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Ion channels are pore-forming Protein s that help to establish and control the small Voltage Gradient across the Plasma Membrane of all living Cell s (see Cell Potential ) by allowing the flow of Ion s down their Electrochemical Gradient . They are present in the Membrane s that surround all Biological Cell s.


BASIC FEATURES

An ion channel is an or Potassium , and conveys them through the membrane single file--nearly as quickly as the ions move through free fluid. In some ion channels, passage through 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 Synapse s, 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. In addition, ion channels figure in a wide variety of biological processes that involve rapid changes in cells, such as Cardiac , Skeletal , and Smooth Muscle Contraction , Epithelial transport of nutrients and ions, T-cell activation and Pancreatic beta-cell Insulin release. In the search for new drugs, ion channels are a favorite target.


DIVERSITY

  • , these channels open and close in response to Membrane Potential . This family contains at least 9 members and is largely responsible for Action Potential creation and propagation. The pore-forming α subunits are very large (up to 4,000 Amino Acid s) and consist of four homologous repeat domains (I-IV) each comprising six transmembrane segments (S1-S6) for a total of 24 transmembrane segments. The members of this family also coassemble with auxiliary β subunits, each spanning the membrane once. Both α and β subunits are extensively Glycosylated .


  • channels, these open and close according to the Membrane Potential . This family contains 10 members, though these members are known to coassemble with α2δ, β, and γ subunits. These channels play an important role in both linking muscle excitation with contraction as well as neuronal excitation with transmitter release. The α subunits have an overall structural resemblance to those of the sodium channels and are equally large.


  • Potassium Channel s: This superfamily is comprised of four families of channels, which are grouped based on homology and activation. Potassium channels are near ubiquitous in their expression and are primarily permeable to potassium over other ions.

  • , these KV channels open and close according to Membrane Potential . This family contains almost 40 members, which are further divided into 12 subfamilies. These channels are known mainly for their role in repolarizing the cell membrane following Action Potential s. The α subunits have six transmembrane segments, homologous to a single domain of the sodium channels. Correspondingly, they assemble as Tetramer s to produce a functioning channel.



  • , PIP2, and G-protein βγ subunits. They are involved in important physiological processes such as the pacemaker activity in the heart, insulin release, and potassium uptake in Glial Cells . They contain only two transmembrane segments, corresponding to the core pore-forming segments of the KV and KCa channels. Their α subunits form tetramers.



  • Chloride Channel s: This superfamily of poorly understood channels consists of approximately 13 members.


  • ), vanilloid receptors ( TRPV ), melastatin ( TRPM ), polycystins ( TRPP ), mucolipins ( TRPML ), and ankyrin transmembrane protein 1 ( TRPA ).


  • Cyclic Nucleotide-gated Channels : This superfamily of channels contains two families: the cyclic nucleotide-gated (CNG) channels and the hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels. It should be noted that this grouping is functional rather than evolutionary.

  • Cyclic nucleotide-gated channels: This family of channels is characterized by activation due to the binding of intracellular CAMP or CGMP , with specificity varying by member. These channels are primarily permeable to monovalent cations such as K+ and Na+. They are also permeable to Ca2+, though it acts to close them. There are 6 members of this family, which is divided into 2 subfamilies.

  • Hyperpolarization-activated, cyclic nucleotide-gated channels: While these channels are Voltage-gated , their opening is due to Hyperpolarization rather than the depolarization required for other like channels. These channels are also sensitive to the cyclic nucleotides CAMP and CGMP , which alter the voltage sensitivity of the channel’s opening. These channels are permeable to the monovalent cations K+ and Na+. There are 4 members of this family, all of which form tetramers of six-transmembrane α subunits. As these channels open under hyperpolarizing conditions, they function as Pacemaking channels in the heart, particularly the SA Node .



  • channels and, more distantly, TRP channels.



  • , this group of channels open in response to specific ligand molecules binding to the extracellular domain of the receptor protein. Ligand binding causes a conformational change in the structure of the channel protein that ultimately leads to the opening of the channel gate and subsequent ion flux across the plasma membrane. Examples of LGICs include the cation-permeable "nicotinic" Acetylcholine Receptor , Ionotropic Glutamate-gated Receptors and ATP-gated P2X Receptors , and the anion-permeable γ-aminobutyric acid-gated GABAA Receptor .



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 existence and mechanism for ion selectivity was first postulated in the 1960s by Clay Armstrong . 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. The detailed 3D structure of the magnesium channel from bacteria can be seen here . 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. Genetic disorders of ion channels and their modifiers are known as for a full list.

Chemicals

Genetic


HISTORY

The existence of ion channels was hypothesized by the British Biophysicist s 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.

The Nobel Prize in Chemistry for 2003 was awarded to two American scientists: Roderick MacKinnon for his studies on the physico-chemical properties of ion channel function, including X-ray Crystallographic Structure studies and Peter Agre for his similar work on Aquaporin s.

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