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P2Y1 receptor signaling is controlled by interaction with the PDZ scaffold NHERF-2.

ABSTRACT: P2Y(1) purinergic receptors (P2Y(1)Rs) mediate rises in intracellular Ca(2+) in response to ATP, but the duration and characteristics of this Ca(2+) response are known to vary markedly in distinct cell types. We screened the P2Y(1)R carboxyl terminus against a recently created proteomic array of PDZ (PSD-95/Drosophila Discs large/ZO-1 homology) domains and identified a previously unrecognized, specific interaction with the second PDZ domain of the scaffold NHERF-2 (Na(+)/H(+) exchanger regulatory factor type 2). Furthermore, we found that P2Y(1)R and NHERF-2 associate in cells, allowing NHERF-2-mediated tethering of P2Y(1)R to key downstream effectors such as phospholipase Cbeta. Finally, we found that coexpression of P2Y(1)R with NHERF-2 in glial cells prolongs P2Y(1)R-mediated Ca(2+) signaling, whereas disruption of the P2Y(1)R-NHERF-2 interaction by point mutations attenuates the duration of P2Y(1)R-mediated Ca(2+) responses. These findings reveal that NHERF-2 is a key regulator of the cellular activity of P2Y(1)R and may therefore determine cell-specific differences in P2Y(1)R-mediated signaling.

SUBMITTER: Fam SR

PROVIDER: S-EPMC1142356 | biostudies-literature | 2005 May

REPOSITORIES: biostudies-literature

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P2Y1 receptor signaling is controlled by interaction with the PDZ scaffold NHERF-2.

Fam Sami R SR Paquet Maryse M Castleberry Amanda M AM Oller Heide H Lee C Justin CJ Traynelis Stephen F SF Smith Yoland Y Yun C Chris CC Hall Randy A RA

Proceedings of the National Academy of Sciences of the United States of America 20050518 22

P2Y(1) purinergic receptors (P2Y(1)Rs) mediate rises in intracellular Ca(2+) in response to ATP, but the duration and characteristics of this Ca(2+) response are known to vary markedly in distinct cell types. We screened the P2Y(1)R carboxyl terminus against a recently created proteomic array of PDZ (PSD-95/Drosophila Discs large/ZO-1 homology) domains and identified a previously unrecognized, specific interaction with the second PDZ domain of the scaffold NHERF-2 (Na(+)/H(+) exchanger regulator ...[more]

PMID: 15901899

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Project description:Despite the characteristic etiologies and phenotypes, different brain disorders rely on common pathogenic events. Glutamate-induced neurotoxicity is a pathogenic event shared by different brain disorders. Another event occurring in different brain pathological conditions is the increase of the extracellular ATP levels, which is now recognized as a danger and harmful signal in the brain, as heralded by the ability of P2 receptors (P2Rs) to affect a wide range of brain disorders. Yet, how ATP and P2R contribute to neurodegeneration remains poorly defined. For that purpose, we now examined the contribution of extracellular ATP and P2Rs to glutamate-induced neurodegeneration. We found both in vitro and in vivo that ATP/ADP through the activation of P2Y1R contributes to glutamate-induced neuronal death in the rat hippocampus. We found in cultured rat hippocampal neurons that the exposure to glutamate (100 µM) for 30 min triggers a sustained increase of extracellular ATP levels, which contributes to NMDA receptor (NMDAR)-mediated hippocampal neuronal death through the activation of P2Y1R. We also determined that P2Y1R is involved in excitotoxicity in vivo as the blockade of P2Y1R significantly attenuated rat hippocampal neuronal death upon the systemic administration of kainic acid or upon the intrahippocampal injection of quinolinic acid. This contribution of P2Y1R fades with increasing intensity of excitotoxic conditions, which indicates that P2Y1R is not contributing directly to neurodegeneration, rather behaving as a catalyst decreasing the threshold from which glutamate becomes neurotoxic. Moreover, we unraveled that such excitotoxicity process began with an early synaptotoxicity that was also prevented/attenuated by the antagonism of P2Y1R, both in vitro and in vivo. This should rely on the observed glutamate-induced calpain-mediated axonal cytoskeleton damage, most likely favored by a P2Y1R-driven increase of NMDAR-mediated Ca2+ entry selectively in axons. This may constitute a degenerative mechanism shared by different brain diseases, particularly relevant at initial pathogenic stages.

Dataset Information

P2Y1 receptor signaling is controlled by interaction with the PDZ scaffold NHERF-2.

Publications

P2Y1 receptor signaling is controlled by interaction with the PDZ scaffold NHERF-2.

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