Ion channels are present in the membranes that surround all biological cells. By conducting and controlling the flow of ions, these pore-forming enzymes help establish the small negative voltage that all cells possess at rest (see cell potential).
An ion channel is an integral membrane protein or more typically an assembly of several proteins. Such "multi-subunit" assemblies usually involve a circular arrangement of identical or related proteins closely packed around a water-filled pore through the membrane single file — nearly as fast as the ions move through free fluid. Access to the pore is governed by "gates," which may be opened or closed by chemical or electrical signals, or mechanical force, depending on the variety of channel.
Because "voltage-gated" channels underlie the nerve impulse and because "transmitter-gated" channels mediate conduction across the synapses, channels are especially prominent components of the nervous system. Indeed, most of the offensive and defensive toxins that organisms have evolved for shutting down the nervous systems of predators and prey (e.g. the venoms produced by spiders, scorpions, snakes, fish, bees, sea snails and others) work by plugging ion channel pores. But ion channels figure in a wide variety of biological processes that involve rapid changes in cells. In the search for any drug, ion channels are a favorite target.
Diversity and activation
- Voltage-gated channels sense the transmembrane potential and open or close in response to depolarization or hyperpolarization, respectively. Examples include the sodium and potassium voltage-gated channels of nerve and muscle, and the voltage-gated calcium channels that control neurotransmitter release in pre-synaptic endings.
- Ligand-gated channels open in response to a specific ligand molecule on the external face of the membrane in which the channel resides. Examples include the "nicotinic" Acetylcholine receptor, AMPA receptor and other neurotransmitter-gated channels.
- cyclic nucleotide-gated channels, Calcium-activated channels and others open in response to internal solutes and mediate cellular responses to second messengers.
- Stretch-activated channels open or close in response to mechanical forces that arise from local stretching or compression of the membrane around them; for example when their cells swell or shrink. Such channels are believed to underlie touch sensation and the transduction of acoustic vibrations into the sensation of sound.
- G-protein-gated channels open in response to G protein-activation via its receptor. An example is the "muscarinic" Acetylcholine receptor
Certain channels respond to multiple influences. For instance, the NMDA receptor is partially activated by interaction with its ligand, glutamate, but is also voltage-sensitive and only conducts when the membrane is depolarized. Some calcium-sensitive potassium channels respond to both calcium and depolarization, with an excess of one apparently being sufficient to overcome an absence of the other.
Channels differ with respect to the ion they let pass (for example, Na+, K+, Cl"), the ways in which they may be regulated, the number of subunits of which they are composed and other aspects of structure. Channels belonging to the largest class, which includes the voltage-gated channels that underlie the nerve impulse, consists of four subunits with six transmembrane helices each. On activation, these helices move about and open the pore. Two of these six helices are separated by a loop that lines the pore and is the primary determinant of ion selectivity and conductance in this channel class and some others. The channel subunits of one such other class, for example, consist of just this "P" loop and two transmembrane helices. The determination of their detailed structure by X-ray crystallography won a share of the 2003 Nobel Prize in Chemistry.
Because of their small size and the difficulty of crystallizing integral membrane proteins for X-ray analysis, it is only very recently that scientists have been able to directly examine what channels "look like." Particularly in cases where the crystallography required removing channels from their membranes with detergent, many researchers regard images that have been obtained as tentative. An example is the long-awaited crystal structure of a voltage-gated potassium channel, which was reported in May 2003. One inevitable ambiguity about these structures relates to the strong evidence that channels change conformation as they operate (they open and close, for example), such that the structure in the crystal could represent any one of these operational states. Most of what researchers have deduced about channel operation so far they have established through electrophysiology, biochemistry, gene sequence comparison and mutagenesis.
The existence of ion channels was hypothesized by the British biophysicists Alan Hodgkin and Andrew Huxley as part of their Nobel Prize-winning theory of the nerve impulse, published in 1952. Channel's existence was confirmed in the 1970s with an electrical recording technique known as the "patch clamp," which led to a Nobel Prize to Erwin Neher and Bert Sakmann, the technique's inventors. Hundreds if not thousands of researchers continue to pursue a more detailed understanding of how these enzymes work.
- The Voltage Sensor in Voltage-Dependent Ion Channels (http://physrev.physiology.org/cgi/content/full/80/2/555)
- X-ray crystal structure of a potassium channel (http://www.cellbio.wustl.edu/faculty/huettner/69.pdf)