Date

11-1-2012

Document Type

Thesis

Degree Name

Ph.D.

Institution

Oregon Health & Science University

Abstract

Designed to detect pH fluctuations, acid-sensing ion channels began as mystifying molecules, initially known to only gate upon proton binding. However, recent studies unveiled a new mode of gating, independent of pH, thus revealing new roles in which they participate in the central and peripheral nervous systems. Harboring a large extracellular domain and anchored to the membrane bilayer with six transmembrane domains, these channels desensitize on a timescale of seconds, thus complicating structural studies investigating mechanisms underlying ion channel gating. To stabilize the activated state of the channel, I utilized potent and highly specific toxins and determined crystal structures of acid-sensing ion channel 1a in complexes with PcTx1 and MitTx, toxins identified from the venom of spider and snake, respectively, locking the channel in distinct open conformations. The structures illustrate that toxins bind at the subunit interface. Whereas the small PcTx1 binds near the acidic p

Comments

This document has been embargoed indefinitely and consequently is not available in full text electronic format. A circulating bound text of the document is available in the stacks of the Library.

Identifier

doi:10.6083/M43F4MNQ

Division

Neuroscience Graduate Program

School

School of Medicine

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