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Curr Opin Cardiol. 2005 May;20(3):189-93.

Ankyrin-based cardiac arrhythmias: a new class of channelopathies due to loss of cellular targeting.

Author information

  • 1Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232, USA. peter.j.mohler@vanderbilt.edu

Abstract

PURPOSE OF REVIEW:

This review addresses a new mechanism for arrhythmia due to abnormal cellular localization of membrane ion channels and transporters. The focus is on ankyrins, a family of proteins that localize diverse membrane ion channels and transporters, and recent evidence that mutations affecting functions of ankyrins result in cardiac arrhythmia.

RECENT FINDINGS:

A loss-of-function mutation of ankyrin-B in humans and a null mutation in mice result in a dominantly-inherited fatal cardiac arrhythmia initially classified as type 4 long QT syndrome. Characterization of additional probands suggests ankyrin-B mutations cause a new cardiac arrhythmia syndrome associated with sinus node dysfunction that is distinct from long QT syndrome. Ankyrin-B mutation results in elevated calcium transients in cardiomyocytes accompanied by loss of cellular targeting of Na/K ATPase, Na/Ca exchanger, and InsP3 receptor (all ankyrin-binding proteins) to cardiomyocyte membrane domains. The principal voltage-gated Na channel in heart, Nav1.5, is directly associated with ankyrin-G, which is encoded by a distinct gene from ankyrin-B. Mutation of Nav1.5 causing loss of binding to ankyrin-G results in Brugada syndrome and loss of targeting of Nav1.5 to the cell surface of cardiomyocytes.

SUMMARY:

Ankyrin-B and ankyrin-G are recently recognized constituents of the heart that target diverse ion channels/pumps/transporters to physiologic sites of action in cardiomyocytes. Mutations of ankyrin-B cause a newly defined cardiac arrhythmia syndrome associated with abnormal calcium homeostasis in a mouse model. Ankyrin-G associates with the principal voltage-gated Na channel in the heart, and loss of this interaction due to mutation of Nav1.5 results in Brugada syndrome.

PMID:
15861006
[PubMed - indexed for MEDLINE]
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