Giant ankyrin-G regulates cardiac function

Omer Cavus,Jordan Williams,Hassan Musa,Mona El Refaey,Dan Gratz,Rebecca Shaheen,Neill A Schwieterman,Sara Koenig,Steve Antwi-Boasiako,Lindsay J Young,Xianyao Xu,Mei Han,Loren E Wold,Thomas J Hund,Peter J Mohler,Elisa A Bradley

doi:10.1016/j.jbc.2021.100507

Omer Cavus, Jordan Williams + Show 14 more

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https://doi.org/10.1016/j.jbc.2021.100507

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Abstract

Cardiovascular disease (CVD) remains the most common cause of adult morbidity and mortality in developed nations. As a result, predisposition for CVD is increasingly important to understand. Ankyrins are intracellular proteins required for the maintenance of membrane domains. Canonical ankyrin-G (AnkG) has been shown to be vital for normal cardiac function, specifically cardiac excitability, via targeting and regulation of the cardiac voltage-gated sodium channel. Noncanonical (giant) AnkG isoforms play a key role in neuronal membrane biogenesis and excitability, with evidence for human neurologic disease when aberrant. However, the role of giant AnkG in cardiovascular tissue has yet to be explored. Here, we identify giant AnkG in the myocardium and identify that it is enriched in 1-week-old mice. Using a new mouse model lacking giant AnkG expression in myocytes, we identify that young mice displayed a dilated cardiomyopathy phenotype with aberrant electrical conduction and enhanced arrhythmogenicity. Structural and electrical dysfunction occurred at 1 week of age, when giant AnkG was highly expressed and did not appreciably change in adulthood until advanced age. At a cellular level, loss of giant AnkG results in delayed and early afterdepolarizations. However, surprisingly, giant AnkG cKO myocytes display normal INa, but abnormal myocyte contractility, suggesting unique roles of the large isoform in the heart. Finally, transcript analysis provided evidence for unique pathways that may contribute to the structural and electrical findings shown in giant AnkG cKO animals. In summary, we identify a critical role for giant AnkG that adds to the diversity of ankyrin function in the heart.

Highlights

Excitable cell function in the human neurologic and cardiovascular systems relies on complex interactions between ion channels and structural proteins; ankyrins are one such membrane-associated protein
The function of canonical AnkG (220 kDa) in neurologic tissue is well described, where it is important for regulating membrane and intracellular protein complexes necessary for normal neurologic function [3, 4] In the heart, our group has shown that canonical AnkG is necessary for Nav channel (Nav1.5) targeting, and in concert with βIV spectrin and CaMKII, for Nav1.5 membrane regulation [5,6,7,8,9] More recently, we have shown that canonical AnkG has been linked to cardiac remodeling and established as a cause for the development and progression of human HF [9], highlighting that ankyrins may be critical for both structural and electrophysiologic function
At the axonal initial segment (AIS), giant AnkG operates as a membrane-associated adaptor protein that has been implicated in organizing voltagegated sodium channels (Nav), βIV spectrin, KCNQ2/3, and neurofascin [10, 11]

Summary

Introduction

Excitable cell function in the human neurologic and cardiovascular systems relies on complex interactions between ion channels and structural proteins; ankyrins are one such membrane-associated protein. The function of canonical AnkG (220 kDa) in neurologic tissue is well described, where it is important for regulating membrane and intracellular protein complexes necessary for normal neurologic function [3, 4] In the heart, our group has shown that canonical AnkG is necessary for Nav channel (Nav1.5) targeting, and in concert with βIV spectrin and CaMKII, for Nav1.5 membrane regulation [5,6,7,8,9] More recently, we have shown that canonical AnkG has been linked to cardiac remodeling and established as a cause for the development and progression of human HF [9], highlighting that ankyrins may be critical for both structural and electrophysiologic function Both ANK2 and ANK3 encode in canonical and “giant” isoforms. Our data support that a single ankyrin gene produces at least two separate products, canonical AnkG and giant AnkG, each with unique roles in cardiac structure and electrical function, the latter of which acts via a novel sodium-channel-independent mechanism in the developing myocardium

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