Link to Pubmed [PMID] – 28442564
Proc. Natl. Acad. Sci. U.S.A. 2017 May;114(19):E3786-E3795
Pore dilation is thought to be a hallmark of purinergic P2X receptors. The most commonly held view of this unusual process posits that under prolonged ATP exposure the ion pore expands in a striking manner from an initial small-cation conductive state to a dilated state, which allows the passage of larger synthetic cations, such as-methyl-d-glucamine (NMDG). However, this mechanism is controversial, and the identity of the natural large permeating cations remains elusive. Here, we provide evidence that, contrary to the time-dependent pore dilation model, ATP binding opens an NMDG-permeable channel within milliseconds, with a conductance that remains stable over time. We show that the time course of NMDGpermeability superimposes that of Naand demonstrate that the molecular motions leading to the permeation of NMDGare very similar to those that drive Naflow. We found, however, that NMDG”percolates” 10 times slower than Nain the open state, likely due to a conformational and orientational selection of permeating molecules. We further uncover that several P2X receptors, including those able to desensitize, are permeable not only to NMDGbut also to spermidine, a large natural cation involved in ion channel modulation, revealing a previously unrecognized P2X-mediated signaling. Altogether, our data do not support a time-dependent dilation of the pore on its own but rather reveal that the open pore of P2X receptors is wide enough to allow the permeation of large organic cations, including natural ones. This permeation mechanism has considerable physiological significance.