A dual polybasic motif determines phosphoinositide binding and regulation in the P2X channel family.
PLoS ONE. 2012-07-11; 7(7): e40595
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1. PLoS One. 2012;7(7):e40595. doi: 10.1371/journal.pone.0040595. Epub 2012 Jul 11.
A dual polybasic motif determines phosphoinositide binding and regulation in the
P2X channel family.
Bernier LP(1), Blais D, Boué-Grabot É, Séguéla P.
(1)Department of Neurology and Neurosurgery, Montreal Neurological Institute,
Alan Edwards Centre for Research on Pain, McGill University, Montréal, Québec,
Phosphoinositides modulate the function of several ion channels, including most
ATP-gated P2X receptor channels in neurons and glia, but little is known about
the underlying molecular mechanism. We identified a phosphoinositide-binding
motif formed of two clusters of positively charged amino acids located on the P2X
cytosolic C-terminal domain, proximal to the second transmembrane domain. For all
known P2X subtypes, the specific arrangement of basic residues in these
semi-conserved clusters determines their sensitivity to membrane phospholipids.
Neutralization of these positive charges disrupts the functional properties of
the prototypical phosphoinositide-binding P2X4 subtype, mimicking
wortmannin-induced phosphoinositide depletion, whereas adding basic residues at
homologous positions to the natively insensitive P2X5 subtype establishes de novo
phosphoinositide-mediated regulation. Moreover, biochemical evidence of in vitro
P2X subunit-phospholipid interaction and functional intracellular
phosphoinositide-binding assays demonstrate that the dual polybasic cluster is
necessary and sufficient for regulation of P2X signaling by phospholipids.
PMID: 22792379 [Indexed for MEDLINE]