The ASIC3/P2X3 cognate receptor is a pain-relevant and ligand-gated cationic channel

Gabriele Stephan, Lumei Huang, Yong Tang, Sandra Vilotti, Elsa Fabbretti, Ye Yu, Wolfgang Nörenberg, Heike Franke, Flóra Gölöncsér, Beáta Sperlágh, Anke Dopychai, Ralf Hausmann, Günther Schmalzing, Patrizia Rubini and Peter Illes ()
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Gabriele Stephan: University of Leipzig
Lumei Huang: University of Leipzig
Yong Tang: Chengdu University of Traditional Chinese Medicine
Sandra Vilotti: International School for Advanced Studies
Elsa Fabbretti: University of Trieste
Ye Yu: Institute of Neuroscience and State Key Laboratory of Neuroscience
Wolfgang Nörenberg: University of Leipzig
Heike Franke: University of Leipzig
Flóra Gölöncsér: Hungarian Academy of Sciences
Beáta Sperlágh: Hungarian Academy of Sciences
Anke Dopychai: Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University
Ralf Hausmann: Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University
Günther Schmalzing: Rheinisch-Westfälische Technische Hochschule (RWTH) Aachen University
Patrizia Rubini: University of Leipzig
Peter Illes: University of Leipzig

Nature Communications, 2018, vol. 9, issue 1, 1-18

Abstract: Abstract Two subclasses of acid-sensing ion channels (ASIC3) and of ATP-sensitive P2X receptors (P2X3Rs) show a partially overlapping expression in sensory neurons. Here we report that both recombinant and native receptors interact with each other in multiple ways. Current measurements with the patch-clamp technique prove that ASIC3 stimulation strongly inhibits the P2X3R current partly by a Ca2+-dependent mechanism. The proton-binding site is critical for this effect and the two receptor channels appear to switch their ionic permeabilities during activation. Co-immunoprecipation proves the close association of the two protein structures. BN-PAGE and SDS-PAGE analysis is also best reconciled with the view that ASIC3 and P2X3Rs form a multiprotein structure. Finally, in vivo measurements in rats reveal the summation of pH and purinergically induced pain. In conclusion, the receptor subunits do not appear to form a heteromeric channel, but tightly associate with each other to form a protein complex, mediating unidirectional inhibition.

Date: 2018
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DOI: 10.1038/s41467-018-03728-5

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