Mechanism of Zinc Potentiation of P2X Receptors

点击翻译按钮获取中文摘要

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.