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Intracellular O-linked glycosylation directly regulates cardiomyocyte L-type Ca2+ channel activity and excitation–contraction coupling

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Abstract

Cardiomyocyte L-type Ca2+ channels (Cavs) are targets of signaling pathways that modulate channel activity in response to physiologic stimuli. Cav regulation is typically transient and beneficial but chronic stimulation can become pathologic; therefore, gaining a more complete understanding of Cav regulation is of critical importance. Intracellular O-linked glycosylation (O-GlcNAcylation), which is the result of two enzymes that dynamically add and remove single N-acetylglucosamines to and from intracellular serine/threonine residues (OGT and OGA respectively), has proven to be an increasingly important post-translational modification that contributes to the regulation of many physiologic processes. However, there is currently no known role for O-GlcNAcylation in the direct regulation of Cav activity nor is its contribution to cardiac electrical signaling and EC coupling well understood. Here we aimed to delineate the role of O-GlcNAcylation in regulating cardiomyocyte L-type Cav activity and its subsequent effect on EC coupling by utilizing a mouse strain possessing an inducible cardiomyocyte-specific OGT-null-transgene. Ablation of the OGT-gene in adult cardiomyocytes (OGTKO) reduced OGT expression and O-GlcNAcylation by > 90%. Voltage clamp recordings indicated an ~ 40% reduction in OGTKO Cav current (ICa), but with increased efficacy of adrenergic stimulation, and Cav steady-state gating and window current were significantly depolarized. Consistently, OGTKO cardiomyocyte intracellular Ca2+ release and contractility were diminished and demonstrated greater beat-to-beat variability. Additionally, we show that the Cav α1 and β2 subunits are O-GlcNAcylated while α2δ1 is not. Echocardiographic analyses indicated that the reductions in OGTKO cardiomyocyte Ca2+ handling and contractility were conserved at the whole-heart level as evidenced by significantly reduced left-ventricular contractility in the absence of hypertrophy. The data indicate, for the first time, that O-GlcNAc signaling is a critical and direct regulator of cardiomyocyte ICa achieved through altered Cav expression, gating, and response to adrenergic stimulation; these mechanisms have significant implications for understanding how EC coupling is regulated in health and disease.

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Funding

This work was supported in part by grants from the National Science Foundation [Division of Molecular and Cellular Biosciences-1856199 to A.R.E and E.S.B., Division of Integrative Organismal Systems-1660926 to E.S.B.]; an American Heart Association Postdoctoral Fellowship (15POST25710010 to A.R.E]; and an American Heart Association Greater Southeast Affiliate Grant-In-Aid [14GRNT20450148 to E.S.B.].

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  1. Department of Neuroscience, Cell Biology and Physiology, Boonshoft School of Medicine and College of Science and Mathematics, Wright State University, 143 Biological Sciences II, 3640 Colonel Glenn Hwy, Dayton, OH, 45435, USA

    Andrew R. Ednie & Eric S. Bennett

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Table 1: Cav activity parameters. Table 2: Echocardiographic Parameters.

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Ednie, A.R., Bennett, E.S. Intracellular O-linked glycosylation directly regulates cardiomyocyte L-type Ca2+ channel activity and excitation–contraction coupling. Basic Res Cardiol 115, 59 (2020). https://doi.org/10.1007/s00395-020-00820-0

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