Publication Date
2019
Document Type
Thesis
Committee Members
Eric Bennett (Advisor), Mark Rich (Committee Member), Kathrin Engisch (Committee Member), Nick Ritucci (Other)
Degree Name
Master of Science (MS)
Abstract
Dilated cardiomyopathy (DCM) is one the most common forms of heart failure, with the majority of cases being idiopathic. Dr. Bennett’s laboratory previously showed that deletion of the Mgat1 gene in cardiomyocytes only (Mgat1KO) is sufficient to cause DCM leading to heart failure and early death. The Mgat1 gene product, GlcNAcT1, is responsible for initiating the formation of hybrid/complex N-glycosylation. These data suggest a link between abnormal glycosylation and heart disease; however, there is a mystery of how the specific changes in glycosylation contribute to heart disease etiology and progression. The proper function and gating of voltage-gated Na+ channels (Nav) and voltage-gated K+ channels (Kv) are vital to the initiation, shape, and conduction of the cardiomyocyte action potential (AP); thus, abnormal channel activity contributes to arrhythmias and other heart diseases. Other labs as well as our own, have shown that modest reductions in channel glycosylation can alter gating of Nav and Kv through electrostatic mechanisms with no change in channel expression levels. Thus, here and in a recent publication by Ednie, Parrish, Sonner, and Bennett entitled, “Reduced Hybrid/Complex N-glycosylation Disrupts Cardiac Electrical Signaling and Calcium Handling in a Model of Dilated Cardiomyopathy“, we showed that cardiomyocyte-specific deletion of Mgat1 that leads to reduced hybrid/complex protein N-glycosylation modulates Nav and Kv activity through direct and indirect mechanisms. Here, we show that Mgat1KO Nav expression was not different between Mgat1KO and control ventricular myocytes; however, there was a reduction in Mgat1KO Nav molecular weight, suggesting that Nav are direct targets of GlcNAcT1 similar to Cav 21. We found that Kv4.2 and Kv1.5 expression levels are significantly lower in the older Mgat1KO ventricular myocyte compared to controls, consistent with an indirect, but disease-related decrease in Kv expression and, as a result, K+ current. Thus, utilization of the Mgat1KO DCM model will allow one to continue uncovering mechanistic glycosylation-dependent links between aberrant electrical signaling and heart disease onset and progression.
Page Count
39
Department or Program
Department of Neuroscience, Cell Biology and Physiology
Year Degree Awarded
2019
Copyright
Copyright 2019, some rights reserved. My ETD may be copied and distributed only for non-commercial purposes and may not be modified. All use must give me credit as the original author.
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 3.0 License.
