RT Journal Article SR Electronic T1 Differential Neuronal Targeting of a New and Two Known Calcium Channel β4 Subunit Splice Variants Correlates with Their Regulation of Gene Expression JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 1446 OP 1461 DO 10.1523/JNEUROSCI.3935-13.2014 VO 34 IS 4 A1 Solmaz Etemad A1 Gerald J. Obermair A1 Daniel Bindreither A1 Ariane Benedetti A1 Ruslan Stanika A1 Valentina Di Biase A1 Verena Burtscher A1 Alexandra Koschak A1 Reinhard Kofler A1 Stephan Geley A1 Alexandra Wille A1 Alexandra Lusser A1 Veit Flockerzi A1 Bernhard E. Flucher YR 2014 UL http://www.jneurosci.org/content/34/4/1446.abstract AB The β subunits of voltage-gated calcium channels regulate surface expression and gating of CaV1 and CaV2 α1 subunits and thus contribute to neuronal excitability, neurotransmitter release, and calcium-induced gene regulation. In addition, certain β 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 β isoforms derived from four genes and abundant alternative splicing, little is known about the roles of individual β variants in specific neuronal functions. In the present study, an alternatively spliced β4 subunit lacking the variable N terminus (β4e) 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 β4 variants (β4a and β4b), β4e is most abundantly expressed in the distal axon, but lacks nuclear-targeting properties. To determine the importance of nuclear targeting of β4 subunits for transcriptional regulation, we performed whole-genome expression profiling of CGCs from lethargic (β4-null) mice individually reconstituted with β4a, β4b, and β4e. Notably, the number of genes regulated by each β4 splice variant correlated with the rank order of their nuclear-targeting properties (β4b > β4a > β4e). Together, these findings support isoform-specific functions of β4 splice variants in neurons, with β4b playing a dual role in channel modulation and gene regulation, whereas the newly detected β4e variant serves exclusively in calcium-channel-dependent functions.