Ca2+ Channel Independent Functions Of An Alternatively Spliced ß4 Subunit

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The [beta] subunits of voltage-gated Ca2+ channels are multifunctional proteins, which act primarily as a Ca2+ channel regulatory subunit to regulate trafficking and gating properties of pore-forming Ca2+ channel [alpha]1 subunits. Recent studies have revealed, however, that [beta]4 subunits also play crucial roles in a variety of Ca2+ channel independent functions. These processes involve translocation of [beta] subunits to the nucleus where they associate with and regulate expression of proteins involved in gene transcription. The latter emerging role of the Ca2+ channel [beta]4 subunit began with the cloning of various alternatively spliced isoforms of the [beta]4 subunit. Here we cloned the mammalian form of an alternatively spliced, truncated [beta]4 subunit ([beta]4c-207aa) from human brain, and showed that it interacts with heterochromatin protein 1[gamma] (HP1[gamma]) through a PXVXL consensus motif. We also showed that [beta]4c is highly expressed in vestibular, and deep cerebellar nuclei of mouse brain. In our subsequent study, we found that [beta]4c nuclear transport is independent of its PXVXL motif interaction with HP1[gamma]. Instead, we found that the nuclear targeting of heterologously expressed [beta]4c in Neuro2a cells is under the control of two sequence motifs that are separated by 63 amino acids. The first is identical to a classical monopartite nuclear localization sequence (cNLS), K(K/R)X(K/R), located in the HOOK domain, and the second is a previously unidentified C-terminal sequence that is generated by alternative splicing. Both sequences are required for optimal targeting of [beta]4c to the nucleus. Next we determined the functional consequences of [beta]4c nuclear targeting by performing a whole genome expression study. We determined that [beta]4c regulates the transcription of a number of genes that include components of the cytoskeleton assembly machinery and other ion channel genes. Notably, [beta]4c did not regulate expression of Ca2+ channel genes. The [beta]4c splice variant was not capable of modulating Ca2+ channel trafficking or gating properties. Therefore, the overall conclusion of this thesis is that [beta]4c does not affect the expression or function of Ca2+ channel subunits, rather it acts independently of Ca2+ channels to regulate genes that are involved in neurite outgrowth.

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Horne, William Alan

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Oswald, Robert Edward
Lin, David M.
Weiss, Robert S.

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Ph. D., Physiology

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Doctor of Philosophy

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