Evidence for Mitochondrial K ⁺ Channels and Their Role in Cardioprotection

Abstract

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...

Mitochondrial Ion Channels in Cardiac Function and Dysfunction

“…In this context, we have employed a variety of methods to identify and characterize which ion channels may be present in isolated mitochondria and in intact cells. K + channel opener compounds, including diazoxide, nicorandil and others, can protect heart cells from ischaemic or oxidative stress through a mechanism which we believe involves the opening of specific mitoK ATP channels on the inner membrane (O'Rourke 2004). Similarly, studies revealed a second class of K + channel on the mitochondrial inner membrane (mitoK Ca ), resembling the Ca 2+ -activated K + channel of the plasmalemma of certain cell types.…”

The KCa channel as a trigger for the cardioprotection induced by kappa‐opioid receptor stimulation – its relationship with protein kinase C

“…Their selectivity for K Ca , but not K ATP , was supported by the fact that the effects of NS1619 are not affected by the mitochondrial channel blocker 5-HD (O'Rourke, 2004;Cao et al, 2005;Sato et al, 2005) and that Pax fails to inhibit the effects of diazoxide, a K ATP channel opener (Cao et al, 2005;Sato et al, 2005). However, precautions should be taken that these two agents may have nonselective actions.…”

Role of epoxyeicosatrienoic acids in protecting the myocardium following ischemia/reperfusion injury

“…Mitochondria are one of these important convergence points, due to their critical function in cell survival and death; notably, ATP production and apoptosis [10,12,48]. Key mitochondrial proteins, such as several potassium (K + ) channels [49][50][51][52][53] and the mitochondrial permeability transition pore (mPTP) [48,[54][55][56], act as effectors integrating these upstream signals into cardioprotective responses. The mechanisms by which CYP metabolites alter these important effectors are not well defined and require further experimentation.…”

“…Importantly, pharmacologic data indicate that selective activation of mito K ATP confers cardioprotection following ischemia and that this channel is the major one mediating ischemic PC [59,60,63,64]. While the precise pathways by which mito K ATP activation confers cardioprotection remain unknown, potentially beneficial consequences of opening mito K ATP include partial depolarization of the intramitochondrial membrane, transient swelling of the intramitochondrial space, enhanced respiration via the electron transport chain, reduced mitochondrial calcium overload, and altered production of reactive oxygen species [59,60,64]. Cardioprotective effects of CYP2J2 overexpression involve activation of mito K ATP channels [31].…”