The Inactivation Mechanism Of The TRPM2 Channel

Background As one kind of ion permeable membrane proteins,ion channels play important roles in the process of cell signal transduction and keeping the healthy physiological condition.Its dysfunction will cause a series of diseases.Inactivation of ion channels is crucial processes that perform important functions in physiological and pathological processes.Previous studies have indicated that ion channels had multiple inactivation ways,such as voltage-gated potassium channel,which has C-type and N-type inactivation ways.But the multiple inactivation phenomena have not been found in ligand-gated channels.As an important nonselective cation channel,TRPM2?Transient receptor potential melastatin 2?channel can be activated by intracellular ADPR?ADP-ribose?,as well as reactive oxidative species?ROS?and other products during oxidative stress reactions.Several studies found that extracellular pysiochemical factors,such as Cu²⁺,Zn²⁺,H+ could inactivate the TRPM2 channel.Besides,the point mutation P1018L which is related to amyotrophic lateral sclerosis?ALS?and Parkinson disease?PD?can also induce inactivation of the TRPM2 channel.However,the relationship of different inactivation factors is not clear.Objectives To study the relationship of inactivation processes of the TRPM2 channel induced by multiple factors.Methods Constructing the TRPM2 mutants by molecular methods to study the inactivation mechanisms of different factors.Using whole-cell recording to explore the channel currents during the inactivation processes caused by different factors.Results The inactivation way of TRPM2 channel caused by Cu²⁺ is different from the inactivated process induced by Zn²⁺,H+ and P1018L mutant.Zn²⁺,H+ and P1018L induced TRPM2 inactivation is selectivity filter dependent,but Cu²⁺ induced TRPM2 inactivation has no relationship with that.Conclusion There are two independent inactivation ways of the TRPM2 channel.