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Am J Physiol Cell Physiol (April 25, 2007). doi:10.1152/ajpcell.00492.2006
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Submitted on September 18, 2006
Accepted on April 13, 2007

Relationship between Kir2.1/Kir2.3 activity and their distribution between cholesterol-rich and cholesterol-poor membrane domains

Saloni Tikku1, Yulia Epshtein2, Heidi Collins3, Alexander J. Travis4, George H. Rothblat5, and Irena Levitan2*

1 IME, Upenn, Philadelphia, Pennsylvania, United States
2 Medicine, UIC, Chicago, Illinois, United States
3 Pediatrics, CHOP, Philadelphia, Pennsylvania, United States
4 Baker Institute for Animal Health, Cornell University College of Veterinary Medicine, Ithaca, New York, United States
5 Dept. of Physiology and Biochemistry, Medical College of Pennsylvania, Philadelphia, Pennsylvania, United States

* To whom correspondence should be addressed. E-mail: levitan{at}uic.edu.

Our earlier studies have shown that Kir2.x channels are suppressed by an increase in the level of cellular cholesterol whereas cholesterol depletion enhances the activity of the channels. In this study, we show that Kir2.1 and Kir2.3 channels have double peak distributions between cholesterol-rich (raft) and cholesterol-poor (non-raft) membrane fractions indicating that the channels exist in two different types of lipid environment. We also show that while M{beta}CD-induced cholesterol depletion removes cholesterol from both raft and non-raft membrane fractions, cholesterol enrichment results in cholesterol increase exclusively in the raft fractions. Kinetics of both depletion-induced Kir2.1 enhancement and enrichment-induced Kir2.1 suppression correlates with the changes in the level of raft cholesterol. Furthermore, we show not only that cholesterol depletion shifts the distribution of the channels from cholesterol-rich to cholesterol-poor membrane fractions but also that cholesterol enrichment has the opposite effect. These observations suggest that change in the level of raft cholesterol alone is sufficient to suppress Kir2 activity and to facilitate partitioning of the channels to cholesterol-rich domains. Therefore, we suggest that partitioning to membrane rafts plays an important role in the sensitivity of Kir2 channels to cholesterol.




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