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Cardiac muscle: Sweet heartbeats

Functional Glycomics (10 September 2009) | doi:10.1038/fg.2009.29

Regulated and aberrant glycosylation control cardiac function.

Michelle Tribe

Cardiac muscle electrical signaling occurs through the propagation and transmission of action potentials — transient membrane depolarizations controlled by the concerted activities of voltage-gated ion channels and transporters. Ion channel activity is remodeled physiologically during development, and pathological changes make the heart more susceptible to arrhythmias. The glycosylations attached to different ion-channel isoforms, and the reduced glycosylation of certain disorders, are known to alter ion channel gating. Now, Eric Bennett and colleagues have demonstrated a direct role for glycans in cardiac function. They report in Proceedings of the National Academy of Sciences of the USA that the cardiac glycome is modulated by heart region and developmental stage, and that both regulated remodeling and aberrant glycosylation alter ion channel function and cardiac electrical signaling.

The expression of individual N-linked glycan structures depends on the differential expression of numerous glycogene products, separately responsible for the synthesis, transfer and removal of specific sugar residues. Using GeneChip microarray, the authors analyzed mRNA from adult and neonatal mouse cardiomyocytes, from both atria and ventricles. Of 239 glycogenes tested, 110 — covering each glycogene type — were significantly differentially expressed among the four types of cells. These differences translated into distinct N-glycan profiles for adults compared with neonates, and atria compared with ventricles. In particular, the levels of two types of terminal sialic acid residues were altered: adult cells had a much greater ratio of N-glyconylneuraminic acid (NeuGc) to N-acetylneuramininc acid (NeuAc) than neonatal cells.

Sialic acid polymers are added to glycans by the polysialyltransferase ST8sia2. The microarray data indicated that ST8sia2 expression is essentially absent in the adult cardiomyocytes, and is higher in the neonatal atria than the ventricles. To investigate the impact of ST8sia2 on ion channel function, the authors compared myocytes from control and ST8sia2(-/-) mice. The knockout of ST8sia2 significantly altered several parameters of the atrial action potential waveforms resulting in prolonged action potentials. This correlated with changes in voltage-gated sodium channel function, including a depolarizing shift in voltage-dependent steady state activation and inactivation. Such a shift will alter the voltage, relative to threshold, at which a persistent current of sodium ions will flow, and might in turn alter excitability. The rate of recovery from fast inactivation was also altered by ST8sia2 knockout. These sorts of changes to ion-channel function, when produced by point mutations, have previously been implicated in cardiac malfunction. ST8sia2 was just one out of over 100 developmentally regulated glycogenes in the heart, which suggests that remodeling of the cardiac glycome has huge potential to alter ion-channel function.

Inherent differences in glycosylation signatures between ion channel isoforms affect channel activity. Besides this subunit-specific mechanism, the data here indicate that channel activity is also controlled by changes in the ability of the cardiomyocyte to glycosylate the channel subunits that are expressed. This adds to our understanding of how disorders of glycosylation predispose individuals to suffer from arrhythmias, and suggests that regulated and aberrant glycosylation modulate the function of all excitable tissues.

Emma Leah

Original research paper:

  1. Montpetit, M. L., et al. Regulated and aberrant glycosylation modulate cardiac electrical signaling. Proc. Natl Acad. Sci. (Published online 7 August 2009) doi: 10.1073/pnas.0905414106 | Article |