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Normal levels of a sodium channel (red, top) are reduced in cardiac cells with too little ankyrin-G (green, bottom).

Without voltage-gated sodium channels, heart muscle cells can't keep a beat. Lowe et al. show how these cells, known as cardiomyocytes, direct channels to the right domain of their plasma membrane.

Opening Na_v1.5 sodium channels allows an inrush of sodium ions that depolarizes a cardiomyocyte. Patients who carry a faulty version of the channel are at risk for potentially lethal heart arrhythmias. Rather than scattering around the membrane, the channels home in on the junctions between cardiomyocytes. In neurons, the membrane skeletal protein ankyrin-G helps direct sodium channels to specific membrane domains, and Lowe et al. tested whether this ankyrin-based pathway performed the same function in heart cells.

When the researchers knocked down ankyrin-G using RNAi, they found that Na_v1.5 resided around the nucleus instead of in the membrane. The amount of Na_v1.5 in the cell also fell, possibly because wayward channels get degraded. After stimulation, cardiac muscle cells lacking ankyrin-G produced a smaller-than-normal current.

The knockdown of ankyrin-G had no effect on the location or activity of the cells' primary voltage-gated calcium channel, suggesting that the targeting pathway in heart cells is specific for Na_v1.5. By testing mutant forms of ankyrin-G that can't bind to the channel, the team showed that interactions between the two proteins are necessary to get Na_v1.5 into position.

The big question now is how ankyrin-G does the job. The protein might haul Na_v1.5 to the membrane or stabilize channels that have already made it there.

Reference:

Lowe, J.S., et al. 2008. J. Cell Biol. 180:173–186.[Abstract/Free Full Text]

Mitch Leslie

mitchleslie{at}comcast.net

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This Article PDF (Full Text) Alert me when this article is cited Services Email this article Similar articles in this journal Alert me to new content in the JCB Download to citation manager Citing Articles Citing Articles via CrossRef Google Scholar Articles by Leslie, M. PubMed Articles by Leslie, M. Social Bookmarking                      What's this?