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Post-translational allosteric activation of the P2X 7 receptor through glycosaminoglycan chains of CD44 proteoglycans

Moura, GEDD; Lucena, SV; Andrade De Lima, M; Nascimento, FD; Gesteira, TF; Nader, HB; Paredes-Gamero, EJ; Tersariol, ILS

Post-translational allosteric activation of the P2X 7 receptor through glycosaminoglycan chains of CD44 proteoglycans Thumbnail


Authors

GEDD Moura

SV Lucena

FD Nascimento

TF Gesteira

HB Nader

EJ Paredes-Gamero

ILS Tersariol



Abstract

Here, we present evidence for the positive allosteric modulation of the P2X7 receptor through glycosaminoglycans (GAGs) in CHO (cell line derived from the ovary of the Chinese hamster) cells. The marked potentiation of P2X7 activity through GAGs in the presence of non-saturating agonists concentrations was evident with the endogenous expression of the receptor in CHO cells. The presence of GAGs on the surface of CHO cells greatly increased the sensitivity to adenosine 5'-triphosphate and changed the main P2X7 receptor kinetic parameters EC50, Hill coefficient and Emax. GAGs decreased the allosteric inhibition of P2X7 receptor through Mg2+. GAGs activated P2X7 receptor-mediated cytoplasmic Ca2+ influx and pore formation. Consequently, wild-type CHO-K1 cells were 2.5-fold more sensitive to cell death induced through P2X7 agonists than mutant CHO-745 cells defective in GAGs biosynthesis. In the present study, we provide the first evidence that the P2X7 receptor interacts with CD44 on the CHO-K1 cell surface. Thus, these data demonstrated that GAGs positively modulate the P2X7 receptor, and sCD44 is a part of a regulatory positive feedback loop linking P2X7 receptor activation for the intracellular response mediated through P2X7 receptor stimulation.

Citation

Moura, G., Lucena, S., Andrade De Lima, M., Nascimento, F., Gesteira, T., Nader, H., …Tersariol, I. (2015). Post-translational allosteric activation of the P2X 7 receptor through glycosaminoglycan chains of CD44 proteoglycans. Cell Death Discovery, 1, 15005--15005. https://doi.org/10.1038/cddiscovery.2015.5

Journal Article Type Article
Acceptance Date Jun 5, 2015
Publication Date Oct 5, 2015
Journal Cell Death Discovery
Print ISSN 2058-7716
Publisher Springer Nature [academic journals on nature.com]
Volume 1
Pages 15005--15005
DOI https://doi.org/10.1038/cddiscovery.2015.5
Keywords cell death; glycobiology; ligand-gated ion channels; oncogenes
Publisher URL https://www.nature.com/articles/cddiscovery20155#article-info

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