Artículo
Abstract:
The P2X7 receptor is a member of the P2X family of ligand-gated ion channels. A single-nucleotide polymorphism leading to a glutamine (Gln) by arginine (Arg) substitution at codon 460 of the purinergic P2X7 receptor (P2X7R) has been associated with mood disorders. No change in function (loss or gain) has been described for this SNP so far. Here we show that although the P2X7R-Gln460Arg variant per se is not compromised in its function, co-expression of wild-type P2X7R with P2X7R-Gln460Arg impairs receptor function with respect to calcium influx, channel currents and intracellular signaling in vitro. Moreover, co-immunoprecipitation and FRET studies show that the P2X7R-Gln460Arg variant physically interacts with P2X7R-WT. Specific silencing of either the normal or polymorphic variant rescues the heterozygous loss of function phenotype and restores normal function. The described loss of function due to co-expression, unique for mutations in the P2RX7 gene so far, explains the mechanism by which the P2X7R-Gln460Arg variant affects the normal function of the channel and may represent a mechanism of action for other mutations.
Registro:
| Documento: | Artículo |
| Título: | Co-Expression of Wild-Type P2X7R with Gln460Arg Variant Alters Receptor Function |
| Autor: | Aprile-Garcia, F.; Metzger, M.W.; Paez-Pereda, M.; Stadler, H.; Acuña, M.; Liberman, A.C.; Senin, S.A.; Gerez, J.; Hoijman, E.; Refojo, D.; Mitkovski, M.; Panhuysen, M.; Stühmer, W.; Holsboer, F.; Deussing, J.M.; Arzt, E. |
| Filiación: | Instituto de Investigación en Biomedicina de Buenos Aires (IBioBA)-CONICET- Partner Institute of the Max Planck SocietyBuenos Aires, Argentina Departamento de Fisiología y Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos AiresBuenos Aires, Argentina Max Planck Institute of Psychiatry, Munich, 80804, Germany Affectis Pharmaceuticals, Dortmund, 44227, Germany Centro de Microscopías Avanzadas, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos AiresBuenos Aires, Argentina Max Planck Institute of Experimental Medicine, Göttingen, 37075, Germany HMNC Brain Health, Munich, Germany |
| Palabras clave: | calcium; P2XR receptor, human; purinergic P2X7 receptor; small interfering RNA; fluorescence resonance energy transfer; genetics; HEK293 cell line; human; immunoprecipitation; metabolism; patch clamp technique; physiology; real time polymerase chain reaction; signal transduction; single nucleotide polymorphism; Western blotting; Blotting, Western; Calcium; Fluorescence Resonance Energy Transfer; HEK293 Cells; Humans; Immunoprecipitation; Patch-Clamp Techniques; Polymorphism, Single Nucleotide; Real-Time Polymerase Chain Reaction; Receptors, Purinergic P2X7; RNA, Small Interfering; Signal Transduction |
| Año: | 2016 |
| Volumen: | 11 |
| Número: | 3 |
| Página de inicio: | e0151862 |
| DOI: | http://dx.doi.org/10.1371/journal.pone.0151862 |
| Título revista: | PloS one |
| Título revista abreviado: | PLoS ONE |
| ISSN: | 19326203 |
| CAS: | calcium, 7440-70-2, 14092-94-5; Calcium; P2XR receptor, human; Receptors, Purinergic P2X7; RNA, Small Interfering |
| Registro: | https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_19326203_v11_n3_pe0151862_AprileGarcia |
Citas:
---------- APA ----------
Aprile-Garcia, F., Metzger, M.W., Paez-Pereda, M., Stadler, H., Acuña, M., Liberman, A.C., Senin, S.A.,..., Arzt, E. (2016) . Co-Expression of Wild-Type P2X7R with Gln460Arg Variant Alters Receptor Function. PloS one, 11(3), e0151862.http://dx.doi.org/10.1371/journal.pone.0151862
---------- CHICAGO ----------
Aprile-Garcia, F., Metzger, M.W., Paez-Pereda, M., Stadler, H., Acuña, M., Liberman, A.C., et al. "Co-Expression of Wild-Type P2X7R with Gln460Arg Variant Alters Receptor Function" . PloS one 11, no. 3 (2016) : e0151862.http://dx.doi.org/10.1371/journal.pone.0151862
---------- MLA ----------
Aprile-Garcia, F., Metzger, M.W., Paez-Pereda, M., Stadler, H., Acuña, M., Liberman, A.C., et al. "Co-Expression of Wild-Type P2X7R with Gln460Arg Variant Alters Receptor Function" . PloS one, vol. 11, no. 3, 2016, pp. e0151862.http://dx.doi.org/10.1371/journal.pone.0151862
---------- VANCOUVER ----------
Aprile-Garcia, F., Metzger, M.W., Paez-Pereda, M., Stadler, H., Acuña, M., Liberman, A.C., et al. Co-Expression of Wild-Type P2X7R with Gln460Arg Variant Alters Receptor Function. PLoS ONE. 2016;11(3):e0151862.http://dx.doi.org/10.1371/journal.pone.0151862
