A Study On Structure And Function Of A HERG Gene Mutant E444D Related To LQT2 And Effect Of Ethanol On HERG Channel

hERG is human ether-a-go-go related gene.It was cloned from human hippocampi. hERG gene encodes a protein that produces the rapidly activating ,voltage dependent cardiac delayed inward rectifier (IKr),it highly expresses in human neuron and heart. hERG current is the fast component ofⅢstage repolarization delayed rectifier in cardiac action potential. In cardiac cell, hERG channel always includes pore-formingαsubunit andβsubunit.LQTS is a inherited heart disease associated with prolonged QT interval. It is associated with syncope (fainting) , tachycardia and sudden death due to ventricular arrhythmias. There are 8 types of LQTS(LQT1-LQT8), they are all related to different genes. hERG gene disfigurement or mutant will cause LQT2. LQT6 is due to the mutant of KCNE2 gene. The study on structure and function hERG gene mutants related to inherited LQTS is very important for us to investigate the mechanism and develop the new drug for this disease.We know that ethanol has negative effect on brain, heart and liver, but we are not clear about the mechanism. hERG channels are highly expressed in heart and have close relationship with inherited heart disease. To study the interaction between hERG channel and alcohol or some other anaesthetic will give us effectively clue to clinic, pharmacology, pathology and development of new drugs.The main research achievements in this study are as follows:(1) We find a hERG gene missense mutant E444D in an inherited LQT2 family. There is no significant difference between current recorded from oocytes injected mutant mRNA and from oocytes injected distilled water.(2) Currents of coexpressing hERG channel mutant E444D and wild type channel are much smaller than wild type alone.(3) Compare the I-V curve of coexpress to wild type , it shifts 10 mV, and the later part becomes more plain. It indicates the inactivation is faster. This suggests that the mutant hERG channels traffic to the membrane but they lose their function.(4) Ethanol has no effect on hERG channels and hERG-KCNE2 channels.