? spectrin-dependent and domain specific mechanisms for Na+ channel clustering.

ABSTRACT: Previously, we showed that a hierarchy of spectrin cytoskeletal proteins maintains nodal Na+ channels (Liu et al., 2020). Here, using mice lacking ?1, ?4, or ?1/?4 spectrins, we show this hierarchy does not function at axon initial segments (AIS). Although ?1 spectrin, together with AnkyrinR (AnkR), compensates for loss of nodal ?4 spectrin, it cannot compensate at AIS. We show AnkR lacks the domain necessary for AIS localization. Whereas loss of ?4 spectrin causes motor impairment and disrupts AIS, loss of ?1 spectrin has no discernable effect on central nervous system structure or function. However, mice lacking both neuronal ?1 and ?4 spectrin show exacerbated nervous system dysfunction compared to mice lacking ?1 or ?4 spectrin alone, including profound disruption of AIS Na+ channel clustering, progressive loss of nodal Na+ channels, and seizures. These results further define the important role of AIS and nodal spectrins for nervous system function.

SUBMITTER: Liu CH 

PROVIDER: S-EPMC7237202 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature