A dual polybasic motif determines phosphoinositide binding and regulation in the P2X channel family.
PLoS One
; 7(7): e40595, 2012.
Article
em En
| MEDLINE
| ID: mdl-22792379
ABSTRACT
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.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fosfatidilinositóis
/
Receptores Purinérgicos P2X
Idioma:
En
Ano de publicação:
2012
Tipo de documento:
Article