Endocytic control of ion channel density as a target for cardiovascular disease.

Full Abstract

Ion channels encoded by the human ether-a-go-go-related gene (HERG) give rise to the rapidly activating delayed rectifier K+ current (IKr), the perturbation of which causes ventricular arrhythmias associated with inherited and acquired long QT syndrome. Electrolyte imbalances, such as reduced serum K+ levels (hypokalemia), also trigger these potentially fatal arrhythmias. In this issue of the JCI, Guo et al. report that physiological levels of serum K+ are required to maintain normal HERG surface density in HEK 293 cells and IKr in rabbit cardiomyocytes. They found that hypokalemia evoked HERG channel ubiquitination, enhanced internalization via endocytosis, and ultimately degradation at the lysosome, thus identifying unbridled turnover as a mechanism of hypokalemia-induced arrhythmia. But too little channel turnover can also cause disease, as suggested by Kruse et al. in a study also in this issue. The authors identified mutations in TRPM4--a nonselective cation channel--in a large family with progressive familial heart block type I and showed that these mutations prevented channel internalization (see the related articles beginning on pages 2745 and 2737, respectively).

Author information

Author/s: Robertson, Gail A (GA);

Affiliation: Department of Physiology, University of Wisconsin-Madison, Madison, Wisconsin 53711, USA. robertson(-atsign-)physiology.wisc.edu

Grants: HL081780 (Agency:NHLBI NIH HHS)

Journal and publication information

Publication Type: Comment; Journal Article; Research Support, N.I.H., Extramural

Journal: The Journal of clinical investigation (J Clin Invest), published in United States. (Language: eng)

Reference: 2009-Sep; vol 119 (issue 9) : pp 2531-4

Dates: Created 2009/09/04; Completed 2009/10/02;

PMID: 19726880, status: MEDLINE (last retrieval date: 10/2/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

Comments and Corrections

CommentOn: J Clin Invest. 2009 Sep;119(9):2737-44. (PMID: 19726882)

CommentOn: J Clin Invest. 2009 Sep;119(9):2745-57. (PMID: 19726881)

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals
Arrhythmias, Cardiac - etiology; genetics; metabolism
Cardiovascular Diseases - etiology; genetics; metabolism
Cell Line
Endocytosis
Ether-A-Go-Go Potassium Channels - genetics; metabolism
Humans
Hypokalemia - complications; genetics; metabolism

Hypokalemia - complications; genetics; metabolism
Ion Channels - genetics; metabolism
Models, Cardiovascular
Mutation
Myocytes, Cardiac - metabolism
Rabbits
Small Ubiquitin-Related Modifier Proteins - metabolism
TRPM Cation Channels - genetics; metabolism

Associated Chemicals: ERG1 potassium channel (0) ; Ether-A-Go-Go Potassium Channels (0) ; Ion Channels (0) ; Small Ubiquitin-Related Modifier Proteins (0) ; TRPM Cation Channels (0) ; TRPM4 protein, human (0)

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