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Mccully-The Mitochondrial KATP Channel and Cardioprotection

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Mccully-The Mitochondrial KATP Channel and Cardioprotection The Mitochondrial KATP Channel and Cardioprotection James D. McCully, PhD, and Sidney Levitsky, MD Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts Adenosine triphosphate (ATP)–sensitive potassium channel openers and blockers. Sufficient evidence exists (KATP) channels allow coupling of membrane potential to indicate that the KATP channels and, in particular, the to cellular metabolic status. Two KATP channel subtypes mitoKATP channels play an important role both as a coexist in the myocardium, with one subtype located in trigger and an effector in surgical cardioprotection. In the sarcolemma (sarcKATP) membrane and the other in this review, the biochemistry and surgical specificity of the inner membrane of the mitochondria (mitoKATP). the KAtp channels are examined. The KATP channels can be pharmacologically modulated by a family of structurally diverse agents of varied (Ann Thorac Surg 2003;75:S667–73) potency and selectivity, collectively known as potassium © 2003 by The Society of Thoracic Surgeons yocardial ischemia/reperfusion injury continues to supplemented potassium cardioplegia affords enhanced M occur after cardiac operations that have been cardioprotection involve the amelioration of cytosolic, performed in a technically adequate manner. This injury mitochondrial, and nuclear calcium overload, enhanced contributes significantly to postoperative morbidity and preservation and resynthesis of high energy phosphates, mortality, despite meticulous adherence to presently and modulation of nuclear and mitochondrial function known principles of myocardial protection. Traditionally, [4–7, 18]. The end effector of these mechanisms remains cardioplegia has been used as a myoprotective agent for to be elucidated; however, recent investigations have the alleviation of surgically induced ischemia/ suggested that the mitochondrial ATP-sensitive potas- reperfusion injury incurred during cardiac operative pro- sium channels play an important role in the cardiopro- cedures, to allow functional preservation of the myocar- tection afforded by K/Mg cardioplegia [14, 17]. dium. These solutions permit rapid electromechanical arrest of the myocardium through alteration of cellular electrochemical gradients [1–3]. Most cardioplegia solu- ATP-Sensitive Potassium Channel Structure tions use high potassium, which maintains the heart in a The ATP-sensitive potassium (KATP) channels belong to depolarized state [3]. The advantages of cardioplegic the ATP-binding cassette transporter superfamily and arrest in providing the surgeon a bloodless field are are comprised of two subunits: (1) a pore-forming, in- tempered in that depolarization also leads to the alter- ward-rectifying potassium channel subunit (Kir), and (2) ation of ion flux across the sarcolemmal membrane and is a regulatory sulfonylurea receptor (SUR). The Kir and associated with both increased cytosolic calcium accumu- SUR subunits coassemble with a 4:4 stoichiometry to lation and the significant depletion of cellular high- form a hetero-octameric KATP channel with the Kir sub- ϩ energy adenosine triphosphate (ATP) reserves [4–10]. In units forming the K ion permeation pathway (Fig 1). SUPPLEMENT previous investigations we have shown that magnesium- Both Kir and SUR subunits are required to form fully supplemented potassium cardioplegia (K/Mg, DSA) pro- functional channels with the SUR subunit cooperating vides superior cardioprotection as compared with high with the Kir subunit to act as ATP-dependent potassium potassium cardioplegia [4–7, 11–17]. In a series of studies, channel complex. using the isolated perfused rabbit heart [4–7, 9–13] and The SUR subunit contains two transmembrane do- in situ, blood-perfused sheep [16] and pig [17] heart mains with 13 to 17 transmembrane segments and two models, we have shown that K/Mg cardioplegia partially nucleotide binding folds (Fig 1). The two nucleotide modifies the biochemical changes that lead to lethal binding folds (NBD-1, NBD-2) are located toward the myocardial ischemia/reperfusion injury. We have also carboxy terminus of the SUR subunit and contain Walker shown that the mechanisms by which magnesium- A and Walker B motifs, essential in providing membrane ϩ sensitivity to ATP and Mg2 -ADP. The Walker A and B rd Presented at the 3 International Symposium on Myocardial Protection motifs are conserved protein sequences. The Walker A From Surgical Ischemic-Reperfusion Injury, Asheville, NC, June 2–6, 2002. motif (also referred to as the ATP/GTP binding site) contains the characteristic glycine-rich amino acid se- Address reprint requests to Dr McCully, Division of Cardiothoracic quence GlyX GlyXXGlyXGlyLys(Ser/Thr) allowing bind- Surgery, Beth Israel Deaconess Medical Center, Harvard Institutes of 6 Medicine, 77 Avenue Louis Pasteur, Room 144, Boston, MA 02115; ing of ATP or GTP by means of the terminal phosphate e-mail: [email protected]. group. The Walker B motif contains the characteristic © 2003 by The Society of Thoracic Surgeons 0003-4975/03/$30.00 Published by Elsevier Science Inc PII S0003-4975(02)04689-1 S668 MYOCARDIAL PROTECTION MCCULLY AND LEVITSKY Ann Thorac Surg mitoKATP CHANNELS AND CARDIOPROTECTION 2003;75:S667–73 Fig 1. Schematic representation of KATP channel. Two-dimensional representations of pore-forming inward rectifying potas- sium channel subunit (Kir) and a regula- tory sulfonylurea receptor (SUR) during closed and open states. Nucleotide binding folds (NBD-1, NBD-2) containing Walker A and Walker B motifs are shown. Under homeostatic conditions KATP channels are closed. High concentrations of ATP allow binding of ATP to Kir closing the pore- forming unit. Binding of ATP to NBD-1 ϩ and hydrolysis of Mg2 -ATP at NBD-2 ϩ allows limited resident binding of Mg2 - ADP to NBD-2 due to catalytic actions of creatine kinase (CK), thus preventing chan- nel opening. Under conditions of ischemia ATP concentrations are decreased and ADP concentrations are increased and the cata- lytic actions of creatine kinase are reduced ϩ or inhibited and resident binding of Mg2 - ADP to NBD-2 is increased allowing con- formational stabilization and KATP channel ϩ opening and K flux across the inner membrane. amino acid sequence ArgX11AspX6Asp and is involved in ing of the KATP channel. Under homeostatsis, the cata- ϩ ϩ ATP hydrolysis and binds the Mg2 moiety of Mg2 - lytic actions of creatine kinase limit the resident binding ϩ ATP. The nucleotide binding fold NBD-1 has limited duration of the Mg2 -ADP to NBD-2, preventing confor- catalytic activity, whereas NBD-2 hydrolyzes ATP and mational stabilization and channel opening (Fig 1). has been shown to play an essential role in KATP channel However, during ischemia/reperfusion, creatine kinase 2ϩ gating [19]. Both NBD-1 and NBD-2 are required for KATP activity is decreased and Mg -ADP concentration is channel function. increased. These events extend the resident binding ϩ time of Mg2 -ADP at NBD-2 and the binding of ATP at NBD-1, resulting in SUR subunit conformational sta- ATP-Sensitive Potassium Channel Regulation bilization. The stabilization of the SUR subunit over- The KATP channels allow coupling of membrane poten- comes ATP-induced Kir subunit pore closure, resulting ϩ tial to cellular metabolic status, and it has been hypoth- in KATP channel opening and K flux across the inner SUPPLEMENT esized that KATP channel gating occurs as a result of the membrane [19]. accumulation of nucleotide diphosphates as a conse- quence of elevated ischemia-induced, metabolic de- ATP-Sensitive Potassium Channel Subtypes in mands [20–23]. Under normal conditions the K chan- ATP the Myocardium nels are inhibited (ie, closed) by direct ATP binding to the ϩ Kir pore-forming subunit, preventing K flux across the Two ATP-sensitive potassium (KATP) channel subtypes membrane. This inhibition occurs by free [ATP]i and coexist in the myocardium, with one subtype located in 2ϩ [Mg -ATP]i at levels greater than 1 mmol/L and is the sarcolemma (sarcKATP) membrane and the other in responsive to changes in [ATP] produced by glycolysis the inner membrane of the mitochondria (mitoKATP). The but not by increases through application of exogenous cardiac sarcKATP channels, first reported in guinea pig ATP [24, 25]. ventricular myocytes and then later shown to exist in a The KATP channels are stimulated (ie, opened) through variety of tissues, have been molecularly characterized as ATP hydrolysis at the SUR subunit, primarily at NBD-2. SUR2A/Kir6.2 [27–30]. The Kir 6.2 subunit has a molecu- Evidence from photolabeling studies suggests that ATP lar mass of 51 kD, whereas the SUR2A subunit has a binds to NBD-1 with high affinity, whereas ATP hydro- molecular mass of 140 kD [28–30]. lysis occurs at NBD-2 [26]. These studies also show that The mitoKATP channels were first identified in the liver ϩ Mg2 -ADP antagonizes ATP binding at NBD-1 [26]. and then in the heart, and have been shown to be located Current hypothetical models suggest that during ho- in the inner membrane of the mitochondria [31, 32]. The 2ϩ meostasis ATP concentration exceeds Mg -ADP, thus mitoKATP channels have yet to be molecularly fully favoring high-affinity binding of ATP to NBD-1, whereas characterized; however, there is sufficient evidence to ϩ ATP hydrolysis at NBD-2 allows binding of Mg2 -ADP at indicate that neither Kir6.1 nor Kir6.2 is a constituent ϩ NBD-2 (Fig 1). Binding of ATP to NBD-1 and Mg2 -ADP member [33, 34]. High-affinity azido-[125I]glyburide and to NBD-2 permits conformational stabilization and open- fluorescent BODIPY-FL-glyburide studies have allowed Ann Thorac Surg MYOCARDIAL PROTECTION MCCULLY AND LEVITSKY S669 2003;75:S667–73 mitoKATP CHANNELS AND CARDIOPROTECTION isolation of a mitochondrial Kir subunit with a molecular have demonstrated that nonspecific potassium channel mass of 55 kD and a mitochondrial SUR subunit with a openers such as nicorandil and pinacidil, which permit molecular mass of 63 kD [35]. Garlid and Paucek [36] have unmodulated opening of both sarc- and mitoKATP chan- predicted that the mitoSUR subunit will be shown to be a nels, significantly enhance cardioprotection when used half-molecule ATP-binding cassette transporter protein.
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