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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31NS051001-03
Application #
7189145
Study Section
Special Emphasis Panel (ZRG1-F03B (20))
Program Officer
Talley, Edmund M
Project Start
2005-01-01
Project End
2007-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
3
Fiscal Year
2007
Total Cost
$31,756
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Tittle, Rachel K; Hume, Richard I (2008) Opposite effects of zinc on human and rat P2X2 receptors. J Neurosci 28:11131-40
Tittle, Rachel K; Power, Jamila M; Hume, Richard I (2007) A histidine scan to probe the flexibility of the rat P2X2 receptor zinc-binding site. J Biol Chem 282:19526-33
Mohr, J P; Biller, J; Hilal, S K et al. (1995) Magnetic resonance versus computed tomographic imaging in acute stroke. Stroke 26:807-12