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Differential neuronal targeting of a new and two known calcium channel β4 subunit splice variants correlates with their regulation of gene expression.
- Source :
-
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2014 Jan 22; Vol. 34 (4), pp. 1446-61. - Publication Year :
- 2014
-
Abstract
- 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.
- Subjects :
- Amino Acid Sequence
Animals
Blotting, Western
Calcium Channels metabolism
Female
Hippocampus metabolism
Immunohistochemistry
Male
Mice
Mice, Inbred BALB C
Mice, Knockout
Molecular Sequence Data
Oligonucleotide Array Sequence Analysis
Patch-Clamp Techniques
Protein Isoforms genetics
Protein Isoforms metabolism
Protein Subunits genetics
Protein Subunits metabolism
Reverse Transcriptase Polymerase Chain Reaction
Calcium Channels genetics
Gene Expression genetics
Neurons metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1529-2401
- Volume :
- 34
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 24453333
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.3935-13.2014