The Mitochondrial Sulfonylurea Receptor: Identification and Characterization

Szewczyk, Adam; Wójcik, Grażyna; Lobanov, Nikolai A.; Nałȩcz, Maciej J.

doi:10.1006/bbrc.1996.6023

Cited by 66 publications

(48 citation statements)

References 26 publications

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“…Western blot analysis of mitochondria isolated from liver and skeletal muscle detected K ir 6.1 (Suzuki et al, 1997). A lowaffinity binding site for glibenclamide in purified mitochondria preparations has been proposed to be a mitochondrial SUR (Szewczyk et al, 1997). Furthermore, mitoK ATP reconstituted in liposomes consists of 55-and 63-kDa proteins that may be mitoK ir and mitoSUR, respectively (Bajgar et al, 2001;Mironova et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Sulfonylurea Receptor-Dependent and -Independent Pathways Mediate Vasodilation Induced by ATP-Sensitive K⁺ Channel Openers

Adebiyi

McNally

Jaggar³

2008

Mol Pharmacol

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ATP-sensitive K ϩ (K ATP ) channel openers are vasodilators that activate both plasma membrane and mitochondrial K ATP channels. Here, we investigated the molecular mechanisms by which diazoxide and pinacidil induce vasodilation by studying diameter regulation of wild-type [SUR2(ϩ/ϩ)] and sulfonylurea receptor (SUR) 2-deficient [SUR2(Ϫ/Ϫ)] mouse myogenic mesenteric arteries. Ryanodine (10 M), a ryanodine-sensitive Ca 2ϩ release (RyR) channel blocker; iberiotoxin (100 nM), a large-conductance Ca 2ϩ -activated K ϩ (K Ca ) channel blocker; 4-aminopyridine (4-AP; 1 mM), a voltage-gated K ϩ (K V ) channel blocker; manganese(III) tetrakis(1-methyl-4-pyridyl)porphyrin (MnTMPyP; 100 M), an antioxidant; and a combination of ryanodine and 4-AP reduced diazoxide (100 M)-induced dilation in pressurized (60 mm Hg) SUR2(ϩ/ϩ) arteries by 45 to 77%. In contrast, these inhibitors did not alter pinacidil (5 M)-induced dilation in SUR2(ϩ/ϩ) arteries. Reverse transcription-polymerase chain reaction indicated that SUR2B was the only SUR isoform expressed in SUR2(ϩ/ϩ) mesenteric artery smooth muscle cells, whereas SURs were absent in SUR2(Ϫ/Ϫ) cells. In SUR2(Ϫ/Ϫ) arteries, pinacidil-induced vasodilation was ϳ10% of that in SUR2(ϩ/ϩ) arteries, whereas diazoxide-induced vasodilation was similar in SUR2(ϩ/ϩ) and SUR2(Ϫ/Ϫ) arteries. Atpenin (1 M), a selective electron transport chain (ETC) complex II inhibitor, dilated arteries similarly to diazoxide, and this effect was attenuated by MnTMPyP and ryanodine ϩ 4-AP. Atpenin also attenuated diazoxide-, but not pinacidil-induced vasodilation. In summary, data indicate that pinacidil-induced vasodilation requires SUR2B, whereas diazoxide-induced vasodilation does not require SURs. Rather, diazoxide-induced vasodilation involves ETC II inhibition; a smooth muscle cell-reactive oxygen species elevation; and RyR, K Ca , and K V channel activation. These data indicate that K ATP channel openers regulate arterial diameter via SUR-dependent and -independent pathways.Plasma membrane ATP-sensitive K ϩ (pmK ATP ) channels couple changes in cellular metabolic activity to membrane electrical excitability (Ashcroft and Ashcroft, 1990). K ATP channels are composed of pore-forming K ir 6.x and regulatory sulfonylurea receptor (SUR) subunits . The assembly of four K ir 6.x and four SUR subunits results in tissue-specific K ATP channel complexes with different functional, electrophysiological, and pharmacological properties .SURs are members of the ATP-binding cassette transporter protein superfamily that are predicted to form 17 transmembrane-spanning helices and two intracellular nucleotide binding domains (Tusná dy et al., 1997). Two distinct SUR isoforms (SUR1 and SUR2) have been identified that are ϳ70% identical . Alternative splicing of the SUR2 gene at the 3Ј end results in two additional isoforms, SUR2A and SUR2B, that have different pharmacological profiles (Isomoto et al., 1996). SURs are the molecular target of pharmacologically diverse and clinically important agonists and antagonists. ...

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Section: Discussionmentioning

confidence: 99%

Sulfonylurea Receptor-Dependent and -Independent Pathways Mediate Vasodilation Induced by ATP-Sensitive K⁺ Channel Openers

Adebiyi

McNally

Jaggar³

2008

Mol Pharmacol

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“…Mitochondria also contain a 28-kDa SUR (mito-SUR), as revealed by binding studies performed in beef heart mitochondria with [ 3 H]glibenclamide and SDS-PAGE (Szewczyk et al 1997), and one of 63 kDa that was purified from rat brain mitochondrial fractions by DEAEcellulose column chromatography (Bajgar et al 2001). It is unknown why there were so many different sizes of mature SUR polypeptides detected in different tissues (Aguilar-Bryan et al 1995;Szamosfalvi et al 2002) or even in the same subcellular fractions (Szewczyk et al 1997;Bajgar et al 2001) in different tissues. It might be as a result of posttranslational modification or the susceptibility of SUR proteins to proteolysis.…”

Section: Discussionmentioning

confidence: 99%

“…K ATP channels are heteromultimers of SURs and Kir6.x with a (SURs-Kir6.x) 4 stoichiometry with an estimated molecular mass of 950 kDa (Clement et al 1997). Although core glycosylated SUR proteins located in the cell surface membrane have been detected at 100-250 kDa (Skeer et al 1994;Aguilar-Bryan et al 1995;Szamosfalvi et al 2002), SUR in mitochondria (mito-SUR) was z28-63 kDa (Szewczyk et al 1997;Bajgar et al 2001). It is possible that mito-SUR protein may be truncated and active in a short form.…”

Section: Discussionmentioning

confidence: 99%

Localization of Sulfonylurea Receptor Subunits, SUR2A and SUR2B, in Rat Heart

Zhou

Suzuki

et al. 2007

J Histochem Cytochem.

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(KK) S U M M A R Y To understand the possible functions and subcellular localizations of sulfonylurea receptors (SURs) in cardiac muscle, polyclonal anti-SUR2A and anti-SUR2B antisera were raised. Immunoblots revealed both SUR2A and SUR2B expression in mitochondrial fractions of rat heart and other cellular fractions such as microsomes and cell membranes. Immunostaining detected ubiquitous expression of both SUR2A and SUR2B in rat heart in the atria, ventricles, interatrial and interventricular septa, and smooth muscles and endothelia of the coronary arteries. Electron microscopy revealed SUR2A immunoreactivity in the cell membrane, endoplasmic reticulum (ER), and mitochondria. SUR2B immunoreactivity was mainly localized in the mitochondria as well as in the ER and cell membrane. Thus, SUR2A and SUR2B are not only the regulatory subunits of sarcolemmal K ATP channels but may also function as regulatory subunits in mitochondrial K ATP channels and play important roles in cardioprotection. (J Histochem Cytochem 55:795-804, 2007)

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“…9 The response of these mice to ischemic injury has not yet been determined, but mitoK ATP opening was apparently not disrupted by elimination of this K ATP subunit. 9 Regarding the possibility that SUR is present in mitochondrial membranes, low-affinity sulfonylurea binding sites were identified in purified mitochondrial preparations, 133,134 and a putative 63-kD sulfonylurea binding protein was reported by Grover and Garlid 21 ; however, the molecular structure of this binding site remains unresolved. A recent study by Munoz et al 11 tested whether elimination of SUR1 influenced ischemic preconditioning in the brain.…”

Section: Molecular Structure?mentioning

confidence: 99%

Evidence for Mitochondrial K ⁺ Channels and Their Role in Cardioprotection

O’Rourke

2004

Circulation Research

399

303

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Abstract-Twenty years after the discovery of sarcolemmal ATP-sensitive K ϩ channels and 12 years after the discovery of mitochondrial K ATP (mitoK ATP ) channels, progress has been remarkable, but many questions remain. In the case of the former, detailed structural information is available, and it is well accepted that the channel couples bioenergetics to cellular electrical excitability; however, in the heart, a clear physiological or pathophysiological role has yet to be defined. For mitoK ATP , structural information is lacking, but there is abundant evidence linking the opening of the channel to protection against ischemia-reperfusion injury or apoptosis. This review updates recent progress in understanding the physiological role of mitoK ATP and highlights outstanding questions and controversies, with the intent of stimulating additional investigation on this topic. Key Words: ischemia Ⅲ reperfusion Ⅲ mitochondria Ⅲ ATP-sensitive potassium channels Ⅲ calcium-activated potassium channels S ince their discovery in cardiac myocytes using singlechannel patch-clamp techniques in the early 1980s, 1 surface membrane ATP-sensitive K ϩ channels have been characterized extensively at the molecular level. Progress has been rapid, facilitated by the cloning of the major components of the heteromeric channel-the sulfonylurea receptor (SUR1 2 and SUR2 3 ), an ABC transporter family member, and the pore-forming inward rectifier K ϩ channel protein (Kir6.1 4 and Kir6.2 5 ). ATP-sensitive K ϩ channels play an important role in translating the metabolic status of a cell into a physiological effect, with perhaps the best examples being the initiation of insulin secretion in pancreatic ␤ cells and modulation of vascular tone. The opening of cardiac sarcolemmal ATP-sensitive K ϩ (sarcK ATP ) channels by metabolic inhibition dramatically affects cardiac myocyte electrical excitability 6 and is responsible for ischemia-induced suppression of excitability, 7 but it is still not clear why this adaptation is important to the cell, organ, or organism. This issue has been revisited in several recent studies of Kir 8 -10 or SUR 11-13 knockout mice.Another door was opened in 1991, with the discovery of mitochondrial K ATP (mitoK ATP ) channels in the liver mitochondrial inner membrane. 14 This finding was bolstered by evidence that a variety of K ϩ channel openers and inhibitors influenced mitochondrial function, [15][16][17][18] culminating in the establishment of a link between the mitoK ATP channel and protection against ischemic injury in intact hearts 18 and isolated myocytes. 19 This hypothesis explained the paradoxical finding that the effects of K ϩ channel openers on the cardiac action potential and their ability to suppress ischemia-reperfusion injury were not correlated. 20 -22 Since then, mitoK ATP has been implicated in cellular protection against metabolic stress in a variety of tissues, including liver, gut, brain, and kidney, and has been shown to be an essential component of the mechanism of ischemic preconditionin...

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The Mitochondrial Sulfonylurea Receptor: Identification and Characterization

Cited by 66 publications

References 26 publications

Sulfonylurea Receptor-Dependent and -Independent Pathways Mediate Vasodilation Induced by ATP-Sensitive K⁺ Channel Openers

Sulfonylurea Receptor-Dependent and -Independent Pathways Mediate Vasodilation Induced by ATP-Sensitive K⁺ Channel Openers

Localization of Sulfonylurea Receptor Subunits, SUR2A and SUR2B, in Rat Heart

Evidence for Mitochondrial K ⁺ Channels and Their Role in Cardioprotection

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The Mitochondrial Sulfonylurea Receptor: Identification and Characterization

Cited by 66 publications

References 26 publications

Sulfonylurea Receptor-Dependent and -Independent Pathways Mediate Vasodilation Induced by ATP-Sensitive K+ Channel Openers

Sulfonylurea Receptor-Dependent and -Independent Pathways Mediate Vasodilation Induced by ATP-Sensitive K+ Channel Openers

Localization of Sulfonylurea Receptor Subunits, SUR2A and SUR2B, in Rat Heart

Evidence for Mitochondrial K + Channels and Their Role in Cardioprotection

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Product

Resources

About

Sulfonylurea Receptor-Dependent and -Independent Pathways Mediate Vasodilation Induced by ATP-Sensitive K⁺ Channel Openers

Sulfonylurea Receptor-Dependent and -Independent Pathways Mediate Vasodilation Induced by ATP-Sensitive K⁺ Channel Openers

Evidence for Mitochondrial K ⁺ Channels and Their Role in Cardioprotection