Studies On Pharmacology Of TREK-1 Potassium Channel And Its Role In Anti-oxidative Effect

Background and purposeTREK-1 is a two-pore-domain potassium channel expressed highly in the human and mammalian central nervous systems and has been proposed to play an important role in general anesthesia.Previous studies have shown that TREK-1 can be activated by several anesthetic agents such as halothane,nitrious oxide, choloroform.However,whether ketamine and etomide affect TREK-1 channel is not characterized.Here we investigated the action of ketamine and etomidate on TREK-1 channel activity.Moreover,TREK-1 has also been proposed to play an important role in neuroprotection.Considering the importance of oxidative stress and damage induced by free radicals in many diseases such as Alzheimer's disease, Parkinson's disease,we thus investigated the possible role of TREK-1 in oxidative stress and damage induced by SNP,H₂O₂ and X/XO system.MethodsMembrane currents were recorded with the use of whole-cell voltage-clamp recordings in Chinese hamster ovary(CHO) cells stably expressing TREK-1.Cell viability was detected by MTT method.Apoptosis were detected by Hoechst33342 staining with fluorescent microscopy.ResultsBoth ketamine and etomidate can enhance the currents passed in Chinese hamster ovary(CHO) cells stably expressing TREK-1.Clinically relevant concentrations of ketamine increased outward currents with an EC₅₀ of 10μM, whereas etomidate can enhance the channel activity with an EC₅₀ of 1.8μM.In the study of CHO and TREK-1/CHO cells after exposure to SNP,H₂O₂ and X/XO system respectively,we find that TREK-1/CHO cells have higher viability rate than CHO cells.As TREK-1 openers,ketamine,etomidate,halothane and isoflurane can improve the cell viability of CHO cells stably expressing TREK-1 after exposure to SNP,H₂O₂ and X/XO.No similar effects were found in nontransfected CHO cells.Conclusion1.Ketamine and etomidate can open the TREK-1 channel in clinically relevant concentrations,which suggested that TREK-1 channel may play a role in the anesthetic process of the two intravenous general anesthetics.2.Overexpression of TREK-1 potassium channel in the Chinese hamster ovary cells have an anti-oxidative effect,which indicted that TREK-1 channel might play an important role in the anti-oxidative effect.3.The study demonstrated that halothane and isoflurane,which can open the TREK-1 channel,can enhance the anti-oxidative ability of TREK-1/CHO cells. These two drugs may play a neuroprotective role,at least in part,by opening TREK-1 channel.Meanwhile,ketamine and etomidate,which can also activate TREK-1 channel,can enhance the anti-oxidative ability of TREK-1/CHO cells.The four anesthetics can increase the cell viability and reduce the apoptosis rate.4.Quinidine can inhibit the anti-oxidative effect by TREK-1 openers. Conclusively,it suggested that TREK-1 channel might play a role in anti-oxidation.