Mitochondrial Potassium Channels

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Biochimica et Biophysica Acta 1757 (2006) 715–720 http://www.elsevier.com/locate/bba

Mitochondrial potassium channels: From pharmacology to function ⁎ Adam Szewczyk a, , Jolanta Skalska a, Marta Głąb a, Bogusz Kulawiak a, Dominika Malińska a, Izabela Koszela-Piotrowska a, Wolfram S. Kunz b

a Laboratory of Intracellular Ion Channels, Nencki Institute of Experimental Biology, 3 Pasteur st., 02-093 Warsaw, Poland b Department of Epileptology, University Bonn Medical Center, Sigmund-Freud-Str. 25, D-53105 Bonn, Germany Received 15 December 2005; received in revised form 19 April 2006; accepted 2 May 2006 Available online 12 May 2006

Abstract

Mitochondrial potassium channels, such as ATP-regulated or large conductance Ca2+-activated and voltage gated channels were implicated in cytoprotective phenomenon in different tissues. Basic effects of these channels activity include changes in mitochondrial matrix volume, mitochondrial respiration and membrane potential, and generation of reactive oxygen species. In this paper, we describe the pharmacological properties of mitochondrial potassium channels and their modulation by channel inhibitors and potassium channel openers. We also discuss potential side effects of these substances. © 2006 Elsevier B.V. All rights reserved.

Keywords: Mitochondria; Potassium channels; Potassium channel openers; Sulfonylurea; Diazoxide

1. Introduction drial metabolism primarily due to the regulation of matrix volume [7]. The basic pharmacological properties of mitochondrial Mitochondria play a fundamental role in energy generation potassium channels such as ATP-regulated potassium (mitoKATP) 2+ within the cell. Apart from this canonical role, mitochondria are channel, large conductance Ca -activated potassium (mitoBKCa) involved in other complex processes such as apoptosis. Mitochon- channel and voltage dependent potassium (mitoKv1.3) channel drial membrane permeabilization induces the release of cytochrome were found to be similar to some of the potassium channels present c, Smac/DIABLO, and AIF, starting various apoptosis pathways. in the plasma membrane of various cell types [8]. Recently, an essential position of potassium transport through mi- Rational application of different pharmacological substances tochondrial inner membrane was identified to trigger cytoprotection (channel inhibitors or potassium channel openers) helps in ex- [1–3]. This transport is strictly ion channel dependent, and accor- plaining the functional role of mitochondrial potassium channels dingly, resembles plasma membrane ion channels activity. Po- within the cell. In this paper, we describe the properties of mito- tassium selective ion channels were found to be present in inner chondrial potassium channels, their modulation by channel in- mitochondrial membrane [4–6]. Potassium ions control mitochon- hibitors and activators (potassium channel openers). Finally, we also discuss side effects of these substances and their potential contribution to cytoprotective effects.

Abbreviations: ANT, mitochondrial adenine nucleotide translocase; BKCa 2. Mitochondrial ATP-regulated K+ channel channel, large conductance Ca2+-activated potassium channel; BLM, black lipid

membrane technique; ChTx, charybdotoxin; IbTx, iberiotoxin; KATP channel, ATP-regulated potassium channel; mitoBKCa channel, mitochondrial large The mitoKATP channel was initially described in isolated liver conductance calcium-activated potassium channel; mitoKATP channel, mito- mitochondria [9]. Subsequently, it was also identified in heart [10], chondrial ATP-regulated potassium channel; mitoKv1.3 channel, mitochondrial brain [11,12], renal [13], skeletal muscle [14] and human T-lym- voltage gated potassium channel; NS1619, 1,3-dihydro-1-[2-hydroxy-5-(tri- phocyte mitochondria [15]. The activity of this channel is modu- fluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazole-2-one; SMP, sub- mitochondrial particles lated by various nucleotides [10] (see Fig. 1). Recently, it was ⁎ Corresponding author. Tel.: +48 22 5892269; fax: +48 22 8225342. shown that ATP effects on the mitoKATP channel can be modulated 2+ E-mail address: [email protected] (A. Szewczyk). by Ca [15].

acid has some mitochondrial specificity as mitoKATP channel blocker. An important contribution to understanding the pharmacological properties of the mitoKATP channel comes from the use of the techniques allowing single channel recording i.e. patch clamp or black lipid membranes [9,15,23–25]. The observed K+ channel activity is in fact a mitoKATP channel if the following pharmacological properties are present in the recorded potassium channel:

(1) The channel has to be blocked by ATP/Mg [9,10,23,26], (2) The ATP/Mg-inhibited channel should be activated by the potassium channel opener diazoxide [26,27], (3) The channel should be blocked by 5-hydroxydecanoic acid (5-HD), a substance known to be a blocker of the mitochondrial channel [23,24,26], (4) The channel should be blocked by glibenclamide [9,10,26], (5) The plasma membrane cardiac KATP channel blocker HMR1098 should be without effect on the channel activity [23,28],

Some of the substances acting on mitoKATP show additional effect on isolated mitochondria. Diazoxide is known to inhibit mitochondrial succinate dehydrogenase [29] and induce uncoupling of mitochondria [30,31]. Similar effects were observed with potassium channel opener—pinacidil [30]. Glibenclamide is also able to uncouple mitochondria at a high concentration [32] or to Fig. 1. Physiological regulators of the mitochondrial potassium channels: ATP- induce mitochondrial permeability transition [33].Recently,it 2+ regulated potassium (mitoKATP) channel, large conductance Ca -activated was shown that 5-HD is rapidly converted to 5-HD-CoA by potassium (mitoBKCa) channel and voltage dependent potassium (mitoKv1.3) mitochondrial fatty acyl-CoA synthetase and acts as a weak channel. ROS, reactive oxygen species; NO, nitric oxide. substrate or inhibitor of respiration in the employed conditions [34,35]. Hence, in some reports the existence of the mitoKATP channel in inner mitochondrial membrane is questioned [19,35– The molecular identity of the mitoKATP channel is presently 37]. It is proposed that the pharmacological preconditioning by unknown. Immunological studies identify both pore forming Kir mitoKATP channel modulators may be related to partial inhibition 6.1 and Kir6.2 subunits in brain mitochondria [16]. It has also been of respiratory chain complexes [35,38]. hypothesized that a complex of five proteins (including succinate These side effects may contribute to the overall effects of dehydrogenase) in the mitochondrial inner membrane is capable of substances used in experimental models with active metabolism, transporting K+ with characteristics similar to those of the mito- for example in experiments on isolated mitochondria or cells (see KATP channel [17]. Recently, adenine nucleotide translocase was Table 1). For example, application of 5-HD, as the KATP channel implicated in ATP-sensitive K+ transport into mitochondria [18– blocker, may be questioned in experimental models with active 20]. Interestingly, the involvement of adenine nucleotide translo- acyl-CoA synthase [35]. Additionally, the channel opener – dia- + case in K traffic was also suggested before description of the KATP zoxide – has a complex action on mitochondrial membrane po- channel activity in inner mitochondrial membrane [20]. tential [39], ROS production [40] and mitochondrial permeability Similarly, molecular properties of the mitochondrial sulfonyl- transition pore [41]. urea receptor (mitoSUR) are also not clear. The use of the sulfonylurea derivative [125I]glibenclamide leads to labeling of a 28 3. Mitochondrial large conductance calcium-activated kDa protein in heart mitochondria [21]. A 64 kDa protein was potassium channel labeled in brain mitochondria with the use of the fluorescent probe BODIPY-glibenclamide [11]. A putative mitochondrial large conductance Ca2+-activated Activity of this channel is modulated by drugs known as potas- potassium channel (mitoBKCa channel) was originally described sium channel openers [22]. All of the potassium channel openers using patch-clamp technique in human glioma cells LN229 [42]. applied on mitochondria were previously used to regulate plasma This channel, with a conductance of 295 pS, was stimulated by membrane ATP-regulated potassium channel or large conductance Ca2+ and blocked by charybdotoxin. Later the presence of a calcium-activated potassium channel. Despite this, potassium channel with properties similar to the surface membrane calcium- channel openers such as diazoxide and BMS191095, are consi- activated K+ channel (stimulated by the potassium channel opener dered mitoKATP-selective openers. Similarly, 5-hydroxydecanoic NS1619 and blocked by charybdotoxin, iberiotoxin and paxilline) A. Szewczyk et al. / Biochimica et Biophysica Acta 1757 (2006) 715–720 717

Table 1

Pharmacological regulators of mitochondrial potassium channels: mitochondrial ATP-regulated potassium (mitoKATP) channel, large conductance calcium-activated potassium (mitoBKCa) channel and voltage gated potassium (mitoKv1.3) channel. BLM—black lipid membranes technique Postulated Compound Experimental Applied Comments [References] channel target [inhibitor/activator] setup concentration or dose mitoKATP Glibenclamide Patch-clamp/ 10–100 μM Studies performed on liver [9] and heart mitochondria [23,25] [inhibitor] BLM Proteoliposomes 0.3–1 μMK+ flux with reconstituted partially purified channel [27] flux Isolated 0.3–50 μM Studies performed on rat liver mitochondria [27] mitochondria and skeletal muscle mitochondria [14] Tissue 50 μM [52] 5-hydroxydecanoic acid Patch-clamp/ 10 μM–1mM [15,23,24,53] [inhibitor] BLM Proteoliposomes 200 μM [54] flux Isolated 40 μ M–1 mM Studies performed on mitochondria isolated from heart [55,56], mitochondria skeletal muscle [14] liver [26], kidney [13] and brain [46] Cells/tissue 10 μM–1 mM Studies performed on cardiomiocytes [57–59], vascular smooth muscle cells [60], endothelial cells [61] and neuronal cultures [62]. quinine [inhibitor] BLM 3–100 μM Additionally 86Rb+ flux and [3H]glibenclamode binding experiments were performed [53] N-ethylmaleimide BLM 2 mM Reconstitution of inner mitochondrial membrane from beef [23] [inhibitor] Diazoxide [activator] Proteoliposomes 0.3–3 μMK+ flux with reconstituted partially purified channel [27] flux Isolated 10–100 μM [14] mitochondria BLM 10–50 μM Reconstitution of inner mitochondrial membrane from beef [23], [53] and rat heart mitochondria [24] were performed Cells/tissue 3.5 mg/kg [63] Cromakalim [activator] Proteoliposomes 0.3–10 μMK+ flux with reconstituted partially purified channel, flux two developmental cromakalim analogues EMD60480 and EMD57970 were also applied [27] Pinacidil [activator] Isolated 50 μM [30] mitochondria BMS191095 [activator] Isolated 10–30 μM Studies performed on heart and brain mitochondria [46,64,73] mitochondria Cells 10–40 μM Studies were performed with primary rat cortical neuronal cultures [65] Tissue 0.4–10 mg/kg [66–69] 6 μM [70,71], RP66471 [activator] Isolated 100 μM Studies performed with liver mitochondria [72] mitochondria Nicorandil [activator] Tissue 1.75 mg/kg [63] Isolated 10–100 μM Studies performed with rat skeletal muscle mitochondria [14] mitochondria P1075 [activator] Tissue 100 μM [52] Proteoliposomes 0.1–1 μM [52] flux Isoflurane [activator] BLM 0.8 mM Reconstitution of inner membrane from rat heart mitochondria [24] were performed mitoBKCa Charybdotoxin (ChTx) Patch-clamp 1–200 nM Mitoplasts from glioma cell line and cardiac tissue were used [42,43] [inhibitor] Mitochondrial 100 nM The surface of cardiac myocytes was permeabilized flux with the use of saponin. ChTx slowed K+ uptake (measured with fluorescent probe PBFI) by approximately 20-fold [43] Iberiotoxin (IbTx) Mitochondrial 100 nM The surface of cardiac myocytes was permeabilized [inhibitor] flux with the use of saponin [43] Paxilline [inhibitor] 2 μM Paxilline was also used to block the protective effect of NS1619 in the experiments of the ischemic damage experiments [43] NS1619 [activator] Mitochondrial 30 μM [43] flux (continued on next page) 718 A. Szewczyk et al. / Biochimica et Biophysica Acta 1757 (2006) 715–720

Table 1 (continued) Postulated Compound Experimental Applied Comments [References] channel target [inhibitor/activator] setup concentration or dose mitoBKCa Cells 30 μM [44] mitoKv1.3 Margatoxin (MgTx) Patch-clamp 2 nM Studies were performed on T lymphocytes mitochondria [51] [inhibitor] Isolated 10 nM A relatively high concentration of toxin was used to mitochondria promote a rapid diffusion to the inner membrane and to achieve complete inhibition [51]

was observed in patch-clamp recordings from mitoplasts of mitoBKCa channel in cardiac mitochondria [48].Additionally,it guinea pig ventricular cells [43]. Immunoblots of cardiac mito- was suggested that the β1 subunit of BKCa channel is present in chondria with antibodies against the C terminal part of BKCa inner mitochondrial membrane and interacts with cytochrome c channel identified a 55 kDa protein as putative channel which oxidase subunit I [48]. + may contribute to the cardioprotective effect of K influx into It has also been reported that two BKCa channel openers, NS004 mitochondria. Very recently, it was reported that cardiac mito and NS1619, inhibit mitochondrial function in human glioma cells BKCa activation by NS1619 (measured by flavoproteins oxida- due to inhibition of the complex I of mitochondrial respiratory tion) is amplified by 8-bromoadenosine-3′,5′-cyclic monophos- chain [49]. Recently, a channel opener NS1619 was shown to phate and forskolin [44]. This suggests that opening of mitoBKCa inhibit the function of isolated cardiac mitochondria in similar is modulated by cAMP-dependent protein kinase. manner [50]. It should be mentioned that the mitoBKCa channel may offer a novel link between cellular/mitochondrial calcium signaling and 4. Voltage regulated potassium channel in inner mitochondrial mitochondrial membrane potential-dependent reactions. Altered membrane intramitochondrial calcium levels directly affect the potassium permeability of the mitochondrial inner membrane thus modula- Recently, a margatoxin-sensitive voltage gated Kv1.3 channel ting the membrane potential. This type of interaction can mo- was identified in T lymphocytes mitochondria [51] with the use of dulate the efficiency of oxidative phosphorylation in a calcium- patch-clamp, electron microscopy and immunological studies. dependent manner. Interestingly, it was shown that Kv1.3 is present both in the plas- The pharmacological, biophysical and molecular character- ma and mitochondrial membranes, despite lacking the N-terminal istics of this channel appear to be similar to the following pro- mitochondrial targeting sequence. Mitochondrial Kv1.3 channel perties of the well known plasma membrane large conductance my represent an important factor in the apoptotic signal trans- potassium channel (BKCa-channel, slo 1) [45]: duction [51].

(i) The mitochondrial channel is potassium selective and ac- 5. Final remarks tivated by calcium ions. (ii) The channel is inhibited by iberiotoxin and charybdotoxin Until presently, three different potassium channels have been at nanomolar concentrations. reported to contribute to the potassium permeability of mito- (iii) The channel is activated by NS1619 at low micromolar chondria—the ATP-regulated potassium channel (mitoKATP concentrations. channel), the large conductance Ca2+-activated potassium channel (mitoBKCa channel) and the voltage gated Kv1.3 chan- Very likely, the mitochondrial channel has its charybdotoxin/ nel. Although the precise molecular identity of these channels iberiotoxin binding site close to the cytosolic compartment since remains to be elucidated, their control of mitochondrial potassium those compounds as peptides cannot easily enter the mitochon- transport has two important implications: drial matrix space. Consequently, the calcium binding site of the Small alterations in the potassium permeability contribute to mitoBKCa channel is close to the matrix compartment (cf. orien- physiological regulation of the mitochondrial matrix volume. tation of the plasma membrane BKCa channel [45]). A larger increase in the potassium permeability of the mito- Similar to the mitochondrial ATP-regulated potassium chan- chondrial inner membrane affects the mitochondrial membrane nel, this novel potassium channel is expected to affect mito- potential (mild uncoupling) with potential beneficial effects on chondrial metabolism due to regulation of matrix volume [7].In cell survival under pathological conditions. addition to this classical physiological effect of mitochondrial In this review, various classes of substances that interact with potassium transport, a pivotal role of mitochondrial potassium mitochondrial potassium channels have been presented. They play channels has been implicated in cardio- and neuroprotection an important role in identification and characterization of mito- [1,2,46]. It is therefore reasonable to expect a possible cyto- chondrial channels in different tissues. In light of the ubiquitous protective effect of mitoBKCa channel activation, probably in the presence of mitochondrial identified potassium channels, novel presence of superoxide radicals [47]. Recently, it was shown that opportunities for novel drug development have been emerged. cardioprotective effects of estradiol include the activation of To reach this stage, however, the molecular identification of A. Szewczyk et al. / Biochimica et Biophysica Acta 1757 (2006) 715–720 719

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