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