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Structural biology

Unexpected opening

Cell membranes contain channels that open to allow ions into cells. The structure of a sodium ion channel helps explain how it opens in response to protons, and settles a long-standing debate about its composition.

What do humans have in common with worms, flies, hydra and sea urchins? One answer is that they all have proteins known as degenerins1 that form pores in cell membranes for the passage of sodium ions. The acid-sensing ion channels (ASICs) belong to this family of proteins. They have been found in all vertebrates examined to date; even organisms with rudimentary nervous systems express at least one kind of ASIC. On page 316 of this issue, Gouaux and colleagues2 report the first crystal structure of one of these intriguing proteins. The structure turns out to be unlike that of any other known ion channel, and provides some surprising answers to questions about the shape and behaviour of ASICs.

Degenerins all share certain structural features: two regions (TM1 and TM2) that cross the cell membrane; short terminal sections that face the cytoplasm; and a large domain that lies outside the cell. Although their constituent amino-acid sequence varies between different degenerins, the extracellular section always contains cysteine amino acids at certain positions. Furthermore, the amino-acid sequence of TM2 — an essential component of the pore through which the ions pass — is remarkably similar in all degenerins. The evolutionary conservation of the TM2 structure makes these channels highly selective for sodium ions. Indeed, they have the highest sodium selectivity of all known ion channels, with a ratio of greater than 100:1 for sodium over potassium.

But the similarities between degenerins end there, as these ion channels have highly diverse functions and means of activation. Channels of the ASIC1 subclass found in the neurons of higher vertebrates open in response to extracellular hydrogen ions (protons, H+)3. The degenerins MEC-4 and MEC-10 in the worm Caenorhabditis elegans are mechanotransducers — slight mechanical stimulation of the worm's body surface induces a current in touch-responsive sensory neurons, an effect that is absent in animals lacking the mec-4 and mec-10 genes (ref. 4). Neurons in the garden snail Helix aspersa express a degenerin that is the only ion channel directly 'gated' by a peptide5. At the other end of the activation spectrum is ENaC (ref. 6), a sodium channel found in organs that regulate body sodium (such as the kidney, lung and the ducts of sweat glands). ENaC does not require a specific stimulus to open, but is constantly active.

A host of ions, toxins, small molecules, and enzymes and other proteins has been reported to bind to the extracellular domains of degenerins to modulate these channels' activities. Cations with two positive charges — particularly calcium ions (Ca2+) — are crucial in this respect, because they stabilize a conformation of ASICs that makes the channels sensitive to protons.

Gouaux and colleagues2 now provide the first three-dimensional structure of one of these functionally eclectic ion channels. They report the structure of chicken ASIC1 in the 'desensitized' state. This is a conformation adopted by the channel after it has opened, when it has ceased to conduct ions because the pore has closed up again, even though protons remain bound to the extracellular domain. Many of the observed structural features support previous experimental results, but the authors report several remarkable findings.

Perhaps one of the most unexpected discoveries is the number of subunits forming the channel. Previously, there were two schools of thought, one favouring four subunits and the other nine. Gouaux and colleagues' structure settles the matter once and for all: there are three. This means that all the other proteins in the degenerin family also have three subunits. In ASIC1, these subunits are of all the same type, but ENaC is known to have three different kinds of subunit; it can therefore now be concluded that ENaC is a heterotrimer.

The overall shape of the extracellular domain is also surprising. It was expected to have a funnel shape that would concentrate sodium ions around the mouth of the pore, but in fact its rather compact mass provides no direct passage for ions. The only access points for sodium ions entering the pore are small windows formed by short loops that tether the extracellular domain to the transmembrane regions. As previously predicted, two transmembrane helices, mostly in TM2, line the pore itself.

The structure also shows that, in the desensitized state, the pore collapses without any ions trapped inside. This finding agrees with the notion that the pores of degenerins are narrow and able to hold only one ion at a time. Such narrow pores would strip water molecules from sodium ions before the ions enter the channel; the pores' narrow shape would also account for the relatively low flow of ions through the channels, and for the fact that the channels select small metal ions — so sodium ions are preferred over the larger potassium ions.

The most intriguing part of ASIC1 is its large extracellular region — its size, 'stickiness' for other molecules and crucial role in channel opening have attracted much attention. Nevertheless, attempts to understand the gating mechanism of degenerin channels have been frustrated by the paucity of structural information about the extracellular domain. Gouaux and colleagues' structure2 provides some much-needed data. The authors identify a cluster of negatively charged amino-acid residues that form the proton sensor; these residues are brought together from distant parts of the protein by an appropriate fold.

Gouaux and colleagues propose that binding of protons to the sensor displaces a thumb-shaped region of the protein; this nudges a short loop that connects the bulk of the extracellular domain to the transmembrane helices, so opening the pore (Fig. 1). This conformational-switch mechanism might not apply to every degenerin because not all of them respond to protons, even though a proton sensor is present. It is therefore reasonable to assume that the proton sensor is necessary, but not sufficient, to elicit conformational changes extending beyond the thumb region.

Figure 1: Proposed mechanism for sodium-ion channel opening.

Gouaux and colleagues2 report the crystal structure of the chicken ASIC1 protein, which forms a channel across cell membranes. The channel opens in response to hydrogen ions (protons, H+), so allowing sodium ions into cells. The authors propose the following mechanism. a, Protons bind to a cleft next to a thumb-shaped region (green) of the extracellular part of the protein. b, The proton-binding slightly displaces the thumb, which causes a conformational change that opens the channel.

Thanks to Gouaux and colleagues' channel structure2, these and other hypotheses can now be tested experimentally. It might also be possible to discover how the different channels can be gated by such diverse stimuli despite sharing a fundamentally common structure. The next task is to obtain the crystal structure of a channel in the open state, where sodium ions are found in the selectivity filter of the pore. This is an even greater technical challenge, but is essential if we are to observe the different conformations of the extracellular domain and so further elucidate the gating mechanism of these ubiquitous ion channels.


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Canessa, C. Unexpected opening. Nature 449, 293–294 (2007).

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