A Paddle in Oil Anthony G

NATURE|Vol 444|7 December 2006 NEWS & VIEWS

ION CHANNELS A paddle in oil Anthony G. Lee How do voltage-gated ion channels in cell membranes open? The latest work suggests that the process depends on having the correct lipid molecules in the membrane, with phosphate groups being mandatory.

Electrical signalling in the nerv- Lipid lipid phosphatidylcholine. So ous system involves voltage-gated Paddle headgroups Exterior it seems that curvature frustra- ion channels, proteins that sit in tion is not important for ion- + + the outer membrane of nerve cells. ++ ++ channel function. This membrane, like all mem- + + MacKinnon and colleagues branes, consists of lipid molecules then turned to the effect of that are organized in the form of + phosphatidylglycerol, a lipid a bilayer — the charged parts of the ++++ +++ molecule with a negatively molecules, the lipid headgroups, Cell interior charged (anionic) headgroup. lie on the outside of the bilayer in Gate Gate K+ Fatty Anionic lipids would be contact with water, with the fatty open closed acyl chains expected to bind strongly to the acyl chains of the lipid molecules positively charged paddle; it has occupying the centre and forming been shown6, for example, that Figure 1 | Lipids and voltage-gated potassium channels. Voltage-gated the oily core. Embedded in this potassium channels contain positively charged ‘paddles’, loosely associated negatively charged lipids bind lipid bilayer are the voltage-gated with the surface of the channel, that move within the lipid bilayer to open the with high affinity to a positively ion channels. On page 775 of this channel. After ruling out some explanations for what bilayer composition is charged patch on the mechano- issue, Schmidt, Jiang and MacKin- required for correct paddle operation, MacKinnon and colleagues1 conclude sensitive channel MscL. But non1 show that having the correct that negatively charged phosphate groups are an essential component. the voltage-gated potassium lipids in the membrane is essential channel was functional in the if the ion channels are to open when the volt- ion channel into the membrane by fusing absence of phosphatidylgly cerol, soany inter- age changes across the membrane*. vesicles containing the purified channel with action between anionic lipids and the paddle The voltage change that opens an ion chan- the membrane. This allowed them to measure cannot be essential for channel function. nel — about 50 mV — seems quite small, but the current flowing through the ion channel Rather, it turns out that what is essential for a voltage change of 50 mV across a membrane as a function of the lipid composition of the function is the presence of a negatively charged 50 Å thick corresponds to a change of about membrane. For their experiments, they used phosphate group in the lipid molecule. The 100,000 V cmǁ1, easily enough to cause a the voltage-gated potassium channel from the channel was totally inactive in non-natural, change in the structure of an ion channel. Our bacterium Aeropyrum pernix because this can positively or negatively charged lipid molecules views of what exactly this structural change be expressed in high quantities in Escherichia lacking a phosphate group, or in an uncharged, might be altered dramatically when MacKin- coli and then purified. sugar-based lipid. It is intriguing that the mem- non’s group determined the X-ray structure The lipid composition chosen by MacKin- brane lipids of A. pernix, from which the chan- of a voltage-gated ion channel2,3. The part of non and colleagues1 for their initial experi- nel originally came, are, unusually, all anionic, the ion channel that senses the change in volt- ments was 70% phosphatidylethanolamine phosphate-containing lipids7. age across the membrane is highly positively and 30% phosphatidylglycerol. This is the lipid Why is the phosphate group vital? MacKinnon charged and is loosely attached to the outer composition of E. coli cell membranes, and the and colleagues suggest that negatively charged face of the channel, exposed to the lipid bilayer. ion channel behaved perfectly in a bilayer of phosphate groups in the lipid molecules may Because of its shape, MacKinnon referred to these lipids. act as counterions for the positively charged this part of the channel as a paddle (Fig. 1). The But what happens when the lipid compo- arginine amino-acid residues in the paddle, sta- idea is that a change in voltage across the mem- sition is changed? The authors looked at the bilizing the charged paddle in the lipid bilayer. brane results in movement of the paddle, which importance of phosphatidylethanolamine. If this idea is correct, it would provide another in turn leads to opening of the central pore of Although this is the most abundant lipid in example of the importance for membrane-pro- the channel, allowing ions to flow through the the E. coli membrane, it is rather unusual in tein function of the local interactions between pore. It is currently a matter of debate whether that it does not, on its own, form bilayers at a membrane protein and its surrounding lipid the paddle moves all the way across the lipid normal temperatures. Rather, because the over- molecules. ■ bilayer when the voltage changes or whether all shape of the molecule is conical, it tends to Anthony G. Lee is in the School of Biological its motion is more restricted4. pack in three dimensions to give curved, non- Sciences, University of Southampton, It seems likely that a bilayer of the correct bilayer structures. However, the presence in the Southampton SO16 7PX, UK. lipid composition is essential for proper membrane of a cylindrically shaped lipid mol- e-mail: [email protected] function of the paddle, because the paddle ecule such as phosphatidylglycerol forces the is exposed to the bilayer and has to move in phosphatidyl ethanolamine to adopt a bilayer 1. Schmidt, D., Jiang, Q.-X. & MacKinnon, R. Nature 444, it. The idea that the lipids are important has structure, with the latter molecules being said 775–779 (2006). 2. Jiang, Y. et al. Nature 423, 33–41 (2003). now been investigated by MacKinnon and to exist in the bilayer in a state of ‘curvature 3. Long, S. B., Campbell, E. B. & MacKinnon, R. Science 309, 1 colleagues in a very direct way. They used the frustration’. There has been much speculation 897–903 (2005). traditional approach of forming lipid-bilayer as to the possible significance of this frus- 4. Tombola, F., Pathak, M. M. & Isacoff, E. Y. Neuron membranes across a small hole in a plastic trated state5. However, the authors found that 48, 719–725 (2005). 5. Lee, A. G. Biochim. Biophys. Acta 1666, 62–87 (2004). partition, and then inserting a voltage-gated channel function was unaltered when phos- 6. Powl, A. M., East, J. M. & Lee, A. G. Biochemistry 44, *This article and the paper concerned1 were published online phatidylethanolamine was substituted with 5873–5883 (2005). on 29 November 2006. the cylindrically shaped, bilayer-favouring 7. Morii, H. et al. Biochim. Biophys. Acta 1436, 426–436 (1999).