Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Etemad, S; Obermair, GJ; Bindreither, D; Benedetti, A; Stanika, R; Di Biase, V; Burtscher, V; Koschak, A; Kofler, R; Geley, S; Wille, A; Lusser, A; Flockerzi, V; Flucher, BE.
Differential neuronal targeting of a new and two known calcium channel β4 subunit splice variants correlates with their regulation of gene expression.
J Neurosci. 2014; 34(4):1446-1461
Doi: 10.1523/JNEUROSCI.3935-13.2014
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- Co-Autor*innen der Med Uni Graz
- Di Biase Valentina
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Amino Acid Sequence -
- Animals -
- Blotting, Western -
- Calcium Channels - genetics
- Calcium Channels - metabolism
- Female -
- Gene Expression - genetics
- Hippocampus - metabolism
- Immunohistochemistry -
- Male -
- Mice -
- Mice, Inbred BALB C -
- Mice, Knockout -
- Molecular Sequence Data -
- Neurons - metabolism
- Oligonucleotide Array Sequence Analysis -
- Patch-Clamp Techniques -
- Protein Isoforms - genetics
- Protein Isoforms - metabolism
- Protein Subunits - genetics
- Protein Subunits - metabolism
- Reverse Transcriptase Polymerase Chain Reaction -
- Find related publications in this database (Keywords)
- Ca2+ channel
- Cacnb4
- Ca(V)2.1
- cerebellar granule cells
- hippocampal neurons
- lethargic mice