An update on transcriptional and post-translational regulation of brain voltage-gated sodium channels

Abstract

Voltage-gated sodium channels are essential proteins in brain physiology, as they generate the sodium currents that initiate neuronal action potentials. Voltage-gated sodium channels expression, localisation and function are regulated by a range of transcriptional and post-translational mechanisms. Here, we review our understanding of regulation of brain voltage-gated sodium channels, in particular SCN1A (NaV1.1), SCN2A (NaV1.2), SCN3A (NaV1.3) and SCN8A (NaV1.6), by transcription factors, by alternative splicing, and by post-translational modifications. Our focus is strongly centred on recent research lines, and newly generated knowledge.

A Novel Ultrasensitive In Situ Hybridization Approach to Detect Short Sequences and Splice Variants with Cellular Resolution

“…In the central nervous system (CNS), alternative splicing is tightly regulated in a spatio-temporal manner, as well as by neuronal activity [ 2 – 4 ]. Different mRNA isoforms encode for ion channels, neurotransmitter receptors, adhesion molecules, and signaling proteins with distinct functional properties [ 5 – 8 ]. Splicing abnormalities are observed in different cancers and neurological diseases [ 9 , 10 ], but are particularly abundant in psychiatric disorders, such as affective and addictive disorders, schizophrenia (Scz) and autism spectrum disorders [ 11 ].…”

Do sodium channel proteolytic fragments regulate sodium channel expression?

“…7 While these and other studies have provided invaluable insight into voltage-gating mechanisms and pore structure, the role and organization of cytosolic domains is less clear. The linker between domains DI and DII (L DI-DII ) of Na V 1.5 contains 295 residues and has been of particular interest to us and other groups due to the fact that L DI-DII undergoes post-translational modifications including phosphorylation and arginine methylation (for a recent review see 8 ). Biochemical, genetic and electrophysiological studies suggest that L DI-DII participates in the regulation of channel inactivation.…”

Sex-Specific Transcriptome Differences in Substantia Nigra Tissue: A Meta-Analysis of Parkinson’s Disease Data

“…Among them, we can highlight several genes which encode for proteins with specific neuronal function, found to be upregulated in males. i.e., the MSRA gene in SN control samples (TRAM CTR, Table 2 ), whose product has a key role in oxidative stress response and a high expression in the brain, including the SN, with a higher immuno-reactivity in neurons than in glial cells [ 56 , 57 ]; the SCN3A and SCN2A genes, that encode for glycoprotein members of a family of voltage-gated sodium channels involved in the generation and propagation of action potentials in neurons and muscle cells [ 58 , 59 ]; the CSRNP3 gene, encoding for a transcriptional activator, whose mouse ortholog Mbu-1 shows a high expression in the central nervous system, in particular in the brain and spinal cord in the course of embryonic development but also in adults [ 60 ]; the NSUN2 gene, whose product is a methyltransferase involved in the stabilization of the anticodon-codon pairing and the correct translation of the mRNA, and whose loss-of-function is associated with increased cellular stress and neurodevelopmental disorders [ 61 ].…”