On the permeation of large organic cations through the pore of ATP-gated P2X receptors
| Autor: | Thomas Grutter, Thierry Chataigneau, Alexandre Specht, Kate Dunning, Juline Beudez, Adrien H. Cerdan, Marco Cecchini, Laurie Peverini, Mahboubi Harkat, Nicolas Calimet, Adeline Martz |
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| Přispěvatelé: | Université de Strasbourg (UNISTRA) |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cell Membrane Permeability Multidisciplinary Chromatography Physiological significance Spermidine Chemistry [SDV]Life Sciences [q-bio] Purinergic receptor Conductance Permeation Models Biological Ion 03 medical and health sciences HEK293 Cells 030104 developmental biology Glutamates PNAS Plus Receptors Purinergic P2X Permeability (electromagnetism) Biophysics Humans Molecule Receptor |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, National Academy of Sciences, 2017, 114 (19), pp.E3786-E3795. ⟨10.1073/pnas.1701379114⟩ |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | International audience; 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 N -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 NMDG + permeability superimposes that of Na + and demonstrate that the molecular motions leading to the permeation of NMDG + are very similar to those that drive Na + flow. We found, however, that NMDG + “percolates” 10 times slower than Na + in 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 NMDG + but 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. |
| Databáze: | OpenAIRE |
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