hide
Free keywords:
-
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.
