Abstract
Abstract 16296: The Acetylatable Lysine Residue of the Cardiac Sodium Channel Regulates Membrane Localization Through Interactions With the Cytoskeletal Anchoring Protein [alpha]-Actinin 2
Circulation (New York, N.Y.), Vol.138(S_1 Suppl 1), p.A16296
11/06/2018
Abstract
Byline: Daniel S Matasic, Dept of Internal Medicine, The Univ of Iowa, Iowa City, IA; Kaikobad Irani, Dept of Internal Medicine, The Univ of Iowa, Iowa City, IA; Charles Brenner, Dept of Biochemistry, The Univ of Iowa, Iowa City, IA; Barry London, Dept of Internal Medicine, The Univ of Iowa, Iowa City, IA Introduction: The main cardiac sodium channel (Nav1.5) is responsible for the inward depolarizing sodium current that initiates and propagates the action potential throughout the heart. Recent studies by our group have shown that acetylation of Nav1.5 at a specific lysine residue (K1479) within the III-IV intracellular linker downregulates channel membrane expression. Although most notably known for its role in regulating Nav1.5 inactivation, the III-IV linker has previously been shown to upregulate channel localization to the membrane through an interaction with the cytoskeleton anchoring protein [alpha]-actinin 2. It is unknown whether acetylation of K1479 alters the effect of [alpha]-actinin 2 on Nav1.5.Objective: To evaluate the role of Nav1.5 K1479 in regulating channel localization through [alpha]-actinin 2.Methods: Site-directed mutagenesis was used to engineer lysine-to-glutamine (K1479Q) and lysine-to-alanine (K1479A) substitutions to imitate the acetylated channel and a channel that is not acetylatable, respectively. The native and mutant channels were transiently co-transfected into HEK293 cells with or without [alpha]-actinin 2 and subjected to whole-cell patch-clamp electrophysiology and co-immunoprecipitation to assess functional channel expression and interaction affinity.Results: Overexpression of [alpha]-actinin 2 increased peak sodium current (INa) in the native Nav1.5 K1479 channel but had no effect on the acetylated-mimic K1479Q and non-acetylatable K1479A channels (Figure 1). Furthermore, co-immunoprecipitation studies illustrated that [alpha]-actinin 2 bound to the wildtype Nav1.5 channel but not with the mutant Nav1.5 channels.Conclusions: The K1479 residue of Nav1.5 is critical in mediating the effect of [alpha]-actinin 2 in upregulating channel surface expression. Acetylation of K1479 may destabilize the channel at the membrane by disrupting its interaction with the cytoskeleton network via [alpha]-actinin 2.
Details
- Title: Subtitle
- Abstract 16296: The Acetylatable Lysine Residue of the Cardiac Sodium Channel Regulates Membrane Localization Through Interactions With the Cytoskeletal Anchoring Protein [alpha]-Actinin 2
- Creators
- Daniel S MatasicKaikobad IraniCharles BrennerBarry London
- Resource Type
- Abstract
- Publication Details
- Circulation (New York, N.Y.), Vol.138(S_1 Suppl 1), p.A16296
- Publisher
- Lippincott Williams & Wilkins, WK Health
- ISSN
- 0009-7322
- eISSN
- 1524-4539
- Language
- English
- Date published
- 11/06/2018
- Description audience
- Professional
- Academic Unit
- Molecular Physiology and Biophysics; Cardiovascular Medicine; Fraternal Order of Eagles Diabetes Research Center; Internal Medicine; Radiation Oncology
- Record Identifier
- 9984302192602771
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