TRPM4 Channel Ion Selectivity Research On Permeabiity Mechanism

The transient receptor potential M-type channel(TRPM)is an important class of cation channel proteins,and the TRPM4 channel is an important member of the TRPM channel family.The TRPM4 channel is involved in many physiological processes and is closely related to various diseases.The function of TRPM4 channel is regulated by various factors,such as calcium ion,phosphatidylinositol 4,5-diphosphate(PIP₂)and so on.The realization of channel function depends on the normal transmembrane permeability of cations.TRPM4 channel is a non-selective cation channel.It has been confirmed that the TPRM4 channel can permeate monovalent cations(Na⁺,K⁺and Cs⁺,etc.),but not divalent cations(Ca²⁺,Mg²⁺,etc.).However,the molecular mechanism of TRPM4 channel ion selective permeability is still unclear.Understanding this molecular mechanism provides an important theoretical basis for the screening and design of targeted drugs for the treatment of diseases related to this channel.The main work contents are as follows:Using the method of molecular dynamics simulation,the dynamic process of combining Na⁺and Ca²⁺in the TRPM4 channel selective filter channel is realized.1.The diameter of the selective filter holes is different.When Na⁺is combined,the diameter of the selective filter becomes larger,and when Ca²⁺is combined,the result is opposite,which indicates that the TRPM4 channel is more conducive to Na⁺permeability and not conducive to Ca²⁺permeability.2.The flexibility of the outer side of the selective filter is different.When Na⁺is combined,the activity of G981 at the extracellular flexible and selective filters is greater than when it is bound to Ca²⁺,which indicates that the extracellular environment of the TRPM4 channel selective filter is more conducive to Na⁺entering the pores,it is not conducive to Ca²⁺entering the pores.3.The combination mode of one and two divalent cations in the selective filter is different.When Na⁺is combined,only the four C=O that constitute the selective filter amino acid G980 main chain interact with Na⁺,while when Ca²⁺is combined,the main chain that constitutes the selective filter amino acid F979 twists and rotates inwards The C=O and the four C=O of the G980 main chain interact with Ca²⁺,which indicates that the TRPM4 channel achieves ion selectivity by selecting different coordination numbers of the main chain C=O and ions in the filter.In summary,the different binding modes of the TRPM4 channel selective filter and Na⁺and Ca²⁺lead to the change of the pore diameter of the selective filter,the different coordination number of the interaction and the difference in the flexibility of the outside of the cell,which further clarifies the TRPM4 channel Molecular mechanism of ion selective permeability.