Title

Ankyrin-spectrin scaffolds, from blood to brain

Date of Completion

January 2006

Keywords

Biology, Neuroscience

Degree

Ph.D.

Abstract

The initiation and rapid transduction of electrical signals in the nervous system depends on the proper expression of voltage-gated sodium channels in the axon initial segment and nodes of Ranvier. The localization of sodium channel in neurons depends on two submembranous scaffolding proteins, βIV spectrin and ankyrin-G. In many cell types, ankyrins and spectrins regulate membrane protein localization and retention. However, in neurons, it is not known whether ankyrin-G or βIV spectrin is responsible for organizing the AIS and nodes of Ranvier. Here we show βIV spectrin regulates nodal membrane integrity and axon shape in a quivering mouse model. We further identify a distinct domain in βIV spectrin required for its localization to the AIS and nodes of Ranvier, and show that this domain mediates βIV spectrin's interaction with ankyrin-G. However, mutant ankyrin-G which binds to βIV spectrin fails to localize to the AIS, suggesting that binding to βIV spectrin is not sufficient for targeting ankyrin-G to the AIS. Thus, our data strongly suggest that ankyrin-G is the key intrinsic organizer for axonal membrane domain formation, while βIV spectrin is involved in the stability of these domains. ^