Most cited article - PubMed ID 31365467
A potential role for T-type calcium channels in homocysteinemia-induced peripheral neuropathy
Elevated plasma homocysteine (Hcy) levels lead to hyperhomocysteinemia, a condition associated with various neurological disorders affecting multiple brain regions, including the hippocampus. In this study, we investigated the effects of exposing cultured rat hippocampal neurons to Hcy concentrations corresponding to mild, moderate, and severe hyperhomocysteinemia. A short 24-hour exposure had minimal effects, whereas prolonged exposure up to 14 days moderately enhanced hippocampal excitability without altering the gene expression of voltage-dependent calcium, sodium, or potassium channels or intracellular calcium levels. These findings suggest that Hcy-induced changes in neuronal excitability may contribute to neuropathologies associated with hyperhomocysteinemia.
- Keywords
- Hippocampal excitability, Hyperhomocysteinemia, Intracellular calcium, Transcriptomics, Voltage gated ion channels,
- MeSH
- Hippocampus * cytology drug effects MeSH
- Homocysteine * pharmacology MeSH
- Ion Channels * genetics metabolism MeSH
- Rats MeSH
- Cells, Cultured MeSH
- Neurons * drug effects metabolism cytology MeSH
- Rats, Sprague-Dawley MeSH
- Gene Expression Regulation * drug effects MeSH
- Calcium metabolism MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Homocysteine * MeSH
- Ion Channels * MeSH
- Calcium MeSH
T-type calcium channels perform crucial physiological roles across a wide spectrum of tissues, spanning both neuronal and non-neuronal system. For instance, they serve as pivotal regulators of neuronal excitability, contribute to cardiac pacemaking, and mediate the secretion of hormones. These functions significantly hinge upon the intricate interplay of T-type channels with interacting proteins that modulate their expression and function at the plasma membrane. In this review, we offer a panoramic exploration of the current knowledge surrounding these T-type channel interactors, and spotlight certain aspects of their potential for drug-based therapeutic intervention.
- Keywords
- Calcium channels, Channelosome, Ion channels, T-type channels,
- MeSH
- Calcium Channel Blockers MeSH
- Neurons metabolism MeSH
- Calcium * metabolism MeSH
- Calcium Channels, T-Type * metabolism MeSH
- Publication type
- Journal Article MeSH
- Review MeSH
- Names of Substances
- Calcium Channel Blockers MeSH
- Calcium * MeSH
- Calcium Channels, T-Type * MeSH
Cav3.2 T-type calcium channels play an essential role in the transmission of peripheral nociception in the dorsal root ganglia (DRG) and alteration of Cav3.2 expression is associated with the development of peripheral painful diabetic neuropathy (PDN). Several studies have previously documented the role of glycosylation in the expression and functioning of Cav3.2 and suggested that altered glycosylation of the channel may contribute to the aberrant expression of the channel in diabetic conditions. In this study, we aimed to analyze the expression of glycan-processing genes in DRG neurons from a leptin-deficient genetic mouse model of diabetes (db/db). Transcriptomic analysis revealed that several glycan-processing genes encoding for glycosyltransferases and sialic acid-modifying enzymes were upregulated in diabetic conditions. Functional analysis of these enzymes on recombinant Cav3.2 revealed an unexpected loss-of-function of the channel. Collectively, our data indicate that diabetes is associated with an alteration of the glycosylation machinery in DRG neurons. However, individual action of these enzymes when tested on recombinant Cav3.2 cannot explain the observed upregulation of T-type channels under diabetic conditions.Abbreviations: Galnt16: Polypeptide N-acetylgalactosaminyltransferase 16; B3gnt8: UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 8; B4galt1: Beta-1,4-galactosyltransferase 1; St6gal1: Beta-galactoside alpha-2,6-sialyltransferase 1; Neu3: Sialidase-3.
- Keywords
- Cav3.2 channel, DRG neurons, Glycosylation, T-type channel, calcium channel, diabetes, transcriptome,
- MeSH
- Cell Line MeSH
- Electrophysiology methods MeSH
- Diabetes Mellitus, Experimental metabolism MeSH
- Glycosylation MeSH
- Humans MeSH
- Mice MeSH
- Polysaccharides metabolism MeSH
- Ganglia, Spinal metabolism MeSH
- Transcriptome genetics MeSH
- Calcium Channels, T-Type genetics metabolism MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Cacna1h protein, mouse MeSH Browser
- Polysaccharides MeSH
- Calcium Channels, T-Type MeSH
Low-voltage-activated T-type calcium channels are important contributors to nervous system function. Post-translational modification of these channels has emerged as an important mechanism to control channel activity. Previous studies have documented the importance of asparagine (N)-linked glycosylation and identified several asparagine residues within the canonical consensus sequence N-X-S/T that is essential for the expression and function of Cav3.2 channels. Here, we explored the functional role of non-canonical N-glycosylation motifs in the conformation N-X-C based on site directed mutagenesis. Using a combination of electrophysiological recordings and surface biotinylation assays, we show that asparagines N345 and N1780 located in the motifs NVC and NPC, respectively, are essential for the expression of the human Cav3.2 channel in the plasma membrane. Therefore, these newly identified asparagine residues within non-canonical motifs add to those previously reported in canonical sites and suggest that N-glycosylation of Cav3.2 may also occur at non-canonical motifs to control expression of the channel in the plasma membrane. It is also the first study to report the functional importance of non-canonical N-glycosylation motifs in an ion channel.
- Keywords
- Asparagine-linked glycosylation, Calcium channel, N-glycosylation, Non-canonical glycosylation, T-type channel, Trafficking, cav3.2 Channel,
- MeSH
- Amino Acid Motifs MeSH
- Asparagine metabolism MeSH
- Glycosylation MeSH
- Humans MeSH
- Calcium Channels, T-Type chemistry metabolism MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Asparagine MeSH
- CACNA1H protein, human MeSH Browser
- Calcium Channels, T-Type MeSH