All ETDs from UAB

Advisory Committee Chair

Dale J Benos

Advisory Committee Members

J Edward Blalock

Champion C Deivanayagam

Louis B Justement

Jere P Segrest

Yuhua H Song

Document Type

Dissertation

Date of Award

2010

Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine

Abstract

Acid Sensing Ion Channel 1 is one of the many proteins in the Epithelial Sodium Channel/Degenerin family. The proteins in this family interact to form cation channels with unique biophysical properties and can all be inhibited by the small molecule amiloride. Their expression in many different cell types underlies their involvement in a large variety of physiological and pathophysiological processes. ASIC-1 containing channels, specifically, are an important therapeutic target for ischemic stroke, nociception, the invasiveness of glioblastoma cells, and many other processes including anxiety and memory formation. Of the members of the ENaC/Deg family, chicken ASIC-1 is the only protein for which crystal structures have been solved. Using homology modeling, structures of the human proteins in the ENaC/Degenerin family were deduced. Further computational methods were applied to examine the interaction of hASIC-1 with known small molecule inhibitors such as amiloride and Psalmotoxin-1, a highly potent peptide toxin. Experimental verification of these computational results was performed using whole-cell and single-channel electrophysiology. Amiloride analogs not known to interact with ASIC-1 were identified by computational studies and verified functionally, showing the strength of this technique for discovering new ASIC ligands. Fully understanding the interactions of these inhibitors with ASIC-1 should permit their manipulation for the benefit of those afflicted with glioblastomas, stroke, anxiety, or pain.

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