title: 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.
authors: Department of Molecular Pharmacology & Physiology, Programs in Cardiovascular Sciences and Neuroscience, University of South Florida College of Medicine, Tampa, FL 33612, USA.
authors: Marty L
authors: ML
authors: Montpetit
authors: Patrick J
authors: PJ
authors: Stocker
authors: Tara A
authors: TA
authors: Schwetz
authors: Jean M
authors: JM
authors: Harper
authors: Sarah A
authors: SA
authors: Norring
authors: Lana
authors: L
authors: Schaffer
authors: Simon J
authors: SJ
authors: North
authors: Jihye
authors: J
authors: Jang-Lee
authors: Timothy
authors: T
authors: Gilmartin
authors: Steven R
authors: SR
authors: Head
authors: Stuart M
authors: SM
authors: Haslam
authors: Anne
authors: A
authors: Dell
authors: Jamey D
authors: JD
authors: Marth
authors: Eric S
authors: ES
authors: Bennett
mesh_terms: D000200:Action Potentials; D000818:Animals; D000831:Animals, Newborn; D016000:Cluster Analysis; D004594:Electrophysiology; D020869:Gene Expression Profiling; D018507:Gene Expression Regulation, Developmental; D006023:Glycoproteins / Q000235:genetics* / Q000378:metabolism; D006031:Glycosylation; D006321:Heart / Q000254:growth & development / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism* / Q000502:physiology; D020411:Oligonucleotide Array Sequence Analysis; D040901:Proteomics / Q000379:methods; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012799:Sialyltransferases / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D015398:Signal Transduction; D015222:Sodium Channels / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D006023:Glycoproteins; D015222:Sodium Channels; C526452:ST8SiaII protein, mouse; D012799:Sialyltransferases