Differential neuronal targeting of a new and 2 known calcium channel M-NM-24 subunit splice variants correlates with their regulation of gene expression

ABSTRACT: The M-NM-2 subunits of voltage-gated calcium channels regulate surface expression and gating of CaV1 and CaV2 M-NM-11 subunits, and thus contribute to neuronal excitability, neurotransmitter release and calcium-induced gene regulation. In addition certain M-NM-2 subunits are targeted into the nucleus, where they directly interact with the epigenetic machinery. Whereas their involvement in this multitude of functions is reflected by a great molecular heterogeneity of M-NM-2 isoforms derived from four genes and abundant alternative splicing, little is known about the roles of individual M-NM-2 variants in specific neuronal functions. In the present study, an alternatively spliced M-NM-24 subunit lacking the variable N-terminus (M-NM-24e) is identified. It is highly expressed in mouse cerebellum and cultured cerebellar granule cells (CGC) and modulates P/Q-type calcium currents in tsA cells and CaV2.1 surface expression in neurons. Compared to the other two known full-length M-NM-24 variants (M-NM-24a, M-NM-24b) M-NM-24e is most abundantly expressed in the distal axon, but lacks nuclear targeting properties. To examine the importance of nuclear targeting of M-NM-24 subunits for transcriptional regulation, we performed whole genome expression profiling of CGCs from lethargic mice individually reconstituted with M-NM-24a, M-NM-24b, and M-NM-24e. Notably, the number of genes regulated by each M-NM-24 splice variant correlated with the rank order of their nuclear targeting properties (M-NM-24b> M-NM-24a> M-NM-24e). Together these findings support isoform-specific functions of M-NM-24 splice variant in neurons, with M-NM-24b playing a dual role in channel modulation and gene regulation, while the newly detected M-NM-24e variant serves exclusively in calcium channel-dependent functions. We used microarrays to identify gene expression changes caused by M-NM-24 splice variants (M-NM-24a, M-NM-24b and M-NM-24e) of the voltage gated calcium channel in cultured cerebellar granule cells of lethargic mice Cultured cerebellar granule cells from lethargic (129/SvJ background) mice reconstituted with the M-NM-24 splice variants (M-NM-24a, M-NM-24b and M-NM-24e) were compared to eGFP transfected controls

ORGANISM(S): Mus musculus

SUBMITTER: Daniel Bindreither 

PROVIDER: E-GEOD-50822 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress