title: Voltage-gated ion channel modulation by lipids: insights from molecular dynamics simulations.
abstract: Cells commonly use lipids to modulate the function of ion channels. The lipid content influences the amplitude of the ionic current and changes the probability of voltage-gated ion channels being in the active or in the resting states. Experimental findings inferred from a variety of techniques and molecular dynamics studies have revealed a direct interaction between the lipid headgroups and the ion channel residues, suggesting an influence on the ion channel function. On the other hand the alteration of the lipids may in principle modify the overall electrostatic environment of the channel, and hence the transmembrane potential, leading to an indirect modulation, i.e. a global effect. Here we have investigated the structural and dynamical properties of the voltage-gated potassium channel Kv1.2 embedded in bilayers with modified upper or lower leaflet compositions corresponding to realistic biological scenarios: the first relates to the effects of sphingomyelinase, an enzyme that modifies the composition of lipids of the outer membrane leaflets, and the second to the effect of the presence of a small fraction of PIP2, a highly negatively charged lipid known to modulate voltage-gated channel function. Our molecular dynamics simulations do not enable to exclude the global effect mechanism in the former case. For the latter, however, it is shown that local interactions between the ion channel and the lipid headgroups are key-elements of the modulation.
authors: Université de Lorraine, SRSMC, UMR 7565, Vandoeuvre-lès-Nancy F-54500, France; Lomonosov Moscow State University, Moscow 119991, Russian Federation. Electronic address: marina.kasimova@univ-lorraine.fr.
authors: Marina A
authors: MA
authors: Kasimova
authors: Université de Lorraine, SRSMC, UMR 7565, Vandoeuvre-lès-Nancy F-54500, France; CNRS, SRSMC, UMR 7565, Vandoeuvre-lès-Nancy F-54500, France. Electronic address: mounir.tarek@univ-lorraine.fr.
authors: Mounir
authors: M
authors: Tarek
authors: Lomonosov Moscow State University, Moscow 119991, Russian Federation. Electronic address: shaytan_ak@mail.bio.msu.ru.
authors: Alexey K
authors: AK
authors: Shaytan
authors: Lomonosov Moscow State University, Moscow 119991, Russian Federation. Electronic address: k.v.shaitan@molsim.org.
authors: Konstantin V
authors: KV
authors: Shaitan
authors: Institute of Computational and Molecular Science, Temple University, Philadelphia, PA 19122, USA. Electronic address: lucie.delemotte@temple.edu.
authors: Lucie
authors: L
authors: Delemotte
mesh_terms: D002462:Cell Membrane / Q000737:chemistry / Q000378:metabolism; D015640:Ion Channel Gating; D051663:Kv1.2 Potassium Channel / Q000737:chemistry* / Q000378:metabolism*; D008051:Lipid Bilayers / Q000737:chemistry* / Q000378:metabolism*; D008055:Lipids / Q000737:chemistry*; D008564:Membrane Potentials / Q000502:physiology; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D024642:Potassium Channels, Voltage-Gated / Q000737:chemistry* / Q000378:metabolism*; D013109:Sphingomyelins / Q000737:chemistry / Q000378:metabolism; D055672:Static Electricity
chemical_list: D051663:Kv1.2 Potassium Channel; D008051:Lipid Bilayers; D008055:Lipids; D024642:Potassium Channels, Voltage-Gated; D013109:Sphingomyelins
keywords: Ceramide; Kv1.2; PIP2; Shaker; Sphingomyelin