrieve]

22. Krapivinsky G, Gordon EA, Wickman K, Velimirovic B, Krapivinsky L, Clapham DE. The G-protein-gated atrial K⁺ channel IKACh is a heteromultimer of two inwardly rectifying K(⁺)-channel proteins. Nature. 1995;374:135-141. [Medline] [Order article via Infotrieve]

23. Bond CT, Pessia M, Xia XM, Lagrutta A, Kavanaugh MP, Adelman JP. Cloning and expression of a family of inward rectifier potassium channels. Receptors Channels. 1994;2:183-191. [Medline] [Order article via Infotrieve]

24. Inagaki N, Tsuura Y, Namba N, Masuda K, Gonoi T, Horie M, Seino Y, Mizuta M, Seino S. Cloning and functional characterization of a novel ATP-sensitive potassium channel ubiquitously expressed in rat tissues, including pancreatic islets, pituitary, skeletal muscle, and heart. J Biol Chem. 1995;270:5691-5694. [Abstract/Free Full Text]

25. Lopatin AN, Nichols CG. Inward rectification of outward rectifying DRK1 (Kv2.1) potassium channels. J Gen Physiol. 1994;103:203-216. [Abstract/Free Full Text]

26. Sanguinetti CM, Jiang C, Curran ME, Keating MT. A mechanistic link between an inherited and an acquired cardiac arrhythmia: HERG encodes the I_Kr potassium channel. Cell. 1995;81:299-307. [Medline] [Order article via Infotrieve]

27. Trudeau MC, Warmke JW, Ganetzky B, Robertson GA. HERG, a human inward rectifier in the voltage-gated potassium channel family. Science. 1995;269:92-95.[Abstract/Free Full Text]

28. Armstrong CM. Inactivation of the potassium conductance and related phenomena caused by quaternary ammonium ion injected in squid axons. J Gen Physiol. 1969;54:553-575. [Abstract/Free Full Text]

29. Horie M, Irisawa H, Noma A. Voltage-dependent magnesium block of adenosine-triphosphate-sensitive potassium channel in guinea-pig ventricular cells. J Physiol (Lond). 1987;387:251-272. [Abstract/Free Full Text]

30. Matsuda H, Saigusa A, Irisawa H. Ohmic conductance through the inwardly rectifying K⁺ channel and blocking by internal Mg²⁺. Nature. 1987;325:156-159. [Medline] [Order article via Infotrieve]

31. Vandenberg CA. Inward rectification of a potassium channel in cardiac ventricular cells depends on internal magnesium ions. Proc Natl Acad Sci. 1987;84:250-256.

32. Matsuda H. Effects of external and internal K⁺ ions on magnesium block of inwardly rectifying K⁺ channels in guinea-pig heart cells. J Physiol (Lond). 1991;435:83-99. [Abstract/Free Full Text]

33. Matsuda H. Open-state substructure of inwardly rectifying potassium channels revealed by magnesium block in guinea-pig heart cells. J Physiol (Lond). 1988;397:237-258. [Abstract/Free Full Text]

34. Lopatin AN, Makhina EN, Nichols CG. Potassium channel block by cytoplasmic polyamines as the mechanism of intrinsic rectification. Nature. 1994;372:366-369.[Medline] [Order article via Infotrieve]

35. Ficker E, Taglialatela M, Wible BA, Henley CM, Brown AM. Spermine and spermidine as gating molecules for inward rectifier K channels. Science. 1994;266:1068-1072. [Abstract/Free Full Text]

36. Lopatin AN, Makhina EN, Nichols CG. The mechanism of inward rectification of potassium channels. J Gen Physiol. In press.

37. Fakler B, Brandle U, Glowatzki E, Weidemann S, Zenner HP, Ruppersberg JP. Strong voltage-dependent inward rectification of inward rectifier K⁺ channels is caused by intracellular spermine. Cell. 1995;80:149-154. [Medline] [Order article via Infotrieve]

38. Tabor CW, Tabor H. Polyamines. Annu Rev Biochem. 1984;53:749-790. [Medline] [Order article via Infotrieve]

39. Nichols CG, Ho K, Hebert S. Mg²⁺ dependent inward rectification of ROMK1 potassium channels expressed in Xenopus oocytes. J Physiol (Lond). 1994;476:399-409. [Abstract/Free Full Text]

40. Lu Z, MacKinnon R. Electrostatic tuning of Mg²⁺ affinity in an inward rectifier K⁺ channel. Nature. 1994;371:243-246. [Medline] [Order article via Infotrieve]

41. Fakler B, Brandle U, Bond C, Glowatzki E, Konig C, Adelman JP, Zenner HP, Ruppersberg JP. A structural determinant of differential sensitivity of cloned inward rectifier K⁺ channels to intracellular spermine. FEBS Lett. 1994;356:199-203. [Medline] [Order article via Infotrieve]

42. Yamada M, Kurachi Y. Spermine gates inward-rectifying muscarinic but not ATP-sensitive K⁺ channels in rabbit atrial myocytes: intracellular substance-mediated mechanism of inward rectification. J Biol Chem. 1995;270:9289-9294. [Abstract/Free Full Text]

43. Yang J, Jan YN, Jan LY. Control of rectification and permeation by residues in two distinct domains in an inward rectifier K⁺ channel. Neuron. 1995;14:1047-1054. [Medline] [Order article via Infotrieve]

44. Yellen G, Jurman ME, Abramson T, MacKinnon R. Mutations affecting internal TEA blockade identify the probable pore-forming region of a K⁺ channel. Science. 1991;251:939-942. [Abstract/Free Full Text]

45. Lopez GA, Jan YN, Jan LY. Evidence that the S6 segment of the Shaker voltage-gated K⁺ channel comprises part of the pore. Nature. 1993;367:179-182.

46. Stanfield PR, Davies NW, Shelton PA, Sutcliffe MJ, Khan IA, Brammar WJ, Standen NB, Conley EC. A single aspartate residue is involved in both intrinsic gating and blockage by Mg²⁺ of the inward rectifier, IRK1. J Physiol (Lond). 1994;478:1-6. [Abstract/Free Full Text]

47. Wible BA, Taglialatela M, Ficker E, Brown AM. Gating of inwardly rectifying K⁺ channels localized to a single negatively charged residue. Nature. 1994;371:246-249. [Medline] [Order article via Infotrieve]

48. Taglialatela M, Wible BA, Caporoso R, Brown AM. Specification of the pore properties by the carboxyl terminus of inwardly rectifying K⁺ channels. Science. 1994;264:844-847. [Abstract/Free Full Text]

49. Bartolome J, Huguenard J, Slotkin TA. Role of ornithine decarboxylase in cardiac growth and hypertrophy. Science. 1980;210:749-790. [Free Full Text]

50. Caldarera CM, Orlandini G, Casti A, Moruzzi GJ. Polyamine and nucleic acid metabolism in myocardial hypertrophy of the overloaded heart. Mol Cell Cardiol. 1974;6:95-104. [Medline] [Order article via Infotrieve]

51. Grover GJ. Protective effects of ATP-sensitive potassium-channel openers in experimental myocardial ischemia. J Cardiovasc Pharmacol. 1994;24(suppl 4):S18-S27.

52. Woosley RL. New antiarrhythmic drugs. In: Zipes DP, Jalife J, eds. Cardiovascular Electrophysiology. Philadelphia, Pa: WB Saunders Co; 1995:chap 116.

This article has been cited by other articles:

				S. Wang, Y. Alimi, A. Tong, C. G. Nichols, and D. Enkvetchakul Differential Roles of Blocking Ions in KirBac1.1 Tetramer Stability J. Biol. Chem., January 30, 2009; 284(5): 2854 - 2860. [Abstract] [Full Text] [PDF]

				H. Morita, D. P. Zipes, S. T. Morita, and J. Wu Mechanism of U wave and polymorphic ventricular tachycardia in a canine tissue model of Andersen-Tawil syndrome Cardiovasc Res, August 1, 2007; 75(3): 510 - 518. [Abstract] [Full Text] [PDF]

				D. Ma, X. D. Tang, T. B. Rogers, and P. A. Welling An Andersen-Tawil Syndrome Mutation in Kir2.1 (V302M) Alters the G-loop Cytoplasmic K+ Conduction Pathway J. Biol. Chem., February 23, 2007; 282(8): 5781 - 5789. [Abstract] [Full Text] [PDF]

				R. J. Sung, S.-N. Wu, J.-S. Wu, H.-D. Chang, and C.-H. Luo Electrophysiological mechanisms of ventricular arrhythmias in relation to Andersen-Tawil syndrome under conditions of reduced IK1: a simulation study Am J Physiol Heart Circ Physiol, December 1, 2006; 291(6): H2597 - H2605. [Abstract] [Full Text] [PDF]

				A. Sridhar, S. J. Dech, V. A. Lacombe, T. S. Elton, S. A. McCune, R. A. Altschuld, and C. A. Carnes Abnormal diastolic currents in ventricular myocytes from spontaneous hypertensive heart failure rats Am J Physiol Heart Circ Physiol, November 1, 2006; 291(5): H2192 - H2198. [Abstract] [Full Text] [PDF]

				S. M. Y Makary, T. W Claydon, D. Enkvetchakul, C. G Nichols, and M. R Boyett A difference in inward rectification and polyamine block and permeation between the Kir2.1 and Kir3.1/Kir3.4 K+ channels J. Physiol., November 1, 2005; 568(3): 749 - 766. [Abstract] [Full Text] [PDF]

				J. M. Nerbonne and R. S. Kass Molecular Physiology of Cardiac Repolarization Physiol Rev, October 1, 2005; 85(4): 1205 - 1253. [Abstract] [Full Text] [PDF]

				J. Fauconnier, A. Lacampagne, J.-M. Rauzier, P. Fontanaud, J.-M. Frapier, O. M. Sejersted, G. Vassort, and S. Richard Frequency-dependent and proarrhythmogenic effects of FK-506 in rat ventricular cells Am J Physiol Heart Circ Physiol, February 1, 2005; 288(2): H778 - H786. [Abstract] [Full Text] [PDF]

				P. Zhabyeyev, T. Asai, S. Missan, and T. F. McDonald Transient outward current carried by inwardly rectifying K+ channels in guinea pig ventricular myocytes dialyzed with low-K+ solution Am J Physiol Cell Physiol, November 1, 2004; 287(5): C1396 - C1403. [Abstract] [Full Text] [PDF]

				A. S. Dhamoon, S. V. Pandit, F. Sarmast, K. R. Parisian, P. Guha, Y. Li, S. Bagwe, S. M. Taffet, and J. M.B. Anumonwo Unique Kir2.x Properties Determine Regional and Species Differences in the Cardiac Inward Rectifier K+ Current Circ. Res., May 28, 2004; 94(10): 1332 - 1339. [Abstract] [Full Text] [PDF]

				R. Bouchard, R. B. Clark, A. E. Juhasz, and W. R. Giles Changes in extracellular K+ concentration modulate contractility of rat and rabbit cardiac myocytes via the inward rectifier K+ current IK1 J. Physiol., May 1, 2004; 556(3): 773 - 790. [Abstract] [Full Text] [PDF]

				D Enkvetchakul, L Ebihara, and C G Nichols Polyamine flux in Xenopus oocytes through hemi-gap junctional channels J. Physiol., November 15, 2003; 553(1): 95 - 100. [Abstract] [Full Text] [PDF]

				L. G. Hommers, M. J. Lohse, and M. Bunemann Regulation of the Inward Rectifying Properties of G-protein-activated Inwardly Rectifying K+ (GIRK) Channels by Gbeta gamma Subunits J. Biol. Chem., January 3, 2003; 278(2): 1037 - 1043. [Abstract] [Full Text] [PDF]

				F. Doring, E. Wischmeyer, R. P. Kuhnlein, H. Jackle, and A. Karschin Inwardly Rectifying K+ (Kir) Channels in Drosophila. A CRUCIAL ROLE OF CELLULAR MILIEU FACTORS FOR Kir CHANNEL FUNCTION J. Biol. Chem., July 5, 2002; 277(28): 25554 - 25561. [Abstract] [Full Text] [PDF]

				R. Preisig-Muller, G. Schlichthorl, T. Goerge, S. Heinen, A. Bruggemann, S. Rajan, C. Derst, R. W. Veh, and J. Daut Heteromerization of Kir2.x potassium channels contributes to the phenotype of Andersen's syndrome PNAS, May 28, 2002; 99(11): 7774 - 7779. [Abstract] [Full Text] [PDF]

				J. J Zaritsky, J. B Redell, B. L Tempel, and T. L Schwarz The consequences of disrupting cardiac inwardly rectifying K+ current (IK1) as revealed by the targeted deletion of the murine Kir2.1 and Kir2.2 genes J. Physiol., June 15, 2001; 533(3): 697 - 710. [Abstract] [Full Text] [PDF]

				G. Xin Liu, C. Derst, G. Schlichthorl, S. Heinen, G. Seebohm, A. Bruggemann, W. Kummer, R. W Veh, J. Daut, and R. Preisig-Muller Comparison of cloned Kir2 channels with native inward rectifier K+ channels from guinea-pig cardiomyocytes J. Physiol., April 1, 2001; 532(1): 115 - 126. [Abstract] [Full Text] [PDF]

				S. Wiese, T. Breyer, A. Dragu, R. Wakili, T. Burkard, S. Schmidt-Schweda, E.-M. Fuchtbauer, U. Dohrmann, F. Beyersdorf, D. Radicke, et al. Gene Expression of Brain Natriuretic Peptide in Isolated Atrial and Ventricular Human Myocardium : Influence of Angiotensin II and Diastolic Fiber Length Circulation, December 19, 2000; 102(25): 3074 - 3079. [Abstract] [Full Text] [PDF]

				O. M. Sejersted and G. Sjogaard Dynamics and Consequences of Potassium Shifts in Skeletal Muscle and Heart During Exercise Physiol Rev, October 1, 2000; 80(4): 1411 - 1481. [Abstract] [Full Text] [PDF]

				S. P. Harris, J. R. Patel, L. J. Marton, and R. L. Moss Polyamines decrease Ca2+ sensitivity of tension and increase rates of activation in skinned cardiac myocytes Am J Physiol Heart Circ Physiol, September 1, 2000; 279(3): H1383 - H1391. [Abstract] [Full Text] [PDF]

				J. J. Zaritsky, D. M. Eckman, G. C. Wellman, M. T. Nelson, and T. L. Schwarz Targeted Disruption of Kir2.1 and Kir2.2 Genes Reveals the Essential Role of the Inwardly Rectifying K+ Current in K+-Mediated Vasodilation Circ. Res., July 21, 2000; 87(2): 160 - 166. [Abstract] [Full Text] [PDF]

				G.-R. Li, B. Yang, H. Sun, and C. M. Baumgarten Existence of a transient outward K+ current in guinea pig cardiac myocytes Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H130 - H138. [Abstract] [Full Text] [PDF]

				A. Stadnicka, Z. J. Bosnjak, J. P. Kampine, and W.-M. Kwok Modulation of Cardiac Inward Rectifier K+Current by Halothane and Isoflurane Anesth. Analg., April 1, 2000; 90(4): 824 - 833. [Abstract] [Full Text] [PDF]

				E. Carmeliet Cardiac Ionic Currents and Acute Ischemia: From Channels to Arrhythmias Physiol Rev, July 1, 1999; 79(3): 917 - 1017. [Abstract] [Full Text] [PDF]

				H. B. Nuss, S. Kaab, D. A. Kass, G. F. Tomaselli, and E. Marban Cellular basis of ventricular arrhythmias and abnormal automaticity in heart failure Am J Physiol Heart Circ Physiol, July 1, 1999; 277(1): H80 - H91. [Abstract] [Full Text] [PDF]

				F. Aimond, J. L Alvarez, J.-M. Rauzier, P. Lorente, and G. Vassort Ionic basis of ventricular arrhythmias in remodeled rat heart during long-term myocardial infarction Cardiovasc Res, May 1, 1999; 42(2): 402 - 415. [Abstract] [Full Text] [PDF]

				L. Aguilar-Bryan and J. Bryan Molecular Biology of Adenosine Triphosphate-Sensitive Potassium Channels Endocr. Rev., April 1, 1999; 20(2): 101 - 135. [Abstract] [Full Text]

				P. Bailly, M. Mouchoniere, J.-P. Benitah, L. Camilleri, G. Vassort, and P. Lorente Extracellular K+ Dependence of Inward Rectification Kinetics in Human Left Ventricular Cardiomyocytes Circulation, December 15, 1998; 98(24): 2753 - 2759. [Abstract] [Full Text] [PDF]

				K. L. MacDonell, D. L. Severson, and W. R. Giles Depression of excitability by sphingosine 1-phosphate in rat ventricular myocytes Am J Physiol Heart Circ Physiol, December 1, 1998; 275(6): H2291 - H2299. [Abstract] [Full Text] [PDF]

				J M Cordeiro, K W Spitzer, and W R Giles Repolarizing K+ currents in rabbit heart Purkinje cells J. Physiol., May 1, 1998; 508(3): 811 - 823. [Abstract] [Full Text] [PDF]

				X W Niu and R W Meech The effect of polyamines on KATP channels in guinea-pig ventricular myocytes J. Physiol., April 15, 1998; 508(2): 401 - 411. [Abstract] [Full Text] [PDF]

				D. J. Huelsing, K. W. Spitzer, J. M. Cordeiro, and A. E. Pollard Conduction between isolated rabbit Purkinje and ventricular myocytes coupled by a variable resistance Am J Physiol Heart Circ Physiol, April 1, 1998; 274(4): H1163 - H1173. [Abstract] [Full Text] [PDF]

				G.-R. Li, H. Sun, and S. Nattel Characterization of a transient outward K+ current with inward rectification in canine ventricular myocytes Am J Physiol Cell Physiol, March 1, 1998; 274(3): C577 - C585. [Abstract] [Full Text] [PDF]

				L. AGUILAR-BRYAN, J. P. CLEMENT IV, G. GONZALEZ, K. KUNJILWAR, A. BABENKO, and J. BRYAN Toward Understanding the Assembly and Structure of KATP Channels Physiol Rev, January 1, 1998; 78(1): 227 - 245. [Abstract] [Full Text] [PDF]

				H. Yokoshiki, M. Sunagawa, T. Seki, and N. Sperelakis ATP-sensitive K+ channels in pancreatic, cardiac, and vascular smooth muscle cells Am J Physiol Cell Physiol, January 1, 1998; 274(1): C25 - C37. [Abstract] [Full Text] [PDF]

				Z. Fan and J. C. Makielski Anionic Phospholipids Activate ATP-sensitive Potassium Channels J. Biol. Chem., February 28, 1997; 272(9): 5388 - 5395. [Abstract] [Full Text] [PDF]

				K. Ishihara Time-dependent Outward Currents through the Inward Rectifier Potassium Channel IRK1: The Role of Weak Blocking Molecules J. Gen. Physiol., February 1, 1997; 109(2): 229 - 243. [Abstract] [Full Text] [PDF]

				N. K. Jurkiewicz, J. Wang, B. Fermini, M. C. Sanguinetti, and J. J. Salata Mechanism of Action Potential Prolongation by RP 58866 and Its Active Enantiomer, Terikalant: Block of the Rapidly Activating Delayed Rectifier K+ Current, IKr Circulation, December 1, 1996; 94(11): 2938 - 2946. [Abstract] [Full Text]

This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Nichols, C.G. Articles by Lopatin, A.N. Search for Related Content PubMed PubMed Citation Articles by Nichols, C.G. Articles by Lopatin, A.N.