Function of P2X4 Receptors Is Directly Modulated by a 1:1 Stoichiometric Interaction With 5-HT 3 A Receptors.

Autor: Soto P; Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile., Gaete PS; Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile., Fuentes C; Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile., Lozano B; Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile., Naulin PA; Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile., Figueroa XF; Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile., Barrera NP; Department of Physiology, Faculty of Biological Sciences, Pontificia Universidad Católica de Chile, Santiago, Chile.
Jazyk: angličtina
Zdroj: Frontiers in cellular neuroscience [Front Cell Neurosci] 2020 May 05; Vol. 14, pp. 106. Date of Electronic Publication: 2020 May 05 (Print Publication: 2020).
DOI: 10.3389/fncel.2020.00106
Abstrakt: Interacting receptors at the neuronal plasma membrane represent an additional regulatory mode for intracellular transduction pathways. P2X4 receptor triggers fast neurotransmission responses via a transient increase in intracellular Ca 2+ levels. It has been proposed that the P2X4 receptor interacts with the 5-HT 3 A receptor in hippocampal neurons, but their binding stoichiometry and the role of P2X4 receptor activation by ATP on this crosstalking system remains unknown. Via pull-down assays, total internal reflection fluorescence (TIRF) microscopy measurements of the receptors colocalization and expression at the plasma membrane, and atomic force microscopy (AFM) imaging, we have demonstrated that P2X4/5-HT 3 A receptor complexes can interact with each other in a 1:1 stoichiometric manner that is preserved after ATP binding. Also, macromolecular docking followed by 100 ns molecular dynamics (MD) simulations suggested that the interaction energy of the P2X4 receptor with 5-HT 3 A receptor is similar at the holo and the apo state of the P2X4 receptor, and the interacting 5-HT 3 A receptor decreased the ATP binding energy of P2X4 receptor. Finally, the P2X4 receptor-dependent Ca 2+ mobilization is inhibited by the 5-HT 3 A interacting receptor. Altogether, these findings provide novel molecular insights into the allosteric regulation of P2X4/5-HT 3 A receptor complex in lipid bilayers of living cells via stoichiometric association, rather than accumulation or unspecific clustering of complexes.
(Copyright © 2020 Soto, Gaete, Fuentes, Lozano, Naulin, Figueroa and Barrera.)
Databáze: MEDLINE
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