Gating mechanisms and pharmacology of P2X receptor channels

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

Ion permeation pathway within the internal pore of P2X receptor channels P2X receptor channels are trimeric ATP-activated ion channels expressed in neuronal and non-neuronal cells that are attractive therapeutic targets for human disorders. Seven subtypes of P2X receptor channels have been identified in mammals that can form both homomeric and heteromeric channels. P2X1-4 and P2X7 receptor channels are cation permeable, whereas P2X5 has been reported to have a significant anion permeability. Structures of several subtypes of P2X receptor channels reveal that each subunit is comprised of two transmembrane helices, with a large extracellular domain that contains the ATP binding sites at subunit interfaces with both N-and C-termini on the intracellular side of the membrane. Recent structures of ATP-bound P2X receptors with the activation gate open reveal the unanticipated presence of a cytoplasmic cap over the central ion permeation pathway, leaving lateral fenestrations that may be partially buried in the membrane as potential pathways for ions to permeate the intracellular end of the pore. In the present study we identify a critical residue with the intracellular lateral fenestrations that is readily accessible to thiol reactive compounds from both sides of the membrane and where substitutions influence the relative permeability of the channel to cations and anions. Taken together, our results suggest that ions can enter or exit the internal pore through lateral fenestrations and that these structural elements play a critical role in determining the ion selectivity of P2X receptor channels.