Lipid Protein Interaction Mediates Ion Transport in P2X Receptors

Abstract

ATP a ubiquitously prevalent biomolecule, apart from being the principal energetic source for living cells, also plays a crucial role in inter-cellular communication, acting as a signaling molecule. One of the major receptors in this signaling cascade are the P2X receptors which are are trimeric, non-selective cation channel activated by ATP and are responsible for key processes such as muscle contraction, neurotransmission, inflammatory response, pain, and taste signal transduction. As a result of their extensive prevalence and important implications in human physiology, P2X receptors serve as important pharmacological targets for cardiovascular, neuronal, and inflammatory diseases. Recently our collaborator Dr Eric Gouax was successful in crystallizing full P2X (human P2X3), which provided us an unprecedented opportunity to explore different facets of ion permeation mechanism and pathway exploration in a lipid rich environment. We have performed an all atom MD simulation of a full P2X channel, embedded in a POPC bi-layer. In order to accelerate the ion permeation, process a constant electric field of 1 V was applied along the membrane normal. Upon the application of external electric field we observed multiple ion permeation events, with the ion entering through the extracellular fenestrations And exiting through the lateral fenestrations that was deeply embedded in the membrane. Interestingly the ion permeation pathway was lined with the lipid head groups which had entered through the lateral fenestrations. The negatively charged phosphate head groups of the POPC lipids interacts with the Sodium ion and assisted in the permeation of the ion through the pore. Thus through this work we were able to propose a unique ion permeation architecture for P2X receptors where the pathway was made of both protein and lipids.