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Removal of phospho-head groups of membrane lipids immobilizes voltage sensors of K+ channels


A fundamental question about the gating mechanism of voltage-activated K+ (Kv) channels is how five positively charged voltage-sensing residues1,2 in the fourth transmembrane segment are energetically stabilized, because they operate in a low-dielectric cell membrane. The simplest solution would be to pair them with negative charges3. However, too few negatively charged channel residues are positioned for such a role4,5. Recent studies suggest that some of the channel’s positively charged residues are exposed to cell membrane phospholipids and interact with their head groups5,6,7,8,9. A key question nevertheless remains: is the phospho-head of membrane lipids necessary for the proper function of the voltage sensor itself? Here we show that a given type of Kv channel may interact with several species of phospholipid and that enzymatic removal of their phospho-head creates an insuperable energy barrier for the positively charged voltage sensor to move through the initial gating step(s), thus immobilizing it, and also raises the energy barrier for the downstream step(s).

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Figure 1: Reaction schemes of lipid hydrolysis and the effect of SMase D on Kv2.1 channels.
Figure 2: Effects of SMase C on Kv2.1, Kir1.1 and a KcsA–Kir2.1 chimaera.
Figure 3: Effect of SMase C and PC-PLC on ionic and gating currents of Shaker channels.
Figure 4: Inhibition of Kv1.3 by SMase C.


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We thank S. Billington for sharing SMase D cDNA; C. Deutsch for Kv1.3 cDNA; K. Ho and S. Hebert for Kir1.1; R. Joho for Kv2.1 cDNA; K. Swartz for Shaker-V478W cDNA; C. Armstrong for comments on the manuscript; and P. De Weer for review and discussion of the manuscript. This study was supported by a grant from the National Institute of General Medical Sciences to Z.L.

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Correspondence to Zhe Lu.

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Xu, Y., Ramu, Y. & Lu, Z. Removal of phospho-head groups of membrane lipids immobilizes voltage sensors of K+ channels. Nature 451, 826–829 (2008).

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