Ion channel


A. Diffusion; B. Ion Channel; C and D. Facilitated Diffusion; E. Active Transport (Pump)

Ion channels are pore-forming proteins that help establish the small voltage gradient that exists across the membrane of all living cells, by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells.

Basic features

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 plane of the membrane or lipid bilayer. While large-pore channels permit the passage of ions more or less indiscriminately, the archetypal channel pore is just one or two atoms wide at its narrowest point. It conducts a specific species of ion, such as sodium or potassium, and conveys them through the membrane single file--nearly as quickly as the ions move through free fluid. In some ion channels, access to the pore is governed by a "gate," which may be opened or closed by chemical or electrical signals, temperature, or mechanical force, depending on the variety of channel.

Biological role

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 new drugs, ion channels are a favorite target.

Diversity and activation

• Voltage-gated channels open or close, depending on the transmembrane potential. Examples include the sodium and potassium voltage-gated channels of nerve and muscle, that are involved in the propagation of the action potential, 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.
• Inward-rectifier K channels allow potassium to flow into the cell in an inwardly rectifying manner, i.e, potassium flows into the cell but not out of the cell. They are involved in important physiological processes such as the pacemaker activity in the heart, insulin release, and potassium uptake in glial cells.
• Light-gated channels like channelrhodopsin are directly opened by the action of light.
• Resting channels remain open at all times.

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 conducts only 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.

Detailed structure

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 molecular structure by Roderick MacKinnon using 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.

Diseases of Ion Channels

There are a number of chemicals and genetic disorders which disrupt normal functioning of ion channels and have disastrous consequences for the organism.

Chemicals

• Tetrodotoxin (TTX), used by puffer fish and some types of newts for defense. It is a sodium channel blocker.
• Saxitoxin, produced by a dinoflagellate also known as red tide. It blocks voltage dependent sodium channels.
• Conotoxin, which is used by cone snails to hunt prey.
• Lidocaine and Novocaine belong to a class of local anesthetics which block sodium ion channels.
• Dendrotoxin produced by mamba snakes blocks potassium channels.

Genetic

• Shaker gene mutations cause a defect in the volatage gated ion channels, slowing down the repolarization of the cell.
• Equine hyperkalaemic periodic paralysis as well as Human hyperkalaemic periodic paralysis (HyperPP) are caused by a defect in voltage dependent sodium channels.
• Paramyotonia congenital (PC) and potassium aggravated myotonias (PAM)
• Generalized epilepsy with febrile seizures (GEFS)
• Episodic Ataxia Type-1 (EA1)
• Familial hemiplegic migraine (FHM)

History

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. The existence of ion channels 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 proteins work. In recent years the development of automated patch clamp devices helped to increase the throughput in ion channel screening significantly.

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