.1. Of Herg Channel Pore Outside The Mouth Of The Missense Mutations On Its Function. Hkcne4 New Gene Cloning, Expression And Function

Cardiac arrhythmia is a leading cause of morbidity and mortality. There are more than 300,000 sudden death in the United States every year, and the underlying cause of the sudden death is reported to be mainly due to primary or secondary arrhythmia in which no structural heart disease can be identified. The LQTS are now commonly considered as likely causes for sudden death. Multiple genes causing LQTS have been identified so far, all encoding cardiac ion channels, which include two potassium channel alpha-subunit (KCNQ1, HERG), two potassium channel beta-subunits (Mink, MiRP1),one sodium channel(SCN5A),and one calcium-release channel (RYR2). In one large French family, LQTS was linked to chromosome 4q25-q27,but no gene defect has been identified.The rapid delayed rectifier (Ikr) is an important repolarizing current in many regions of the heart. The major subunit that forms the Ikr channel in human heart is HERG. Inherited mutation in HERG have been identified and linked to congenital long QT syndrome (LQT2). Furthermore, drugs that suppress Ikr have been linked to "acquired LQTS". These all point to the critical role that is played by Ikr in maintaining cardiac electrical stability. Therefore information about the structure of the Ikr/HERG channel is important. Such information will help in rational drug design not only for agents that are useful for combating some forms of LQTS (Ikr/HERG agonists), but also for agents with low risk for inducing acquired LQTS.One of the most critical factors in determining Ikr/HERG function is its C-type inactivation process. This is the basis for the inward rectification property of HERG, which is important for shaping the action potentials in the heart. Inward rectification dictates that there is little or no outward Ikr at positive plateau voltages, but large outward Ikr during phase 3. Furthermore, C-inactivation process in HERG channel appears to be intimately related to channel sensitivity to many different drugs. C-type inactivation results from conformational changes in the outer mouth region of the channel that prevent...