Preferential use of unobstructed lateral portals as the access route to the pore of human ATP-gated ion channels (P2X receptors)

Damien S K Samways (1) , Baljit S Khakh (2) , Sébastien Dutertre (3) , Terrance M Egan (1)

1 SLU - Saint Louis University
2 UCLA - University of California [Los Angeles]
3 IBMM - Institut des Biomolécules Max Mousseron [Pôle Chimie Balard]

P2X receptors are trimeric cation channels with widespread roles in health and disease. The recent crystal structure of a P2X4 receptor provides a 3D view of their topology and architecture. A key unresolved issue is how ions gain access to the pore, because the structure reveals two different pathways within the extracellular domain. One of these is the central pathway spanning the entire length of the extracellular domain and covering a distance of ≈70 Å. The second consists of three lateral portals, adjacent to the membrane and connected to the transmembrane pore by short tunnels. Here, we demonstrate the preferential use of the lateral portals. Owing to their favorable diameters and equivalent spacing, the lateral portals split the task of ion supply threefold and minimize an ion's diffusive path before it succumbs to transmembrane electrochemical gradients.

Mots clés: fenestration; fractional calcium current; ligand-gated ion channel; cysteine scanning mutagenesis

Domaines: Biologie structurale [q-bio.BM]; Neurobiologie; Pharmacologie

Damien S K Samways, Baljit S Khakh, Sébastien Dutertre, Terrance M Egan. Preferential use of unobstructed lateral portals as the access route to the pore of human ATP-gated ion channels (P2X receptors). Proceedings of the National Academy of Sciences of the United States of America, 2011, 108 (33), pp.13800-13805. ⟨10.1073/pnas.1017550108⟩. ⟨hal-02306894⟩