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Regulated and Aberrant Glycosylation Modulate Cardiac Electrical Signaling

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Regulated and Aberrant Glycosylation Modulate Cardiac Electrical Signaling Regulated and aberrant glycosylation modulate cardiac electrical signaling Marty L. Montpetita, Patrick J. Stockera, Tara A. Schwetza, Jean M. Harpera, Sarah A. Norringa, Lana Schafferb, Simon J. Northc, Jihye Jang-Leec, Timothy Gilmartinb, Steven R. Headb, Stuart M. Haslamc, Anne Dellc, Jamey D. Marthd, and Eric S. Bennetta,1 aDepartment of Molecular Pharmacology & Physiology, Programs in Cardiovascular Sciences and Neuroscience, University of South Florida College of Medicine, Tampa, FL 33612; bDNA Microarray Core, The Scripps Research Institute, La Jolla, CA 92037; and cDivision of Molecular Biosciences, Imperial College London, London SW7 2AZ, United Kingdom; and dDepartment of Cellular and Molecular Medicine, The Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA 92093 Edited by Richard W, Aldrich, University of Texas, Austin, TX, and approved July 2, 2009 (received for review May 18, 2009) Millions afflicted with Chagas disease and other disorders of aberrant phied and more susceptible to arrhythmias (3). Electrical remod- glycosylation suffer symptoms consistent with altered electrical sig- eling occurs during development and aging, among species, and naling such as arrhythmias, decreased neuronal conduction velocity, throughout the heart (4, 5). In nearly all cardiac pathologies and hyporeflexia. Cardiac, neuronal, and muscle electrical signaling is including hypertrophy, heart failure, and long QT syndrome controlled and modulated by changes in voltage-gated ion channel (LQTS), at least one type of remodeling occurs (3, 6). activity that occur through physiological and pathological processes Voltage-gated ion channels are heavily glycosylated, with such as development, epilepsy, and cardiomyopathy. Glycans at- glycan structures comprising upwards of 30% of the mature channel mass (7, 8). Previous reports indicated that the sugars tached to ion channels alter channel activity through isoform-specific ϩ mechanisms. Here we show that regulated and aberrant glycosyla- attached to cardiac voltage-gated Na channels (Nav) and Kv tion modulate cardiac ion channel activity and electrical signaling may impact channel gating (9, 10). Glycosylation of Nav and Kv through a cell-specific mechanism. Data show that nearly half of 239 subunits were shown to alter channel gating in isoform- and subunit-dependent manners (11–14). Most studies established glycosylation-associated genes (glycogenes) were significantly differ- that the sugar-dependent gating effects were imposed by the entially expressed among neonatal and adult atrial and ventricular terminal residue attached to carbohydrate structures, sialic myocytes. The N-glycan structures produced among cardiomyocyte acid. A recent work showed that variable sialic acid levels types were markedly variable. Thus, the cardiac glycome, defined as attached to a single Nav isoform, Nav1.5, were responsible for the complete set of glycan structures produced in the heart, is differences in channel gating observed among neonatal and remodeled. One glycogene, ST8sia2, a polysialyltransferase, is ex- adult atrial and ventricular cardiomyocytes (15). pressed only in the neonatal atrium. Cardiomyocyte electrical signal- There are at least two major types of disorders of aberrant ؊ ؊ ing was compared in control and ST8sia2( / ) neonatal atrial and glycosylation that result in decreased glycoprotein sialylation and ventricular myocytes. Action potential waveforms and gating of less afflict nearly 20 million people: Congenital disorders of glycosyl- sialylated voltage-gated Na؉ channels were altered consistently in ation (CDGs; Ϸ30 known diseases) and Chagas disease, caused by ST8sia2(؊/؊) atrial myocytes. ST8sia2 expression had no effect on parasitic infection. The primary target organ for Chagas disease and ventricular myocyte excitability. Thus, the regulated (between atrium for some CDGs is the heart, leading to an increased susceptibility and ventricle) and aberrant (knockout in the neonatal atrium) expres- to conduction anomalies, cardiac arrhythmias, and heart failure sion of a single glycogene was sufficient to modulate cardiomyocyte (16–19). Thus, these diseases lead to aberrant cardiac glycosylation excitability. A mechanism is described by which cardiac function is and to symptomatic changes in cardiac excitability. controlled and modulated through physiological and pathological Previous studies established that N-glycosylation, typically sialic processes that involve regulated and aberrant glycosylation. acids, modulate voltage-gated ion channel gating through isoform- PHYSIOLOGY specific mechanisms. Individuals afflicted with certain disorders of action potentials ͉ cardiomyocyte ͉ glycomics ͉ ion channels ͉ sialic acids reduced glycosylation present with arrhythmias consistent with changes in cardiac ion channel function. However, little is known about a direct role for glycans in cardiac function. Here we show he glycome, defined as the complete set of glycan structures that electrical communication in the heart is modulated by regu- Tproduced by the body, is comprised of hundreds of thousands lated and aberrant glycosylation. Specifically, the cardiac glycome of unique structures (1). Such structural diversity is the result of the is different in the atria than in the ventricles and the glycome is activity of nearly 250 known glycosylation-associated genes such as remodeled differentially during development of each cardiac cham- glycosyltransferases, glycosidases, and nucleotide sugar synthesis ber. Further, regulated and aberrant glycosylation modulate cardi- and transporter genes (glycogenes) that are responsible collectively omyocyte excitability and Nav channel function consistently. for producing the glycans attached to lipids and proteins (2). Functional roles for glycans in cellular communication include cell Results adhesion, self-recognition, protein trafficking and clearance, and Cardiac Glycogene Expression Is Highly Regulated. To test the poten- receptor activation (2). tial role for regulated glycosylation in cardiac excitability, our Electrical signaling occurs in all cells of the body and is of primary importance to excitable cell function. Neurons, skeletal muscle, and cardiac muscle communicate through production and conduction Author contributions: M.L.M., P.J.S., T.A.S., J.M.H., S.J.N., S.R.H., S.M.H., and E.S.B. designed research; M.L.M., P.J.S., T.A.S., J.M.H., S.A.N., S.J.N., J.J.-L., T.G., S.R.H., S.M.H., and E.S.B. of orchestrated electrical signals called action potentials (AP). performed research; S.J.N., S.R.H., S.M.H., A.D., and J.D.M. contributed new reagents/ Neuronal and muscle APs are transient membrane depolarizations analytic tools; M.L.M., L.S., S.J.N., J.J.-L., T.G., S.R.H., S.M.H., and E.S.B. analyzed data; and produced by the concerted activities of many types of voltage-gated M.L.M. and E.S.B. wrote the paper. ion channels and transport proteins. Slight alterations in ion chan- The authors declare no conflict of interest. nel activity can lead to altered excitability observed as a change in This article is a PNAS Direct Submission. AP waveform and/or conduction. For example, the types and 1To whom correspondence should be addressed. E-mail: [email protected]. ϩ relative densities of the set of voltage-gated K channel (Kv) This article contains supporting information online at www.pnas.org/cgi/content/full/ isoforms expressed change as the healthy heart becomes hypertro- 0905414106/DCSupplemental. www.pnas.org͞cgi͞doi͞10.1073͞pnas.0905414106 PNAS ͉ September 22, 2009 ͉ vol. 106 ͉ no. 38 ͉ 16517–16522 Downloaded by guest on September 30, 2021 A tetra-antennary structures, which are mono-, di-, tri-, and tetra- All glycogenes (110 of 239) sialylated with a mixture of two forms of sialic acids, N- acetylneuraminic acid (NeuAc) and N-glycolylneuraminic acid (NeuGc). Nucleotide sugar (15 of 35) The data indicate N-glycan structures are regulated throughout cardiomyocyte development, exemplified by the change in the relative levels of NeuAc and NeuGc attached to atrial and ventric- Glycosidases (16 of 39) ular myocyte N-glycans. Recent studies demonstrated that MALDI-MS analyses of permethylated glycans provide reliable relative quantitative information based on signal intensities, par- Glycosyltransferases (79 of 165) ticularly when comparisons are made over a small mass range in the same spectrum (20). In making such comparisons, the adult N- 0 1020304050 glycan profiles exhibited a significant increase in the ratio of NeuGc % Genes Differentially Expressed to NeuAc relative to the neonatal samples (Fig. 2, inset), indicating a change in glycan structures, particularly sialic acids, during B VN:AN VA:AA cardiomyocyte development. Overall Overall Regulated and Aberrant Sialylation Impact Cardiomyocyte Excitabil- Nucleotide Sugar Nucleotide Sugar Chamber ity. To determine whether the remodeled glycome modulates Comparison Glycosidases Glycosidases cardiac function, we observed the impact of the regulated and aberrant expression of a single glycogene on cardiomyocyte Glycosyltransferases Glycosyltransferases electrical activity. We studied the effect of the polysialyltrans- 0 5 10 15 20 25 0 1020304050 ferase, ST8sia2 (responsible for addition of sialic acid poly- % Genes Differentially Expressed % Genes Differentially Expressed mers to N- and O-glycans), on cardiac function for several AA:AN VA:VN reasons that include: (i) Cardiac dysfunctions including ar- Overall Overall rhythmias and cardiomyopathy that are
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