Functions of Kir2 and Kir3 in heart
To date, IK1, formed by coassembly of the Kir2.1.x subfamily of proteins (Kir 2.1, 2.2, and 2.3) In cardiac tissue, is the major component of inward rectifier potassium current and have a vital role in determinant of the resting membrane potential and conduces to the terminal phase of repolarization (phase 3). Loss of function of Kir2 channel > 90%, the heart of transgene (TG) mice led to prolongation of QRS and QT intervals as well as expected prolongation of action potential. Surprisingly, resting membrane potential in TG ventricular myocytes was nearly unaffected. It is unexpectedly that upregulation of IK1 in TG mice expressing Kir2.1 subunits, gain of function, cause to multiple abnormalities of cardiac excitability contained significant AP shortening and various types of atrial and ventricular arrhythmias.
In heart, another contribution of IK1 to excitability is through an unusual and strong dependence on extracellular K+. During repetitive firing, cardiac activity is followed by markedly changes in the concentration of K+ in the restricted (0.01-5 ^M) intercellular space, even more accumulation in the t-tubules. Increase of extracellular K+ should be accompanied by the increase of IK1 conductance with results on electrical activity, e.g., AP duration and propagation To date, four channelopathies related with inward rectifier currents have been detected, all due to loss of function or gain of function of IK1 currents (encoded by KCNJ2), LQT7, catecholaminergic polymorphic ventricular tachycardia (CPVT), familial atrial fibrillation (FAF), and short QT3. LQT7 at early is also called Andersen syndrome (AS) or Andersen-Tawil syndrome (ATS).
Fig. 5.Mutations on Kir2.1 protein associated with channelopathies of the classical inward rectifier channel. Mutant residues are color coded to represent the long QT7 (LQT7; black), catecholaminergic polymorphic ventricular tachycardia (CPVT; red), familial atrial fibrillation (FAF; green), and short QT3 (SQT3; blue).
Symptoms of the disease are characterized by a triad of clinical phenotypes affecting morphogenesis as well as the functioning of skeletal and cardiac muscles. ATS patients are often companied by features that include scoliosis, cleft palate, and short stature and display skeletal muscle weakness. Besides that, cardiac electrical abnormalities include prolongation of the QT interval, short runs of ventricular tachycardia, ventricular bigeminy and multi-focal ventricular ectopy mediated by adrenergic stimulation. However, recent works suggest that classification of ATS into LQTS is incorrect because of the former largely related to the abnormalities of the T-U complex. Because more than half of ATS is the mutations in KCNJ2 the term AST1 is reffered to the disease of IKir2. To date, more than 33 mutation in KCNJ2 is related to AST1 and the mutations have been identified as the autosomal-dominant. Some of mutations, such as D71V in AST1 patients, can decrease by ~94% of the magnitude of wild type currents IKir2. Several of ATS1 mutations, such as R21Q/W mutations, result in a loss-of function in the Kir2.1 channels due to reduced interaction with membrane PIP2.
Short QT syndrome (SQTS) is charactered by the shorten of QT interval on ECG. SQTS is an inherited abnormality that predisposes afflicted individuals to a high risk of having fibrillation (atrial/ventricular) and sudden death. Three forms of SQTS have been identified and SQTS3 is caused by the gain of function of mutations in inward rectifier channel gene, KCNJ2. SQTS3, charactered by electrocardiographic phenotype with asymmetrical T waves, is distinguished with other two kinds of SQTS. The molecular basis of SQTS3 is the mutation D172N at a position critical for inward rectification of Kir2.1 channel. Heterologous coexpression of wild type and mutant Kir2.1 subunits showed increased outward currents in mutant channels which account for the tall, asymmetrical T waves on the ECG of LQTS3 patients. Researches by computer simulations suggest that mutations in SQT3 might predispose patients to a higher risk of reentrant arrhythmias.
Mutation of V93I in Kir2.1 is associated with familial atrial fibrillation, thereby implicating IK1 in this disease. In addition, the mutant channels have larger outward currents by whole-cell patch-clamp studies, however the underlying mechanism(s) responsible for the increase remains unknown.
In a recent study, three novel (R67Q, R85W, and T305A) mutations belonged to CPVT3 and one previously described (T75M) mutations in KCNJ2 are identified. ECG analysis reveals prominent U-waves, ventricular ectopy, and polymorphic ventricular tachycardia. It is interestingly that there were no dysmorphic features or skeletal muscle abnormalities in the patients. Whole-cell patch-clamp experiments revealed that mutant channels had significantly reduced by > 95 % amplitude of wild type outward current and that T75M and R67Q mutations had dominant negative effects when co-expressed with wild type channels. Importantly, the study showed that the T305A mutation selectively affected channel rectification properties.
Cardiac strong inward rectifier potassium channels continue to surprise researchers with their novel roles in cardiac excitability, complex structure, function, and regulation. While significant progress has been made in recent years, clearly, many questions still remain to be answered and we certainly will soon witness new, and likely unexpected, discoveries in this field.
Kjr6.2
ATP-sensitive potassium (KATP) channels (encoded by KCNJ11) are evolutionarily conserved and are first discovered in the cardiac sarcolemma where they are expressed in high density.
IKATP is formed by the complex protein composed by the pore-forming subunit and the regulatory sulfonylurea receptor which is an ATPase-harboring ATP-binding cassette protein. To date, members of the inwardly rectifying K+ channel family (Kir6.1 and Kir6.2) and the sulfonylurea receptor isoforms (SUR1, SUR2A and SUR2B) have been identified. In cardiac tissue, KATP channel is a hetero-octameric complex composed of four pairs of these two distinct subunits Kir6.2 and SUR2A. The structure of Katp channel is very similar to Kir3 and Kir2. Therefore, there is no redundant description in this part.
Functions of Katp channels in heart
KATP channels, as a cardio-protective role, were recognized early in ischemia heart. The channel can mediate shortening of the cardiac action potential by increase of the IKATP currents then control calcium influx into the cytosol. Moreover, when the heart expose to a brief periods of ischemia causing a sustained ischemic insult KATP channel activity can depress significantly the injury produced by ischemia such as infarct size, coined ischemic preconditioning. Therefore, in ischemia heart, KATP channel can degrade markedly heart injure caused by ischemia.
Another important function of KATP channel is during the process of stress without distress in heart. The concept of "stress without distress" is referred to describe the ability of an organism to confront and/or escape imposed threat. The concept is very likewise to the "flight-or-fight" response, through the general adaptation syndrome. For example, acute exercise-stress causes a systemic sympathetic stimulation that raises cardiac contractility, heart rate and thereby provides the necessary higher cardiac output. How huge change of the heart excitability has happened after acute exercise. Many researches suggest that stress without distress is dependent in the KATP channel in heart. The change of this enhanced cardiac output imposes a significant metabolic in large part of the heart due to the highly energy consuming calcium handling machinery. A compensatory increase in outward potassium current formed by KATP channel is normally activated to offset the resulting calcium influx in order to reducing energy-demanding myocardial calcium overload.
KATP channel also has important roles in heart failure. Heart failure has no effect on the intrinsic biophysical properties of the cardiac KATP channel whereas the structural remodeling disrupts communication of energetic signal and channel. Then the disruption leads to interfere markedly the metabolic regulation of the channel at last. Accordingly, metabolic dysregulation of KATP channels created by the disease-induced structural remodeling appears to contribute to the dysfunction of heart failure.
