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Abstract
We report identification of an ankyrin-B-based macromolecular complex of Na/K ATPase (alpha 1 and alpha 2 isoforms), Na/Ca exchanger 1, and InsP3 receptor that is localized in cardiomyocyte T-tubules in discrete microdomains distinct from classic dihydropyridine receptor/ryanodine receptor “dyads.” E1425G mutation of ankyrin-B, which causes human cardiac arrhythmia, also blocks binding of ankyrin-B to all three components of the complex. The ankyrin-B complex is markedly reduced in adult ankyrin-B+/− cardiomyocytes, which may explain elevated [Ca2+]i transients in these cells. Thus, loss of the ankyrin-B complex provides a molecular basis for cardiac arrhythmia in humans and mice. T-tubule-associated ankyrin-B, Na/Ca exchanger, and Na/K ATPase are not present in skeletal muscle, where ankyrin-B is expressed at 10-fold lower levels than in heart. Ankyrin-B also is not abundantly expressed in smooth muscle. We propose that the ankyrin-B-based complex is a specialized adaptation of cardiomyocytes with a role for cytosolic Ca2+ modulation.
Highlights
Defects in Ca2þ homeostasis underlie major diseases of the heart including congestive heart failure, cardiac hypertrophy, and fatal cardiac arrhythmias [1,2]
Residual inositol 1 (InsP3R), Na/K ATPase (NKA), and Na/Ca exchanger 1 (NCX1) rarely co-localize with ankyrin-B
This study presents the discovery of an ankyrin-B-based macromolecular complex of NKA, NCX1, and InsP3R in cardiomyocytes
Summary
Defects in Ca2þ homeostasis underlie major diseases of the heart including congestive heart failure, cardiac hypertrophy, and fatal cardiac arrhythmias [1,2]. Ca2þ ions enter cardiomyocytes through voltage-sensitive Ca2þ channels (dihydropyridine receptor [DHPR]) located in invaginations of the plasma membrane known as transverse tubules (T-tubules). DHPR is localized in a microdomain of the T-tubule that is synapsed with sites in the sarcoplasmic reticulum (SR) that are enriched in Ca2þ-release channels (ryanodine receptor [RyR]; [3,4]). Ca2þ that enters through DHPR must be balanced in each contraction cycle (;100 ms in mouse) by Ca2þ export. The requirement for rapid export of Ca2þ is a specialized feature of heart that is not present in skeletal muscle, where DHPR directly activates RyR without Ca2þ import
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