Review article
Molecular aspects of ATP-sensitive K+ channels in the cardiovascular system and K+ channel openers

https://doi.org/10.1016/S0163-7258(99)00050-9Get rights and content

Abstract

ATP-sensitive K+ (KATP) channels are inhibited by intracellular ATP (ATPi) and activated by intracellular nucleoside diphosphates and thus, provide a link between cellular metabolism and excitability. KATP channels are widely distributed in various tissues and may be associated with diverse cellular functions. In the heart, the KATP channel appears to be activated during ischemic or hypoxic conditions, and may be responsible for the increase of K+ efflux and shortening of the action potential duration. Therefore, opening of this channel may result in cardioprotective, as well as proarrhythmic, effects. These channels are clearly heterogeneous. The cardiac KATP channel is the prototype of KATP channels possessing ∼80 pS of single-channel conductance in the presence of ∼150 mM extracellular K+ and opens spontaneously in the absence of ATPi. A vascular KATP channel called a nucleoside diphosphate-dependent K+ (KNDP) channel exhibits properties significantly different from those of the cardiac KATP channel. The KNDP channel has the single-channel conductance of ∼30–40 pS in the presence of ∼150 mM extracellular K+, is closed in the absence of ATPi, and requires intracellular nucleoside di- or triphosphates, including ATPi to open. Nevertheless, KATP and KNDP channels are both activated by K+ channel openers, including pinacidil and nicorandil, and inhibited by sulfonylurea derivatives such as glibenclamide. It recently was found that the cardiac KATP channel is composed of a sulfonylurea receptor (SUR)2A and a two-transmembrane-type K+ channel subunit Kir6.2, while the vascular KNDP channel may be the complex of SUR2B and Kir6.1. By precisely comparing the functional properties of the SUR2A/Kir6.2 and the SUR2B/Kir6.1 channels, we shall show that the single-channel characteristics and pharmacological properties of SUR/Kir6.0 channels are determined by Kir and SUR subunits. respectively, while responses to intracellular nucleotides are determined by both SUR and Kir subunits.

Introduction

The ATP-sensitive K+ (KATP) channel is a weakly inward-rectifying K+ channel that is inhibited by intracellular ATP (ATPi) and activated by intracellular nucleoside diphosphates (NDPis). Thus, it provides a link between the cellular metabolism and excitability. The KATP channel, which was first discovered in heart muscle, has been identified also in a variety of tissues, including pancreatic β-cells, skeletal muscle, smooth muscle, and renal tubular cells, and in the CNS. These KATP channels have been associated with diverse cellular functions, such as insulin secretion from pancreatic β-cells, smooth muscle relaxation, regulation of skeletal muscle excitability, and neurotransmitter release. KATP channels in the cardiovascular system might have a physiological role in modulating cardiac function, particularly under conditions of metabolic stress, such as hypoxia, ischemia, and metabolic inhibition when ATPi is reduced.

The KATP channels also exhibit characteristic pharmacological properties: they are selectively inhibited by antidiabetic sulfonylurea derivatives, such as glibenclamide and tolbutamide, and activated by a certain class of vasorelaxants, such as pinacidil, levcromakalim, and nicorandil, which are collectively termed K+ channel openers (KCOs) (Table 1).

The cardiac KATP channel may be involved in the increase of K+ efflux and shortening of the action potential duration in the ischemic heart. Both are major factors contributing to the electrophysiological abnormalities that predispose the heart to the development of re-entrant arrhythmias. On the other hand, opening of the cardiac KATP channel also has been implicated as a cardioprotective mechanism underlying ischemia-related preconditioning. In the coronary arteries, the KATP channel is believed to mediate coronary vasodilation, particularly during ischemia, because the vasodilation induced by ischemia, hypoxia, and metabolic inhibition can be prevented by glibenclamide, a blocker of KATP channels, and can be mimicked by cromakalim, one of the KCOs. The KCOs also have been shown to relax vascular smooth muscle in organs other than the heart, and this is also glibenclamide-sensitive. Thus, KATP channels play important roles not only in the pathology of heart muscle, but also in vasculature, and thus, may have potential importance in treatment of heart diseases, such as ischemic heart diseases and hypertension. However, the physiological role of the KATP channels in cardiac myocytes is unclear at present.

The pancreatic, cardiac, and skeletal muscle KATP channels all exhibit the single-channel conductance of ∼70–90 pS under the symmetrical 150 mM K+ conditions (Table 1; Ashcroft 1988, Terzic et al. 1995, Yamada et al. 1998). This class of KATP channels has often been referred to as “classical-type” KATP channels. Their responses to intracellular nucleotides or to pharmacological agents, however, are diverse (Table 1). The pancreatic and skeletal muscle KATP channels are more sensitive to Mg2+-free than Mg2+-bound ATPi, while the cardiac KATP channel is equally sensitive to both forms of ATPi. The pancreatic KATP channel is inhibited by tens of micromolar of tolbutamide, while submillimolar concentrations of this agent are needed to inhibit the cardiac KATP channel. The pancreatic KATP channel is activated by diazoxide, but not by pinacidil, while vice versa for cardiac and skeletal muscle KATP channels. Thus, KCOs exhibit clear tissue specificity. These KATP channels, therefore, can be similar, but distinct, members of the same family of K+ channels.

The fact that various KCOs, such as pinacidil and diazoxide, potently induce vasorelaxation in a sulfonylurea derivative-sensitive manner indicates that vascular smooth muscle may also possess some types of KATP channels (Edwards & Weston, 1993). Indeed, many distinct types of K+ channels have been reported as KATP channels in vascular smooth muscle cells (Table 1) (Quayle et al., 1997). However, despite the similarity in pharmacology, these channels exhibit single-channel characteristics and nucleotide-regulation distinct from those of the classical KATP channels. For example, the most commonly observed vascular KATP channel, which is often called the “small-conductance” KATP channel or the “nucleoside diphosphate-dependent” K+ (KNDP) channel Zhang & Bolton 1995, Zhang & Bolton 1996, Kamouchi & Kitamura 1994, Beech et al. 1993a, Beech et al. 1993b, Kajioka et al. 1991, exhibits less than one-half of the single-channel conductance of the classical KATP channels (Table 1). The classical KATP channels open spontaneously when ATPi is removed from the internal surface of the membrane, while the KNDP channel requires NDPis to open. Furthermore, the KNDP channel is reported to be activated rather than inhibited by ATPi. Such striking differences between classical KATP channels and vascular KNDP channels have yielded some confusion as to the identity of so-called KATP channels in vascular smooth muscle cells.

In this article, we will review recent progress in molecular dissection of cardiovascular KATP channels and show that the apparent differences between cardiac KATP and vascular KNDP channels can be explained in terms of different combination of subunits with a similar molecular structure.

Section snippets

Regulation of ATP-sensitive K+ channels by intracellular nucleotides

The KATP channels are known to be regulated by various intracellular factors, such as ATPi (Fig. 1) and nucleoside diphosphates (NDPs). ATPi is the main regulator of classical KATP channels and has two functions: to close the channels and to maintain channel activity in the presence of Mg2+ Takano et al. 1990, Ohno-Shosaku et al. 1987, Findlay & Dunne 1986, Trube & Heschler 1984. The first action of ATPi is referred to as the “ligand action” because the binding of ATPi to the KATP channel is

Pharmacological regulation of ATP-sensitive K + channels

KATP channels in various tissues including cardiac muscle are the targets of two important classes of drugs: (1) the antidiabetic sulfonylureas, which block the channels and (2) a series of compounds called KCOs, which tend to maintain the channels in an open conformation. Sulfonylureas, including glibenclamide and tolbutamide, are hypoglycemic agents that stimulate insulin secretion by blocking the KATP channel, resulting in membrane depolarization and thus, an increase of Ca2+ influx (Dunne &

Molecular structure of ATP-sensitive K+ channels

In 1993, an ATP-dependent Kir channel, ROMK/Kir1.1 (Ho et al., 1993), and a classic Kir channel, IRK1/Kir2.1 (Kubo et al., 1993a), were cloned by the expression cloning technique from the outer medulla of rat kidney and a mouse macrophage cell lines, respectively. They have a common molecular motif in the primary structure, i.e., two putative membrane-spanning regions (M1 and M2) and one potential pore-forming loop (H5) (Fig. 2B, part a). Thus, the primary structure of these Kir channel

Molecular heterogeneity of sulfonylurea receptors

The first SUR, SUR1, was cloned from insulinoma cells by Aguilar-Bryan et al. (1995). Its protein is assumed to possess 17 potential transmembrane regions (Fig. 4) (Tusnády et al., 1997), 2 nucleotide-binding folds (NBFs) with Walker A and B consensus motifs, 2 N-linked glycosylation sites, and several protein kinase A- and C-dependent phosphorylation sites. Co-expression of hamster (ha)-SUR1 and mouse (m)-Kir6.2 elicits KATP conductance (IKATP), which is inhibited by glibenclamide

Molecular mechanism of ATP-sensitive K+ channel inhibition by intracellular ATP

One of the hallmarks of the classical KATP channels is the inhibition of channel activity by micromolar concentrations of ATPi Terzic et al. 1995, Ashcroft 1988, Noma 1983. Tucker et al. (1997) recently found that the Kir6.2, whose last 26 amino acids at the C-terminus are deleted (Kir6.2ΔC26), can be functionally expressed in the absence of SUR. A charge-neutralization mutation on Lys185 of Kir6.2ΔC26 reduces the ATPi sensitivity of the Kir6.2ΔC26 channel by ∼40 times. The ATPi sensitivity of

Molecular mechanism of response to intracellular nucleoside diphosphates

NDPis such as UDP exhibit distinct effects on the cardiac KATP channel before and after rundown Terzic et al. 1994a, Terzic et al. 1995. UDP antagonizes the inhibitory effect of ATPi before rundown. After rundown, UDP restores the channel activity without attenuating the ATPi sensitivity of the channels (Tung & Kurachi, 1991). The SUR2A/Kir6.2 channel well-mimicked such a dualistic response of the cardiac KATP channel to NDPis (Fig. 6) (Okuyama et al., 1998).

As shown in Fig. 6A (part a), ATPi

Molecular mechanism of rundown

Rundown of channel activity in inside-out patch membranes is not necessarily a phenomenon specifically associated with KATP channels, but can be seen in other Kir channels as well. Nevertheless, many investigators have been interested in the mechanism underlying the rundown of KATP channels because KATP channels run down more prominently than other Kir channels Terzic et al. 1995, Ashcroft 1988. The KATP channels can be reactivated after rundown with ATPi in the presence, but not in the

Conclusions

Recent molecular dissection of Kir channels and SURs has identified molecular structures of KATP channels in the cardiovascular system. Further understandings at the molecular level of the KATP channels in the cardiovascular system may enable us to clarify the roles of these channels in cardiovascular physiology and pathophysiology, which may allow further development of strategy and pharmacological agents to treat various cardiovascular diseases.Krapivinsky Gordon Wickman Velimirovic

References (114)

  • N. Inagaki et al.

    A family of sulfonylurea receptors determines the pharmacological properties of ATP-sensitive K+ channels

    Neuron

    (1996)
  • N. Inagaki et al.

    Subunit stoichiometry of the pancreatic β-cell ATP-sensitive K+ channel

    FEBS Lett

    (1997)
  • A. Inanobe et al.

    Immunological and physical characterization of the brain G protein-gated muscarinic potassium channel

    Biochem Biophys Res Commun

    (1995)
  • S. Isomoto et al.

    A novel ubiquitously distributed isoform of GIRK2 (GIRK2B) enhances GIRK1 expression of the G-protein-gated K+ current in Xenopus oocytes

    Biochem Biophys Res Commun

    (1996)
  • S. Isomoto et al.

    A novel sulfonylurea receptor forms with BIR (Kir6.2) a smooth muscle type ATP-sensitive K+ channel

    J Biol Chem

    (1996)
  • G. Krapivinsky et al.

    A novel inward rectifier K+ channel with unique pore properties

    Neuron

    (1998)
  • F. Lesage et al.

    Cloning provides evidence for a family of inward rectifier and G-protein coupled K+ channels in the brain

    FEBS Lett

    (1994)
  • K. Morishige et al.

    Molecular cloning, functional expression and localization of an inward rectifier potassium channel in the mouse brain

    FEBS Lett

    (1993)
  • H. Sakura et al.

    Cloning and functional expression of the cDNA encoding a novel ATP-sensitive potassium channel subunit expressed in pancreatic β-cells, heart and skeletal muscle

    FEBS Lett

    (1995)
  • N. Takahashi et al.

    Molecular cloning and functional expression of cDNA encoding a second class of inward rectifier potassium channels in the mouse brain

    J Biol Chem

    (1994)
  • T. Takumi et al.

    A novel ATP-dependent inward rectifier potassium channel expressed predominantly in glial cells

    J Biol Chem

    (1995)
  • A. Terzic et al.

    G proteins activate ATP-sensitive K+ channels by antagonizing ATP-dependent gating

    Neuron

    (1994)
  • L. Aguilar-Bryan et al.

    Cloning of the β cell high-affinity sulfonylurea receptora regulator of insulin secretion

    Science

    (1995)
  • B. Allard et al.

    Activation of ATP-dependent K+ channels by metabolic poisoning in adult mouse skeletal musclerole of intracellular Mg2+ and pH

    J Physiol (Lond)

    (1995)
  • C. Ämmälä et al.

    Promiscuous coupling between the sulfonylurea receptor & inwardly rectifying potassium channels

    Nature

    (1996)
  • J.P. Arena et al.

    Enhancement of potassium-sensitive current in heart cells by pinacidilevidence of modulation of the ATP-sensitive potassium channel

    Circ Res

    (1989)
  • F.M. Ashcroft

    Adenosine 5′-triphosphate-sensitive potassium channels

    Annu Rev Neurosci

    (1988)
  • F.M. Ashcroft et al.

    ATP-sensitive K+ channels in rat pancreatic β-cellsmodulation by ATP and Mg2+ ions

    J Physiol (Lond)

    (1989)
  • T. Baukrowitz et al.

    PIP2 and PIP as determinants for ATP inhibition of KATP channels

    Science

    (1998)
  • D.J. Beech et al.

    K channel activation by nucleotide diphosphates and its inhibition by glibenclamide in vascular smooth muscle cells

    Br J Pharmacol

    (1993)
  • D.L. Beech et al.

    Single channel and whole-cell K-currents evoked by levcromakalim in smooth muscle cells from the rabbit portal vein

    Br J Pharmacol

    (1993)
  • D.C. Benton et al.

    Effects of cromakalim on the membrane potassium permeability of frog skeletal muscle in vitro

    Br J Pharmacol

    (1992)
  • C.T. Bond et al.

    Cloning and expression of a family of inward rectifier potassium channels

    Recept Channels

    (1994)
  • W.A. Chutkow et al.

    Cloning, tissue expression, and chromosomal localization of SUR2, the putative drug-binding subunit of cardiac, skeletal muscle, and vascular KATP channels

    Diabetes

    (1996)
  • D.L. Cook et al.

    Intracellular ATP directory blocks K+ channels in pancreatic β-cells

    Nature

    (1984)
  • N. Dascal et al.

    Expression of an atrial G-protein-activated potassium channel in Xenopus oocytes

    Proc Natl Acad Sci USA

    (1993)
  • N.W. Davies et al.

    Multiple blocking mechanisms of ATP-sensitive potassium channels of frog skeletal muscle by tetraethylammonium ions

    J Physiol (Lond)

    (1989)
  • N. Deutsch et al.

    Surface charge and properties of cardiac ATP-sensitive K+ channels

    J Gen Physiol

    (1994)
  • F. Döring et al.

    The epithelial inward rectifier channel Kir7.1 displays unusual K+ permeation properties

    J Neurosci

    (1998)
  • G. Edwards et al.

    The pharmacology of ATP-sensitive potassium channels

    Annu Rev Pharmacol Toxicol

    (1993)
  • D. Escande et al.

    Potassium channel openers act through an activation of ATP-sensitive K+ channels in guinea-pig cardiac myocytes

    Pflügers Arch

    (1989)
  • I. Findlay

    ATP4- and ATP-Mg inhibit the ATP-sensitive K+ channel of rat ventricular myocytes

    Pflügers Arch

    (1988)
  • I. Findlay

    Inhibition of ATP-sensitive K+ channels in cardiac muscle by the sulfonylurea drug glibenclamide

    J Pharmacol Exp Ther

    (1992)
  • I. Findlay et al.

    ATP maintains ATP-inhibited K+ channels in an operational state

    Pflügers Arch

    (1986)
  • I. Findlay et al.

    ATP-sensitive inward rectifier and voltage and calcium activated K+ channels in cultured pancreatic islet cells

    J Membr Biol

    (1985)
  • M.G. Garrino et al.

    Effects of putative activators of K+ channels in mouse pancreatic β-cells

    Br J Pharmacol

    (1989)
  • F.M. Gribble et al.

    Properties of cloned ATP-sensitive K+ currents expressed in Xenopus oocytes

    J Physiol (Lond)

    (1997)
  • F.M. Gribble et al.

    The essential role of the Walker A motifs of SUR1 in K-ATP channel activation by Mg-ADP and diazoxide

    EMBO J

    (1997)
  • R.A. Haworth et al.

    Inhibition of ATP-sensitive potassium channels of adult rat heart cells by antiarrhythmic drugs

    Circ Res

    (1989)
  • D.W. Hilgeman et al.

    Regulation of cardiac Na+, Ca2+ exchanger and KATP potassium channels by PIP2

    Science

    (1996)
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