Regulated and aberrant glycosylation modulate cardiac electrical signaling

Abstract

Millions afflicted with Chagas disease and other disorders of aberrant glycosylation suffer symptoms consistent with altered electrical signaling such as arrhythmias, decreased neuronal conduction velocity, and hyporeflexia. Cardiac, neuronal, and muscle electrical signaling is controlled and modulated by changes in voltage-gated ion channel activity that occur through physiological and pathological processes such as development, epilepsy, and cardiomyopathy. Glycans attached to ion channels alter channel activity through isoform-specific mechanisms. Here we show that regulated and aberrant glycosylation modulate cardiac ion channel activity and electrical signaling through a cell-specific mechanism. Data show that nearly half of 239 glycosylation-associated genes (glycogenes) were significantly differentially expressed among neonatal and adult atrial and ventricular myocytes. The N-glycan structures produced among cardiomyocyte types were markedly variable. Thus, the cardiac glycome, defined as the complete set of glycan structures produced in the heart, is remodeled. One glycogene, ST8sia2, a polysialyltransferase, is expressed only in the neonatal atrium. Cardiomyocyte electrical signaling was compared in control and ST8sia2 (؊/؊) neonatal atrial and ventricular myocytes. Action potential waveforms and gating of less sialylated voltage-gated Na ؉ channels were altered consistently in ST8sia2 (؊/؊) atrial myocytes. ST8sia2 expression had no effect on ventricular myocyte excitability. Thus, the regulated (between atrium and ventricle) and aberrant (knockout in the neonatal atrium) expression of a single glycogene was sufficient to modulate cardiomyocyte excitability. A mechanism is described by which cardiac function is controlled and modulated through physiological and pathological processes that involve regulated and aberrant glycosylation. action potentials ͉ cardiomyocyte ͉ glycomics ͉ ion channels ͉ sialic acids

Quantitative N-linked Glycoproteomics of Myocardial Ischemia and Reperfusion Injury Reveals Early Remodeling in the Extracellular Environment

“…Glycopeptides from voltage-gated and other ion transporters were up-regulated following 40I/20R. Changes in ion channel glycosylation have been associated with altered electrical signaling (23) and changes in sialic acids of voltage-gated sodium channel (Na v ) have been linked with cardiac conduction disorders and heart failure (22,24). A number of ␣ and ␤ subunits are expressed: Na v1.1 , 1.3 , 1.4 , 1.5 and Na v1.6 ; however, Na v1.5 is the major subunit in the sarcolemma and is primarily responsible for the action potential in ventricular systole (65).…”

“…Modulation of ion channel glycosylation is implicated in altering electrical signaling in the heart (23) and has been linked with cardiac conduction disorders and heart failure (22,24). There is also growing evidence that extracellular glycosidase activity modifies surface glycans and alters protein function.…”

Sialic Acids Attached to O-Glycans Modulate Voltage-gated Potassium Channel Gating

“…Glycosidase gel shift data were analyzed using the Quantity One one-dimensional gel analysis software (Bio-Rad), as described previously (32). (26).…”

“…To question whether K v 2.1, K v 4.2, and K v 4.3 are O-glycosylated and sialylated, we employed previously used methods of glycosidase gel shift analysis (10,14,32,33). Fig.…”

The Role of Drosophila Cytidine Monophosphate-Sialic Acid Synthetase in the Nervous System

“…Vertebrate voltage-gated Na ϩ channels, the major determinants of neural excitability, are heavily sialylated, which affects their gating properties in vitro (Recio-Pinto et al, 1990;Bennett, 2002). The role of sialylation in the regulation of these channels has been mostly attributed to a large negative charge due to the channels' prominent polysialylation (Zuber et al, 1992;Montpetit et al, 2009). However, polysialylation and sialylation appear to have different effects on voltage-gated Na ϩ channels, and the regulation of these channels was shown to be affected by some "functional" Sia residues rather than their total charge (Stocker and Bennett, 2006;Ahrens et al, 2011).…”