A molecular switch controls the impact of cholesterol on a Kir channel

Author:

Corradi Valentina12ORCID,Bukiya Anna N.3,Miranda Williams E.12,Cui Meng4ORCID,Plant Leigh D.4ORCID,Logothetis Diomedes E.45ORCID,Tieleman D. Peter12ORCID,Noskov Sergei Y.12ORCID,Rosenhouse-Dantsker Avia6

Affiliation:

1. Centre for Molecular Simulation, University of Calgary, Calgary, AB T2N 1N4, Canada

2. Department of Biological Sciences, University of Calgary, Calgary, AB T2N 1N4, Canada

3. Department of Pharmacology, Addiction Science, and Toxicology, The University of Tennessee Health Science Center, Memphis, TN 38163

4. Department of Pharmaceutical Sciences, School of Pharmacy, Bouvé College of Health Sciences, Northeastern University, Boston, MA 02115

5. Department of Physiology and Biophysics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298

6. Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607

Abstract

Significance Cholesterol is one of the main components found in plasma membranes and is involved in lipid-dependent signaling enabled by integral membrane proteins such as inwardly rectifying potassium (Kir) channels. Similar to other ion channels, most of the Kir channels are down-regulated by cholesterol. One of the very few notable exceptions is Kir3.4, which is up-regulated by this important lipid. Here, we discovered and characterized a molecular switch that controls the impact (up-regulation vs. down-regulation) of cholesterol on Kir3.4. Our results provide a detailed molecular mechanism of tunable cholesterol regulation of a potassium channel.

Funder

American Heart Association

Gouvernement du Canada | Canadian Institutes of Health Research

Office of Extramural Research, National Institutes of Health

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

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