Impairment of Human Ether-à-Go-Go-related Gene (HERG) K+ Channel Function by Hypoglycemia and Hyperglycemia

Abstract

Hyperglycemia and hypoglycemia both can cause prolongation of the Q-T interval and ventricular arrhythmias. Here we studied modulation of human ether-à -gogo-related gene (HERG) K ؉ channel, the major molecular component of delayed rectifier K ؉ current responsible for cardiac repolarization, by glucose in HEK293 cells using whole-cell patch clamp techniques. We found that both hyperglycemia (extracellular glucose concentration Glucose, the primary end product of the digestion of glycogen, is essential for maintaining life activities in organisms. As a major source of metabolic fuel, degradation of glucose via glycolysis and subsequent oxidative phosphorylation generates high energy phosphates to power the biological processes in the cell. Yet, through an exquisitely complex network of control mechanisms, the rate of glucose metabolism is only as great as needed by the organisms. Moreover, glucose also has other regulatory effects on many cellular functions. Either inadequate or excessive glucose can be harmful to the living system. Therefore, the blood glucose level is dynamically controlled. However, under pathological conditions like diabetes, glucose cannot be efficiently utilized, and the blood glucose level rises. When the blood level of glucose is maintained higher than 7 mM, it is considered as hyperglycemia. Diabetes therapy, on the other hand, can lead to an overly low level of blood glucose, which is referred to as hypoglycemia when the level falls below 3 mM.Either hypoglycemia or hyperglycemia can have deleterious effects on the cells. One common feature of electrophysiological alterations caused by both hypoglycemia and hyperglycemia in the heart is prolongation of Q-T interval and the associated ventricular arrhythmias that are presumably responsible for sudden cardiac death in diabetic patients (1-10). However, the ionic mechanisms by which hyperglycemia and hypoglycemia prolong Q-T interval remained unclear, which is at least a part of the reasons why diabetic patients die of mainly cardiac complications.The human either-à -go-go-related gene (HERG) 1 encodes the rapid component of delayed rectifier K ϩ current in the heart, which is the major repolarizing current in the plateau voltage range of cardiac action potentials. HERG K ϩ channels are susceptible to genetic defects and environmental cues, with the consequence being depression of HERG function in most situations (9). Indeed, most of the cases of long Q-T syndrome are ascribed to dysfunction of HERG channels, particularly that induced by therapeutic drugs (13). It is conceivable that HERG alteration might also be involved in the Q-T prolongation induced by hyperglycemia and hypoglycemia. This thought prompted us to carry out a series of experiments to study the effects of glucose on HERG K ϩ channels and the potential mechanisms.

Functional consequences of methionine oxidation of hERG potassium channels

“…Previous studies have reported that functional properties of hERG channels are altered by RS [14][15][16][17]41]. However, different effects on hERG channel functions were shown for different RS.…”

“…In these studies, involvement of cysteine oxidation is probable but it was not directly addressed. In contrast, the hERG channel function was impaired by RS that were generated by exposure to tumor necrosis factor-α and hyperglycemia [16,41]. There are several explanations for the observed different effects.…”

The case for hypoglycaemia as a proarrhythmic event: basic and clinical evidence

“…Moreover, patients with congestive heart failure frequently have increased levels of catecholamines [68] and may be on inotropic agents, both of which cause Ca 2+ overload and increase the risk of sudden death. [72] showed that hypoglycaemia inhibits current through the human ether-a-go-go related gene channel, which generates I Kr , one of the main repolarising K + channels in human myocytes. Interestingly, the same team also showed that hyperglycaemia impairs current flow through the same channels, but by a different mechanism.…”

Glycaemia Self-Control Role in Prevention of Cardiovascular Diseases in Diabetes Mellitus Patients

“…Избыток катехоламинов и гиперинсулинемия могут также вызвать гипокалиемию и увеличить внутриклеточную концентрацию кальция (Ca 2+). Это может привести к замедлению и асинхронизации процесса реполяризации в кардиомиоцитах, электрической негомогенности мио-карда и возникновению нарушений ритма сердца [19].…”