| First Author | Etemad S | Year | 2014 |
| Journal | J Neurosci | Volume | 34 |
| Issue | 4 | Pages | 1446-61 |
| PubMed ID | 24453333 | Mgi Jnum | J:206966 |
| Mgi Id | MGI:5553415 | Doi | 10.1523/JNEUROSCI.3935-13.2014 |
| Citation | Etemad S, et al. (2014) Differential neuronal targeting of a new and two known calcium channel beta4 subunit splice variants correlates with their regulation of gene expression. J Neurosci 34(4):1446-61 |
| abstractText | The beta subunits of voltage-gated calcium channels regulate surface expression and gating of CaV1 and CaV2 alpha1 subunits and thus contribute to neuronal excitability, neurotransmitter release, and calcium-induced gene regulation. In addition, certain beta subunits are targeted into the nucleus, where they interact directly with the epigenetic machinery. Whereas their involvement in this multitude of functions is reflected by a great molecular heterogeneity of beta isoforms derived from four genes and abundant alternative splicing, little is known about the roles of individual beta variants in specific neuronal functions. In the present study, an alternatively spliced beta4 subunit lacking the variable N terminus (beta4e) is identified. It is highly expressed in mouse cerebellum and cultured cerebellar granule cells (CGCs) and modulates P/Q-type calcium currents in tsA201 cells and CaV2.1 surface expression in neurons. Compared with the other two known full-length beta4 variants (beta4a and beta4b), beta4e is most abundantly expressed in the distal axon, but lacks nuclear-targeting properties. To determine the importance of nuclear targeting of beta4 subunits for transcriptional regulation, we performed whole-genome expression profiling of CGCs from lethargic (beta4-null) mice individually reconstituted with beta4a, beta4b, and beta4e. Notably, the number of genes regulated by each beta4 splice variant correlated with the rank order of their nuclear-targeting properties (beta4b > beta4a > beta4e). Together, these findings support isoform-specific functions of beta4 splice variants in neurons, with beta4b playing a dual role in channel modulation and gene regulation, whereas the newly detected beta4e variant serves exclusively in calcium-channel-dependent functions. |
