Transcriptomic analysis of glycan-processing genes in the dorsal root ganglia of diabetic mice and functional characterization on Ca_v3.2 channels

Abstract

Ca v 3.2 T-type calcium channels play an essential role in the transmission of peripheral nociception in the dorsal root ganglia (DRG) and alteration of Ca v 3.2 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 Ca v 3.2 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 glycanprocessing genes encoding for glycosyltransferases and sialic acid-modifying enzymes were upregulated in diabetic conditions. Functional analysis of these enzymes on recombinant Ca v 3.2 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 Ca v 3.2 cannot explain the observed upregulation of T-type channels under diabetic conditions.

Polypeptide N-acetylgalactosaminyltransferase-Associated Phenotypes in Mammals

“…A recent GWAS reported an association with risk for cardiovascular disease [ 123 ]. In mice, Galnt16 expression was very low in the tissues tested, including brain, colon, heart, kidney, liver, lung, skeletal muscle, ovary, prostate, spleen, sublingual gland, testis, thymus and thyroid [18 (as GalNAc-Ta)], but upregulation through an unknown mechanism was observed in diabetic mice [ 124 ].…”

Functional identification of potential non-canonical N-glycosylation sites within Cav3.2 T-type calcium channels

“…Glycosylation of T-type channels has emerged as an important post-translational modification to control the expression and functioning of the channel in the plasma membrane, and it was suggested that alteration of the glycoproteome of Ca v 3.2 may contribute to the development of peripheral pain associated with diabetes [8,10]. While several studies have previously reported the importance of canonical glycosylation sites in the expression and function of Ca v 3.2 channels [7,8,11,12], the potential role for non-canonical motifs has never been explored.…”