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Keywords:

  • KATP;
  • Kir6.2 ;
  • sulfonylurea receptor;
  • phospholipids;
  • PtdInsP2;
  • phospholipase C;
  • ATP;
  • ADP

Abstract

  1. Top of page
  2. Abstract
  3. Molecular architecture of katp
  4. Mechanism and molecular determinants of ATP inhibition
  5. Antagonism of ATP inhibition by ADP and ATP acting at the sur
  6. Phospholipids: a new class of regulatory molecules for kir channels
  7. Phospholipids reduce atp sensitivity of katp channels
  8. Physiological implications for ptdinsp modulation
  9. Conclusions
  10. References

The KATP channel is a heterooctamer composed of two different subunits, four inwardly rectifying K+ channel subunits, either Kir6.1 or Kir6.2, and four sulfonylurea receptors (SUR), which belong to the family of ABC transporters. This unusual molecular architecture is related to the complex gating behaviour of these channels. Intracellular ATP inhibits KATP channels by binding to the Kir6.x subunits, whereas Mg-ADP increases channel activity by a hydrolysis reaction at the SUR. This ATP/ADP dependence allows KATP channels to link metabolism to excitability, which is important for many physiological functions, such as insulin secretion and cell protection during periods of ischemic stress. Recent work has uncovered a new class of regulatory molecules for KATP channel gating. Membrane phospholipids such as phosphoinositol 4,5-bisphosphate and phosphatidylinositiol 4-monophosphate were found to interact with KATP channels resulting in increased open probability and markedly reduced ATP sensitivity. The membrane concentration of these phospholipids is regulated by a set of enzymes comprising phospholipases, phospholipid phosphatases and phospholipid kinases providing a possible mechanism for control of cell excitability through signal transduction pathways that modulate activity of these enzymes. This review discusses the mechanisms and molecular determinants that underlie gating of KATP channel by nucleotides and phospholipids and their physiological implications.

Abbreviations
KATP

ATP-sensitive K+ channel

PtdInsPs

phosphatidylinositolphosphates

PtdInsP2

phosphatidylinositol 4,5-bisphosphate

PtdInsP

phosphatidylinositiol 4-monophosphate

PtdIns

phosphatidylinositol

PLC

phospholipase C

SUR

sulfonylurea receptor

Kir

inward-rectifier potassium channel

NBF

nucleotide binding fold

TM

transmembrane segment, CFTR, cystic fibrosis transmembrane conductance regulator

KcsA

potassium channel of Streptomyces lividans

KATP channels, which were first described in cardiac tissue [1], have now been identified in most excitable cells including pancreatic β-cells, neurons, cardiac myocytes, skeletal and smooth muscle cells [2–6]. These channels are weakly inwardly rectifying K+ channels that stabilize the membrane potential close to the equilibrium potential for K+, thereby counteracting membrane depolarization. The hallmark property of this channel is its high sensitivity to inhibition by intracellular ATP. This sensitivity to ATP in combination with the activating potency of Mg-ADP make the KATP channel a metabolic sensor linking cellular metabolic state, reflected by the ATP/ADP ratio, to membrane excitability [2–6]. Insulin secretion from pancreatic β-cells in response to glucose uptake is the showpiece for KATP channels as a metabolic sensor ( Fig. 1). Metabolism of glucose results in elevation of intracellular ATP and decrease of ADP, which leads to closure of KATP channels, resulting in membrane depolarization, activation of voltage-dependent calcium (Ca2+) channels and influx of Ca2+, which finally triggers the release of insulin [4,7]. Given its pivotal role in insulin secretion it was not surprising to find that pharmaceuticals used to alter insulin secretion target the KATP channel [8,9]. Sulfonylureas, such as tolbutamide and glibenclamide, that inhibit pancreatic KATP channels are used in treatment of noninsulin-dependent diabetes mellitus because of their stimulating effect on insulin secretion. Conversely, KATP channel openers such as diazoxide activate pancreatic KATP channels and are therefore used to induce insulin secretion [10]. A further example of the physiological function of KATP channels is ischemia-related hyperpolarization in cardiac myocytes, where a decrease in intracellular ATP releases ATP-inhibition, which via an increase in the KATP-mediated potassium conductance causes shortening of the action potential. The concomitant reduction in excitation and contractile force decreases energy consumption and therefore favours cell survival in periods of metabolic impairment [2,3,11].

image

Figure 1. Schematic representation of the relationship between glucose metabolism, changes in the ATP/ADP ratio, KATP channel activity and secretion of insulin in pancreatic β-cells as discussed in the text.

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Molecular architecture of katp

  1. Top of page
  2. Abstract
  3. Molecular architecture of katp
  4. Mechanism and molecular determinants of ATP inhibition
  5. Antagonism of ATP inhibition by ADP and ATP acting at the sur
  6. Phospholipids: a new class of regulatory molecules for kir channels
  7. Phospholipids reduce atp sensitivity of katp channels
  8. Physiological implications for ptdinsp modulation
  9. Conclusions
  10. References

Recently, the molecular identity of KATP channels was elucidated ( Fig. 2A): uniquely among potassium channels they are formed from an ATP binding cassette (ABC) protein, the sulfonylurea receptor (SUR), and an inward-rectifier (Kir) potassium channel (Kir6.1 or Kir6.2) [12,13]. The Kir6.x subunit demonstrates the prototypic transmembrane topology of Kir channels, comprising hydrophilic N- and C-termini and two hydrophobic transmembrane segments (TM1 and TM2) flanking a well-conserved pore domain. The SUR protein (about 1580 amino acids in length) presents with 17 putative TMs and two nucleotide-binding folds (NBFs) [14,15]. Functional KATP channels are conceived as octamers with a 1 : 1 stoichiometry of Kir6.x and SUR [16–18]. The four Kir6.x subunits form the pore at the central axis of the channel complex and determine single channel conductance and block by magnesium and polyamines [19,20]. The four SURs that are thought to be grouped symmetrically around this central pore formation act as regulatory subunits endowing the KATP channel with sensitivity to sulfonylureas, channel openers and Mg-ADP [13,21–24]. Furthermore, SUR is necessary for surface expression of Kir6.2. Both SUR and Kir6.2 subunits contain ER retention motifs that prevent surface expressing of each subunit type in the absence of the other. Formation of the octameric complex inactivates these retention motifs guaranteeing surface expression of properly assembled KATP channels [25].

image

Figure 2. Molecular architecture and physiological properties of KATP channels. (A) Topological model of Kir6.x and SUR. Kir6.x has two putative membrane spanning segments linked by a loop (P-loop) thought to form part of the pore. SUR has 17 TMs and two NBFs indicated by dark boxes. From these two subunits the KATP channel is formed as an octamer with (Kir6.x/SUR)4 stoichiometry. (B) Time course of ATP inhibition thought to be mediated by the Kir6.2 subunits. Macroscopic currents of KATP (Kir6.2/SUR1) channels in an excised patch at a holding potential of −80 mV. Application of 100 µm ATP with a rapid perfusion system for the duration indicated (experimental conditions described in [66]). Time course of ADP activation thought to be mediated by the NBFs of SUR. Application of 100 µm ATP and 100 µm ADP as indicated. Solutions with nucleotides contained 1 m m free Mg2+ (experimental conditions described in [66]).

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The different isoforms of Kir6.x (Kir6.1 or Kir6.2) and SUR (SUR1, SUR2A, SUR2B) show a distinct expression pattern. Thus, pancreatic/neuronal KATP channels are assembled from Kir6.2 and SUR1, cardiac channels from and SUR2A and vascular channels from Kir6.1 (or Kir6.2) and SUR2B. These brands of KATP channels differ in their pharmacology and sensitivity to inhibition by ATP [3,6,12,13,21,29]. In contrast to Kir6.2, Kir6.1 is ubiquitously expressed in the inner membrane of mitochondria and thought to be part of the mitochondrial KATP channel [30,31]. The recent findings [31] indicating that the mitochondrial KATP channel is responsible for at least part of the cell-protective effects (especially in cardiac tissue) that have been previously attributed to the classical surface membrane KATP channels .

The cloning of the KATP channel’s subunits initiated molecular work that shed light on the mechanisms underlying the regulation of KATP channels by intracellular factors and pharmacological agents which will be discussed below.

Mechanism and molecular determinants of ATP inhibition

  1. Top of page
  2. Abstract
  3. Molecular architecture of katp
  4. Mechanism and molecular determinants of ATP inhibition
  5. Antagonism of ATP inhibition by ADP and ATP acting at the sur
  6. Phospholipids: a new class of regulatory molecules for kir channels
  7. Phospholipids reduce atp sensitivity of katp channels
  8. Physiological implications for ptdinsp modulation
  9. Conclusions
  10. References

The property of KATP channels giving them their name is demonstrated by heterologously expressed Kir6.2/SUR1 channels in a fast solution exchange experiment ( Fig. 2B, left panel). Application of 100 µm ATP inhibits channel activity almost completely within a few milliseconds and upon removal of ATP, inhibition is released within less than 100 ms. Therefore, KATP channels may be regarded as ligand-gated ion channels and ATP as a ligand with micromolar affinity and fast reaction kinetics. Single channel analysis has provided insight into the mechanism underlying ATP inhibition. The current gating scheme for KATP channels postulates several closed states and one open state. ATP is thought to bind to a closed state and by stabilizing this state to cause inhibition of KATP[20,32,33].

Comparing the inhibitory potency of ATP to that of other nucleotides revealed structural features critical for the ligand. One prerequisite for high affinity inhibition was found to be the adenosine ring, as subtle changes in this moiety resulted in markedly less effective inhibitory ligands [4]. Accordingly, GTP, ITP and UTP were found to be more than 100-fold less effective than ATP [34], which has an inhibition constant (Ki) of about 10 µm for Kir6.2/SUR1 channels. Furthermore, the number of phosphate groups is critical [1,2,4]. AteP (adenosine tetraphosphate) and ATP have similar affinities [35], while ADP displays about 10-fold lower affinity and AMP causes only weak inhibition even at millimolar concentrations [34]. Thus, the α- and β-phosphate groups appear to be necessary for ligand binding whereas the γ-phosphate group is less important, although it contributes to the ability of ATP to cause high affinity inhibition. Finally, ATP hydrolysis is not required for channel inhibition since nonhydrolysable analogues of ATP are equally effective as ATP [7,36,37].

Cloning of the KATP channel subunits raised the question on the localization of the ATP binding site within the channel complex. A step towards its identification came from experiments with a mutant of Kir6.2 lacking the 26 C-terminal residues [19]. This mutant Kir6.2 forms functional channels in the absence of SUR. These homomeric Kir6.2 channels were sensitive to inhibition by ATP establishing Kir6.2 as the subunit that inherits the ATP binding site. This outcome was somehow surprising, given that Kir6.2 lacks a classical ATP binding motive. Subsequent mutagenesis then uncovered three regions in the cytoplasmic N- and C-termini of Kir6.2 that might be involved in the binding of ATP, as mutations in these regions profoundly affected ATP inhibition as measured in electrophysiological experiments [20,34,38,39]. The exact location of the binding site, however, remains unknown mainly because electrophysiological assays do not distinguish between direct effects on ATP binding and indirect effects on the transduction machinery by which bound ATP initiates channel closure. Thus, a number of mutations reported to reduce ATP sensitivity probably do not interfere with the binding of ATP, but impair the channel’s ability to close. Interestingly, many of these mutations are located in the cytoplasmic end of the second transmembrane segment (TM2) [20,34,38], a region that is thought to form the inner vestibule of the pore [40–43]. In voltage-gated potassium (Kv) channels, the homologous region (TM6) has been shown to undergo structural rearrangements during activation gating [44]. Thus, in KATP channels this region might be speculated to form part of the gate (or be coupled to the gate) that closes the pore upon binding of ATP. This hypothesis has been recently strengthened by the finding that binding of cadmium ions to cyteines introduced into TM2 is inhibited when the channel is closed by ATP [42].

Antagonism of ATP inhibition by ADP and ATP acting at the sur

  1. Top of page
  2. Abstract
  3. Molecular architecture of katp
  4. Mechanism and molecular determinants of ATP inhibition
  5. Antagonism of ATP inhibition by ADP and ATP acting at the sur
  6. Phospholipids: a new class of regulatory molecules for kir channels
  7. Phospholipids reduce atp sensitivity of katp channels
  8. Physiological implications for ptdinsp modulation
  9. Conclusions
  10. References

In the absence of Mg, ADP inhibits KATP channels in a manner similar to ATP. In contrast, under physiological conditions with millimolar concentrations of Mg2+ and ATP, ADP was found to be a potent activator of KATP[45,46]. Application of 100 µm Mg-ADP markedly released the inhibition produced by 100 µm Mg-ATP, thereby effectively activating the channel ( Fig. 2B, right panel). The requirement of Mg2+ as a cofactor might indicate a hydrolysis reaction as the underlying mechanism [22]. The SUR could be the subunit performing this hydrolysis, reaction via its NBFs. Each NBF contains Walker A and B motifs, that are known to bind and hydrolyse ATP in other ABC transporters and ATPases [47–51]. Indeed, mutations of critical residues in these motifs were found to result in reduced or abolished potency of Mg-ADP-mediated activation of KATP[22,23,52]. Furthermore, a natively occurring mutation in the Walker B motif causes persistent hyperinsulinemic hypoglycemia of infancy [52,53], which is characterized by glucose-independent insulin secretion from pancreatic β-cells. This mutation was found to abolish Mg-ADP-mediated activation, thus supporting the importance of ADP activation for the function of KATP as metabolic sensors. Presently it is not clear if ADP itself is hydrolysed or if it stimulates hydrolysis (or binding) of ATP. Further studies (especially biochemical investigations) will be necessary to clarify the issue.

Nucleotide hydrolysis is also likely to be involved in the action of K+ channel openers (e.g. diazoxide, cromakalim). The latter activate KATP channels in a manner similar to Mg-ADP, by antagonizing ATP inhibition. K+ channel openers require Mg2+ and hydrolyzable nucleotides to exert their effect [54]. Moreover, mutations in the NBFs that abolish the effect of Mg-ADP also impair the ability of KATP to respond to diazoxide [22,23].

How nucleotides acting at the NBFs of SUR are able to release ATP inhibition at the Kir6.2 is the subject of ongoing investigations. As a possible mechanism, nucleotide hydrolysis might induce a particular conformation of SUR that stabilizes the open channel state and counteracts the effect of ATP, which is thought to stabilize a close state [23]. This mechanism would resemble the role of ATP hydrolysis in the gating of CFTR Cl channels, where ATP hydrolysis at the NBFs of CFTR is thought to provide the energy to open the channel [55–58]. Thus, in KATP and CFTR, nucleotide hydrolysis at the NBFs may drive conformational changes that open the channel pores.

Phospholipids: a new class of regulatory molecules for kir channels

  1. Top of page
  2. Abstract
  3. Molecular architecture of katp
  4. Mechanism and molecular determinants of ATP inhibition
  5. Antagonism of ATP inhibition by ADP and ATP acting at the sur
  6. Phospholipids: a new class of regulatory molecules for kir channels
  7. Phospholipids reduce atp sensitivity of katp channels
  8. Physiological implications for ptdinsp modulation
  9. Conclusions
  10. References

Many Kir channels undergo severe rundown when measured in excised membrane patches. This behaviour suggested washout of a factor that is required for the channel’s functional integrity. In many cases, channel activity could be restored by application of Mg-ATP to the excised patches [59,60]. Recently, the nature of this Mg-ATP dependent process was uncovered as phosphorylation of the membrane lipid phosphatidylinositol (PtdIns) by PtdIns kinases [61]. Both depletion of PtdIns from the membrane and the PtdIns kinases inhibitor wortmannin prevent Mg-ATP dependent recovery of channel activity [61,62]. Application of phosphatidylinositiol 4-monophosphate (PtdInsP) and phosphatidylinositiol 4,5-bisphosphate (PtdInsP2), which are formed by phosphorylation of PtdIns via PtdIns kinases, reverse channel rundown establishing phosphatidylinositolphosphates (PtdInsPs) as potent regulators of Kir channel activity [61,63–65].

Phospholipids reduce atp sensitivity of katp channels

  1. Top of page
  2. Abstract
  3. Molecular architecture of katp
  4. Mechanism and molecular determinants of ATP inhibition
  5. Antagonism of ATP inhibition by ADP and ATP acting at the sur
  6. Phospholipids: a new class of regulatory molecules for kir channels
  7. Phospholipids reduce atp sensitivity of katp channels
  8. Physiological implications for ptdinsp modulation
  9. Conclusions
  10. References

In KATP channels, PtdInsPs do not only reverse channel rundown and increase open probability, they also exert a profound effect on ATP-gating [66–68]. The effect of PtdInsP2 on KATP channels is demonstrated in Fig. 3A. Application of 1 m m ATP to a patch containing (at least) four KATP channels results in complete inhibition of channel activity, application of PtdInsP2 increases the channel’s open probability and subsequent application of ATP revealed KATP channels that could only be weakly inhibited by ATP. This loss of ATP sensitivity is persistent in excised patches indicating that phospholipids are stably incorporated into the membrane. As illustrated in Fig. 3B, the reduction in ATP sensitivity results from a shift of the ATP concentration–response curve by several orders of magnitude towards higher concentrations [66,67]. Interestingly, this shift is not associated with a change in slope indicating that ATP sensitivity of individual channels is changed gradually rather than in an ‘all-or-nothing’ manner. Experiments on the kinetics of ATP inhibition revealed that PtdInsP2 reduces the apparent on-rate for ATP inhibition but had no effect on the apparent unbinding rate [66]. These experiments indicate that PtdInsP2 does not alter the stability of ATP–receptor interaction, rather it reduces the availability of the receptor site for ATP binding. This might result from direct competition between PtdInsP2 and ATP for an overlapping binding site, or PtdInsP2 might restrict access to the ATP binding site by an allosteric mechanism.

image

Figure 3. Effects of PtdInsPs on KATP channels (modified from [ 66 ]). (A) Single channel currents at a holding potential of −80 mV in a patch containing (at least) four channels. Application of PtdInsP2 increased channel open probability and reduced sensitivity to inhibition by ATP. (B) ATP concentration–response curves before and after several applications of 100 µm PtdInsP2 (cumulative application times are indicated). (C) Current response to voltage steps from 20 to 80 mV in a patch expressing macroscopic KATP currents. Application of PtdInsP2, PtdInsP and PtdIns reduced inhibition by 1 m m ATP with different potencies. Schematic structures for PtdInsPs are plotted to visualize the relationship between the number of phosphate groups (P) attached to the inositol head group and the potency of the PtdInsPs, R is fatty acid.

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Biochemical and electrophysiological experiments indicate that PtdInsP2 interacts with basic residues in the C-terminus of Kir6.2 [64,65]. The nature of this interaction appears to be electrostatic as the number of phosphate groups and thereby the number of negative charges attached to the inositol ring is critical for the phospholipid effect on ATP inhibition [66,67]. Accordingly, PtdInsP2 is more potent in reducing ATP inhibition than PtdInsP, whereas PtdIns has no effect ( Fig. 3C). Moreover, polycations such as polylysine, which are known to bind to phospholipids and screen their negative charges, abolish the effect of PtdInsPs on ATP inhibition [64,67]. In addition, for the phosphorylated inositol ring to be effective, membrane localization is important as inositol 1,4,5-trisphosphate, the ‘headgroup’ of PtdInsP2, did not exert any effect on ATP-inhibition [67].

Physiological implications for ptdinsp modulation

  1. Top of page
  2. Abstract
  3. Molecular architecture of katp
  4. Mechanism and molecular determinants of ATP inhibition
  5. Antagonism of ATP inhibition by ADP and ATP acting at the sur
  6. Phospholipids: a new class of regulatory molecules for kir channels
  7. Phospholipids reduce atp sensitivity of katp channels
  8. Physiological implications for ptdinsp modulation
  9. Conclusions
  10. References

The involvement of PtdInsPs in the control of ATP sensitivity of KATP channels might provide an explanation for a number of puzzling phenomena. In general, when measured in excised patches, micromolar concentrations of ATP are sufficient to inhibit channel activity, whereas in intact cells KATP channels were found to be active despite millimolar concentrations of intracellular ATP [69]. Thus, similarly to Mg-ADP, PtdInsPs might shift the channel’s sensitivity for ATP into the physiological range. Furthermore, ATP inhibition shows considerable variability when examined in different tissues [4], but also when tested in cells from the same tissue. Thus, in excised patches from cardiac myocytes, ATP sensitivity may vary by as much as 60-fold [70] and could be markedly increased by application of polycations [71], which also abolish the effect of PtdInsPs on ATP inhibition [67]. Moreover, ATP sensitivity can change during different regulatory states of cells, e.g. metabolic stress can profoundly reduce ATP sensitivity in cardiac myocytes [72]. Thus, variability and modulation of ATP sensitivity of KATP channels might result from differences in membrane concentrations of PtdInsPs.

Levels of PtdInsPs may change as a result of altered phospholipid metabolism, which is governed by PtdIns kinases, PtdInsPs phosphatases and phospholipases (e.g. phospholipase C; PLC).

Activity of these enzymes is regulated by G-proteins and tyrosine kinases linking activity of KATP channels and thereby cell excitability to various signal transduction pathways [73,74]. Stimulation of PtdIns kinases will increase PtdInsPs levels, which is expected to release ATP inhibition, whereas PtdInsPs phosphatases and phospholipases break down PtdInsPs and their activation should result in increased ATP sensitivity of KATP channels. In agreement with this concept, activation of PLC by G-proteins was shown to reduce KATP-mediated currents due to increased ATP inhibition in heterologous expression systems [66,75]. Furthermore, overexpression of a PtdIns kinase resulted in increased KATP currents displaying reduced ATP sensitivities [76]. Intriguingly, up-regulation of PtdIns kinase activity through tyrosine kinases has been suggested to underlie activation of KATP channels in hypothalamic neurons and pancreatic β-cells [77,78]. Besides KATP channels, both G-protein regulated (GIRKs) and pH-regulated (ROMK) inwardly rectifying channels were shown to be modulated by PtdInsPs [63,65]. Thus, regulations of Kir channel activity by PtdInsPs might serve as a potent means to couple excitability to cellular metabolism in variety of cells.

Conclusions

  1. Top of page
  2. Abstract
  3. Molecular architecture of katp
  4. Mechanism and molecular determinants of ATP inhibition
  5. Antagonism of ATP inhibition by ADP and ATP acting at the sur
  6. Phospholipids: a new class of regulatory molecules for kir channels
  7. Phospholipids reduce atp sensitivity of katp channels
  8. Physiological implications for ptdinsp modulation
  9. Conclusions
  10. References

Cloning of the subunits making up the ATP-sensitive K+ channel (KATP) has allowed immense progress in the molecular understanding of the complex gating of this channel. The inhibitory site for ATP was localized to the Kir6.2 subunit. Identification of its precise location within the subunit, and the molecular mechanism linking ATP binding to channel closure will be the next goals. Mg-ADP was found to activate the channel via interactions with the NBFs of the SUR. How the binding of ADP and other effectors (ATP, sulfonylureas, channel openers) to the SUR is transduced to the Kir6.2 subunits are further challenging questions. Recent work has uncovered phospholipids such as PtdInsP2 and PtdInsP as a new class of regulatory molecules for KATP channels. These phospholipids were found to interact with the C-terminus of Kir6.2 causing channel activation and markedly reduced ATP sensitivity. Phospholipid regulation of KATP and other Kir channels might represent an effective mechanism for control of cell excitability via signal transduction pathways linked to phospholipid metabolism. However, further (especially in vivo) studies are needed to demonstrate the physiological relevance of this concept.

References

  1. Top of page
  2. Abstract
  3. Molecular architecture of katp
  4. Mechanism and molecular determinants of ATP inhibition
  5. Antagonism of ATP inhibition by ADP and ATP acting at the sur
  6. Phospholipids: a new class of regulatory molecules for kir channels
  7. Phospholipids reduce atp sensitivity of katp channels
  8. Physiological implications for ptdinsp modulation
  9. Conclusions
  10. References
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