Study On The Mechanism Of PIP2 Regulating Three Kir Channels

Inward rectifier potassium (Kir) channels are a potassium ion channel widelydistributed in various tissues, whose role is maintaining potassium homeostasis andsecretion of the renal, maintaining membrane resting potential and controlling thewaveform of membrane action potential, regulating heart rate and excitability of neurons,maintaining potassium homeostasis of kidney and nerve Gallia , regulating cell metabolicstate and membrane excitably ,regulating insulin secretion , protecting cell and maintainvascular tone. The functions of all channels in this family are subject to the regulation ofmembrane phospholipids PIP2, while Kir2.1, Kir3.1, and Kir6.1 are regulated moregreatly and in order of decreasing. But the molecular mechanism that regulating Kirchannel's affinity for PIP2 is not very clear.In this paper, we research the mechanism of PIP2 regulating three types Kir channelsmainly from two aspects that the Kir channel kinetics and PIP2 interaction with Kirchannels ,by the methods of sequence alignment,homology modeling,moleculardynamics simulation,molecular docking ,and have these achievements : First, PIP2regulate Kir2.1,Kir3.1,Kir6.1 through the Intermolecular weak interactions ,and thebinding energy of PIP2 to Kir2.1,Kir3.1,Kir6.1 are in order of decreasing, consistentwith the results in the experiments. Second , The binding site PIP2 to Kir is determinedby the charge distribution and the overall structure of the channel. The Kir2.1, Kir3.1,Kir6.1 cytoplasmic pore have two highly homologous parts DE Loop and G Loop which may be an important reason of al all Kir channels are regulated by PIP2 .But in the LMLoop, they are very different which may lead to the differences in the three types KirThird, Except for effecting interaction between PIP2 and Kir2.1, R218Q mutation maydirectly disable the channel by changing the conformation of G Loop. Fourth, weexplained why they can not crystallize Kir2.1/R218Q channel loss but can crystallizeKir2.1/R218QandT309K channel in Scott Pegan's experiments.Fifth,the residues 241-253may be an important domain transmits the interaction between PIP2 with Kir2.1.