Ions move across cell membranes through either ion channels or ion pumps. Ions flow passively through ion channels, down electrical and concentration gradients, at speeds that can approach the diffusion limit. By contrast, ion pumps generate those gradients by expending energy (usually in the form of ATP, or gradients of sodium ions or protons) to slowly move ions thermodynamically uphill.
So that ions flow only when needed, the pathway through an ion channel can be opened and closed by conformational changes that displace an obstruction called a gate. Although a channel needs only a single gate, a pump needs at least two gates that must open and close strictly alternately to provide access to its binding sites from only one side of the membrane at a time. A pump's two gates should never both be open, lest it behave like an ion channel and allow dissipative ion flow that would in an instant undo the pump's concentrative work.
X-ray crystal structures of cation channels and cation pumps perfected by evolution reveal distinct design principles. In ion channels, the narrow region that recognizes and selects ions for conduction is physically separated from the activation gate. But in pumps, these functions are intertwined, as the ion-binding pocket is remodelled with each alternation of access. The need for two gating reactions per transport event accounts for the orders of magnitude slower ion movement through pumps than through channels.
High-resolution structures have also been obtained of a member of a family that contains both anion channels and anion pumps. The structures are of a pump, but structural and functional analysis of mutants suggests that only microscopic differences distinguish the two family branches from one another. Moreover, channel members bear vestiges of pump behaviour, implying that the channels evolved from a pump member in which one of the gates failed.
There are other examples of ion channels that belong to pump families, and that likely arose from inherited gate dysfunction. Pharmacological interference with gate function can also transform a pump into an ion channel. There are even hybrid molecules that, while pumping their substrate, allow uncoupled, channel-like, electrodiffusive ion leakage.
Ion transport proteins can thus span a wide spectrum, from highly evolved ion channels to evolutionarily perfected ion pumps. Somewhere between these extremes, the distinction between channels and pumps becomes blurred. Determining the structures and mechanisms of ion transport proteins throughout the spectrum remains an important challenge.
The incessant traffic of ions across cell membranes is controlled by two kinds of border guards: ion channels and ion pumps. Open channels let selected ions diffuse rapidly down electrical and concentration gradients, whereas ion pumps labour tirelessly to maintain the gradients by consuming energy to slowly move ions thermodynamically uphill. Because of the diametrically opposed tasks and the divergent speeds of channels and pumps, they have traditionally been viewed as completely different entities, as alike as chalk and cheese. But new structural and mechanistic information about both of these classes of molecular machines challenges this comfortable separation and forces its re-evaluation.
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I thank present and past laboratory members for their contributions to the research and ideas encapsulated here, A. Takeuchi, A. Gulyás-Kovács, P. Vergani, P. Artigas and P. Hoff for help with figures, R. Dutzler and R. MacKinnon for images and the National Institutes of Health for funding via grants HL36783, HL49907 and DK51767.
- Membrane potential
The difference in electrical potential between one side of a membrane and the other; usually the electrical potential inside a cell measured with respect to that of the extracellular space.
- Activation gate
A gate in an ion channel that when opened initiates ion flow through the channel pore.
- Gating reaction
A change in the conformation of a transmembrane transport protein that alters access to the substrate translocation pathway.
- Selectivity filter
The narrow region of an ion translocation pathway in which the transport protein interacts with the ions to select among them on the basis of their physicochemical characteristics.
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Gadsby, D. Ion channels versus ion pumps: the principal difference, in principle. Nat Rev Mol Cell Biol 10, 344–352 (2009). https://doi.org/10.1038/nrm2668
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