Co-Expression of Wild-Type P2X7R with Gln460Arg Variant Alters Receptor Function

被引：21

作者：

Aprile-Garcia, Fernando ^{[1
,2
]}

Metzger, Michael W. ^{[3
]}

Paez-Pereda, Marcelo ^{[3
]}

Stadler, Herbert ^{[4
]}

Acuna, Matias ^{[1
]}

Liberman, Ana C. ^{[1
]}

Senin, Sergio A. ^{[1
]}

Gerez, Juan ^{[1
]}

Hoijman, Esteban ^{[5
]}

Refojo, Damian ^{[3
]}

Mitkovski, Miso ^{[6
]}

Panhuysen, Markus ^{[4
]}

Stuehmer, Walter ^{[6
]}

Holsboer, Florian ^{[3
,7
]}

Deussing, Jan M. ^{[3
]}

Arzt, Eduardo ^{[1
,2
,3
]}

机构：

[1] Max Planck Gesell, CONICET, Inst Invest Biomed Buenos Aires IBioBA, Partner Inst, Buenos Aires, DF, Argentina

[2] Univ Buenos Aires, Fac Ciencias Exactas & Nat, Dept Fisiol & Biol Mol & Celular, Buenos Aires, DF, Argentina

[3] Max Planck Inst Psychiat, D-80804 Munich, Germany

[4] Affectis Pharmaceut, D-44227 Dortmund, Germany

[5] Univ Buenos Aires, Fac Ciencias Exactas & Nat, Ctr Microscopias Avanzadas, Buenos Aires, DF, Argentina

[6] Max Planck Inst Expt Med, Hermann Rein Str 3, D-37075 Gottingen, Germany

[7] HMNC Brain Hlth, Munich, Germany

来源：

PLOS ONE | 2016年 / 11卷 / 03期

关键词：

SINGLE NUCLEOTIDE POLYMORPHISMS; MAJOR DEPRESSIVE DISORDER; RESONANCE ENERGY-TRANSFER; HUMAN P2X(7) RECEPTOR; PURINERGIC RECEPTOR; P2RX7; GENE; MICROGLIAL CELLS; IMMUNE-SYSTEM; OF-FUNCTION; TNF-ALPHA;

D O I：

10.1371/journal.pone.0151862

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：16

共 61 条

[1] P2X4 receptors interact with both P2X2 and P2X7 receptors in the form of homotrimers [J].