Cholesterol sensitivity of KIR2.1 is controlled by a belt of residues around the cytosolic pore.
Kir channels play an important role in setting the resting membrane potential and modulating membrane excitability. A common feature of several Kir channels is that they are regulated by cholesterol. Yet, the mechanism by which cholesterol affects channel function is unclear. We recently showed that the cholesterol sensitivity of Kir2 channels depends on several CD-loop residues. Here we show that this cytosolic loop is part of a regulatory site that also includes residues in the G-loop, the N-terminus, and the connecting segment between the C-terminus and the inner transmembrane helix. Together, these residues form a cytosolic belt that surrounds the pore of the channel close to its interface with the transmembrane domain, and modulate the cholesterol sensitivity of the channel. Furthermore, we show that residues in this cluster are correlated with residues located in the most flexible region of the G-loop, the major cytosolic gate of Kir2.1, implying that the importance of these residues extends beyond their effect on the channel's cholesterol sensitivity. We suggest that the residues of the cholesterol sensitivity belt are critical for channel gating.
Department of Medicine, University of Illinois at Chicago, USA. dantsker@uic.edu
Avia
A
Rosenhouse-Dantsker
Diomedes E
DE
Logothetis
Irena
I
Levitan
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism*; D003600:Cytosol / Q000502:physiology*; D015640:Ion Channel Gating / Q000502:physiology; D008564:Membrane Potentials / Q000502:physiology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009865:Oocytes / Q000378:metabolism*; D024661:Potassium Channels, Inwardly Rectifying / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D014981:Xenopus
C489461:Kir2.1 channel; D024661:Potassium Channels, Inwardly Rectifying; D002784:Cholesterol
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