Mechanism of Zinc Potentiation of P2X Receptors

锌增强 P2X 受体的机制

• 批准号: 6886475
• 负责人: Rachel K. Tittle
• 金额: $ 3.18万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6886475
• 关键词: Xenopus; Xenopus oocyte; adenosine triphosphate; chemical binding; crosslink; histidine; membrane channels; predoctoral investigator; protein structure function; purinergic receptor; receptor expression; zinc

DESCRIPTION (provided by applicant): P2X receptors are cation channels gated by extra cellular ATP. Defects in signaling by these channels result in deficits in pain perception, male fertility, and sound transduction. Homomeric channels made up of the P2X2 subunit show potentiation of ATP-induced current when extra cellular zinc is applied. In P2X2, extra cellular histidines 120 and 213 are independently required for zinc potentiation. It is hypothesized that these residues directly participate in a zinc binding site, and that when zinc is bound, the distance between these two residues changes such that the open state of the ion channel is stabilized. To test this hypothesis, a search will be made for other residues potentially involved in binding zinc. Additionally, residues 120 and 213 will be blocked by the binding of a small molecule, and the amount of zinc potentiation will be measured. Based on the hypothesis, it is expected that zinc potentiation will decrease. Finally, residues 120 and 213 will be cross-linked with various molecules. It is expected that rigid cross linkers of certain size will yield channels that are permanently either in the potentiated or non-potentiated state, regardless of the presence of zinc.

描述（由申请人提供）：P2X 受体是由细胞外 ATP 门控的阳离子通道。这些通道的信号传导缺陷会导致疼痛感知、男性生育能力和声音传导方面的缺陷。当应用细胞外锌时，由 P2X2 亚基组成的同源通道显示出 ATP 诱导电流的增强。在 P2X2 中，细胞外组氨酸 120 和 213 独立地需要锌增强作用。假设这些残基直接参与锌结合位点，并且当锌结合时，这两个残基之间的距离发生变化，使得离子通道的开放状态稳定。为了检验这一假设，将寻找可能参与结合锌的其他残基。此外，残基 120 和 213 将被小分子的结合封闭，并测量锌增强的量。根据该假设，预计锌的增强作用将会降低。最后，残基 120 和 213 将与各种分子交联。预计一定尺寸的刚性交联剂将产生永久处于增强或非增强状态的通道，无论是否存在锌。