In:
The Journal of Neuroscience, Society for Neuroscience, Vol. 34, No. 4 ( 2014-01-22), p. 1446-1461
Abstract:
The β subunits of voltage-gated calcium channels regulate surface expression and gating of Ca V 1 and Ca V 2 α 1 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 β 4 subunit lacking the variable N terminus (β 4e ) 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 Ca V 2.1 surface expression in neurons. Compared with the other two known full-length β 4 variants (β 4a and β 4b ), β 4e is most abundantly expressed in the distal axon, but lacks nuclear-targeting properties. To determine the importance of nuclear targeting of β 4 subunits for transcriptional regulation, we performed whole-genome expression profiling of CGCs from lethargic (β 4 -null) mice individually reconstituted with β 4a , β 4b , and β 4e . Notably, the number of genes regulated by each β 4 splice variant correlated with the rank order of their nuclear-targeting properties (β 4b 〉 β 4a 〉 β 4e ). Together, these findings support isoform-specific functions of β 4 splice variants in neurons, with β 4b playing a dual role in channel modulation and gene regulation, whereas the newly detected β 4e variant serves exclusively in calcium-channel-dependent functions.
Type of Medium:
Online Resource
ISSN:
0270-6474
,
1529-2401
DOI:
10.1523/JNEUROSCI.3935-13.2014
Language:
English
Publisher:
Society for Neuroscience
Publication Date:
2014
detail.hit.zdb_id:
1475274-8
SSG:
12
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