Transient receptor potential (TRP) channels are permeable to cations, with most conducting both monovalent and divalent ions. TRP melastatin subfamily member 4 (TRPM4) and TRPM5 have the distinction among TRPM channels of permeability to both mono- and divalent cations. The TRPM4 and TRPM5 channel are preferred conduction for monovalent cations (Na⁺ and K⁺ etc), impermeable to divalent cations (Ca²⁺, etc). However, the molecular mechanisms of the selectivity of transport for the TRPM4 and TRPM5 channels remain elusive.
The crystal structures of TRPM4 channel have been determined in many complexes with bound ligands and ligand-frees. To understand the detailed mechanism of Na⁺/Ca²⁺ selectivity in TRPM4 Channel, we have combined homology modeling with molecular dynamics (MD) simulations to address the molecular dynamics study of Na⁺/Ca²⁺ transportation through the selectivity filter of TRPM4 channel.
Our data show that the diameter and flexibility of the selective filter become larger in the Na⁺ bound state than Ca²⁺ bound state, which demonstrates the TRPM4 channel is preferred conduction for Na⁺. The binding modes of mono- and divalent cations in the selectivity filter is different. Only the four C=Os of the G980 that constitute the selectivity filter interact with Na⁺, but eight C=Os of the F979 and G980 that constitute the selective filter interact with Ca²⁺. The different binding modes of the TRPM4 channel selectivity filter with Na⁺ and Ca²⁺ lead to the change of the diameter of the selective filter, the different coordination number of the interaction and the difference in the flexibility of the outside of the pore, which further clarifies the TRPM4 channel molecular mechanism of ion selectivity of transportation. Our findings support to understand modulation mechanisms of TRP channels that can be exploited for drug designs and synthesis.
 

TRPM4 channel,Selectivity,molecular dynamics simulation,monovalent and divalent cations