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Potassium Channels: Physiological Pathological and Protective Roles Journal of Clinical and Basic Cardiology An Independent International Scientific Journal Journal of Clinical and Basic Cardiology 1999; 2 (1), 5-7 Potassium channels: physiological pathological and protective roles Opie LH Homepage: www.kup.at/jcbc Online Data Base Search for Authors and Keywords Indexed in Chemical Abstracts EMBASE/Excerpta Medica Krause & Pachernegg GmbH · VERLAG für MEDIZIN und WIRTSCHAFT · A-3003 Gablitz/Austria FOCUS ON KATP-CHANNELS Potassium channels: physiological, pathological and protective roles J Clin Basic Cardiol 1999; 2: 5 Potassium channels: physiological, pathological and protective roles L. H. Opie Potassium channels play a crucial physiological role. Without their activity, cardiac life would cease. In disease states, potas- sium outflow is seen as harmful and associated with depolarization. Opening of one specific potassium channel, the K(ATP) channel, may however, be the final common path in the protective phenomenon of preconditioning. Of interest, several cardioprotective agents such as the opiates or the calcium blocker mibefradil, also appear to act via this channel. The antianginal agent, nicorandil, may also promote preconditioning, although this is a challenging concept to be proven in patients. J Clin Basic Cardiol 1999; 2: 5–7. otassium channels must function normally for life to con- transmembrane helices and one pore. To achieve a functioning Ptinue. Of the many potassium channels, I wish to select potassium channel pore requires the combination of multiple three, each potentially life-saving in a different way. First, with- subunits, that is the combination of four units each of only 2 out the inward rectifier potassium current IK1 (also called IKir), spans. Kir passes an outward current when the membrane po- there would be no resting membrane potential, no polariza- tential is above the potassium equilibrium potential (Ek) to tion of cells, no depolarization, and no cardiac contraction. contribute to the repolarization phase of the action potential Second, without the delayed rectifier current, IK (also called and thereby to help end the action potential, thereby regain- IKv), there would be no recovery of the cardiac action poten- ing the resting membrane potential. Conversely, this same tial after depolarization, so that the heart cells would die in channel potentially passes a large inward K+ current, when hypercontracture as the calcium ions continued to pour in. the cell membrane is hyperpolarized (ie, when the resting Third, the ATP-sensitive potassium channel is the major pro- membrane potential is below -85 mV) and this inward cur- tective potassium channel, sensitive to ATP-depletion. By rent helps to maintain the high internal K+ activity and hence opening, it protects the heart cells in a still poorly understood the membrane polarity. The unusual nature of the current way from the effects of hypoxia and ischaemia. These three flow, which is much larger in one direction, has given rise to major potassium channels stem from two distinct molecular the name anomalous rectifier. families, namely the inward rectifier family that includes the Rectification of potassium current: Normally, the relationship K(ATP) channel, and the voltage-gated (or voltage-operated) between the voltage and current is a straight line (Ohm’s law). family of channels. Without these families of potassium cur- When a current can pass through the channel in both direc- rents, life would cease. tions, but the flow in one direction is greater, then this selec- tive process is called rectification. The Kir channel rectifies in Physiological role an inward direction when the voltage drops below the equi- librium potential for potassium (at about -90 mV). At a mo- Evolution of potassium channels lecular level, the concept is that the inward current “unplugs” Seen from an evolutionary perspective, a very simple K+ chan- an internal divalent ion such as magnesium that would nor- nel, probably with only two transmembrane helices (spans), mally block the channel pore. Because of the marked devia- might first have come into existence to generate the resting tion of the voltage-current relationship for this channel, the membrane potential of primitive cells. This simple structure current is also called the anomalous rectifier. Outward rectifica- is now called the inward rectifier, Kir. The other major mem- tion occurs when the major current flow is in the outward + ber of this family, the ATP-sensitive K channel, K(ATP), sup- direction but voltage is more positive than zero. Thus, hypo- posedly evolved to stop damaged heart cells from contracting, thetically, rectification of the Kir channel can be achieved by thereby conserving ATP. When the beating heart emerged in plugging or unplugging by Mg2+ ions of the inner side of the evolution, the Kv superfamily came into existence. Members pore. of the Kir family also evolved into a third major branch of the + superfamily that includes KACh and KADO that respond re- Voltage-operated K channel, Kv or K spectively to acetylcholine and to adenosine, in each case This channel, also called the delayed rectifier (and including acting to decrease the heart rate, another protective event. the rapid and slow components, Kr and Ks) conducts the cur- To achieve a functioning potassium channel pore requires rent Ik that physiologically makes a major contribution to the combination of multiple subunits, that is either 4 subunits repolarization. There is some resemblance to the sodium or each of 6 spans or the combination of four units each of only calcium channel structure, but here the α-subunit of each 2 spans. Such variable combinations mean that a great mo- channel has only six helices in contrast to the twenty-four of lecular diversity of potassium channels is possible. the sodium or calcium channels. To make one single potas- sium pore that functions, four of the potassium-type α- + The inward rectifier superfamily, Kir subunits must combine, so that as in the case of the Na or Potassium channels of this family set the resting membrane Ca2+ channel, there is one pore per 24 helices. The super- potential of cardiac myocytes. Structurally, this type of chan- family that includes this channel is sometimes called the Shaker nel is an extremely simple channel with a basis of only two family because the delayed rectifier was first cloned in a mu- From the Department of Medicine, Heart Research Unit, University of Cape Town, South Africa. Correspondence to: Professor Lionel H. Opie, Heart Research Unit, University of Cape Town, Medical School, Observatory 7925, Cape Town, South Africa; E-mail: [email protected] FOCUS ON KATP-CHANNELS J Clin Basic Cardiol 1999; 2: 6 Potassium channels: physiological, pathological and protective roles tant of the fruitfly, Drosophila. When this channel is geneti- Protective role cally absent from the fruitfly, exposure to ether provokes spasms of muscular shaking. Role of K(ATP) channel in preconditioning The mechanism of the protective effect of preconditioning is ATP-sensitive potassium channel still speculative and controversial. A common view is that ad- Hypothetically, this channel evolved to conserve cell ATP enosine plays a role in the phenomenon, possibly being linked during hypoxic or ischaemic damage, which would cause ATP to activation of protein kinase C and thence to opening of the to run down and thereby invoke irreversible damage. In gen- ATP-sensitive potassium channel. For example, adenosine A1 eral, this channel is very sensitive to inhibition by ATP and is receptor stimulation of rat ventricular myocytes activates the firmly closed in physiological conditions when ATP is high. δ-protein kinase C isoform [1]. Alternatively or additionally, As ATP breaks down during ischaemia with formation of ADP there may be an increased activity of the inhibitory G-pro- + and adenosine, opening of this K channel is promoted. This tein, Gi, which links the adenosine and opioid receptors to channel represents a hybrid between the Kir superfamily and the ATP-sensitive potassium channel [2, 3]. Upregulation of the totally different ABC (ATP-binding cassette) family. The Gi would explain the protective effects of activation of those latter provides two different inhibitory binding sites, one for receptors coupled to it, such as adenosine A1 and muscarinic the SURs (sulfonylureas, epitomized by the oral antidiabetic M2 receptors, because of greater inhibition of adenylate cy- agent, glibenclamide) and the other for ATP. Because the chan- clase, and hence an indirect antiadrenergic effect. In addition, nel is controlled by the binding of internal ATP to the ATP Gi may mediate other potentially protective mechanisms, such site, it is called the K(ATP) channel. The evolutionary function as direct inhibition of L-calcium channels and activation of of the SUR binding site is at all not clear (how would the the K(ATP) channel [4]. evolving heart cell know what the structure of an antidiabetic sulfonylurea drug could be?) Preconditioning in patients There appears to be no physiological role for K(ATP) in car- Preconditioning is, therefore, an important phenomenon with diac myocytes. Pathophysiologically, one hypothesis is that, as probable clinical application because it invokes protection ATP breaks down in response to severe ischaemia, the out- against postischaemic and other types of ischaemia-related im- ward passage of K+ ions and their accumulation on the out- paired LV dysfunction. Although the clinical evidence for pre- side of the cell causes loss of the normal membrane polariza- conditioning is not yet firm, there is suggestive evidence that tion, with a decreased contractile response and an induced it occurs in humans [5]. Patients with effort angina who have state of inactivity or rest that conserves ATP. had one attack may be protected from subsequent attacks as The function of K(ATP) in vascular smooth muscle is much clearer. in “warm-up” angina. Those undergoing coronary angioplasty There, in response to the formation of adenosine, this chan- have more severe features of ischaemia, such a potassium re- nel opens and participates in coronary vasodilation.
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