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ION CHANNEL

Another, unrelated ion channeling process is part of ion implantation.

Ion channels are pore-forming proteins that help to establish and control the small voltage gradient that exists across the plasma membrane of all living cells (see cell potential) by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells.

Contents

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 homologous proteins closely packed around a water-filled pore through the plane of the membrane or lipid bilayer.[1] The pore-forming subunit(s) are called the α subunit, while the auxiliary subunits are denoted β, γ, and so on. While some channels permit the passage of ions based solely on charge, 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, 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 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. 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

  • Voltage-gated sodium channels: Like other voltage-gated channels, 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 acids) 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.
  • Voltage-gated calcium channels: As with the other voltage-gated 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 channels: 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.
  • Voltage-gated potassium channels: Like other voltage-gated channels, 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 potentials. The α subunits have six transmembrane segments, homologous to a single domain of the sodium channels. Correspondingly, they assemble as tetramers to produce a functioning channel.
  • Calcium-activated potassium channels: This family of channels is, for the most part, activated by intracellular Ca2+ and contains 8 members. It should be noted, however, that some of these channels (the KCa4 and KCa5 channels) are responsive instead to intracellular Na+ and Cl-. Furthermore, the KCa1 family is both Ca2+ and voltage activated, further complicating the description of this family. The KCa channel α subunits have six transmembrane segments similar to the KVs, except KCa1, in which the N-terminus makes a seventh pass across the membrane to end up outside the cell. The α subunits make homo- and hetero-tetrameric complexes.
  • Inward-rectifier potassium channels: These channels allow potassium to flow into the cell in an inwardly rectifying manner, i.e, potassium flows effectively into, but not out of, the cell. This family is composed of 15 official and 1 unofficial members and is further subdivided into 7 subfamilies based on homology. These channels are affected by intracellular ATP, 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.
  • Two-pore-domain potassium channels: This family of 15 members form what is known as leak channels. They have a distinct structure, being formed from two subunits, each of which is a tandem-repeat of a pair of channel sequences, versus the normal four seen in all other potassium channels, and follow Goldman-Hodgkin-Katz (open) rectification. These channels are regulated by numerous mechanisms, including: oxygen tension, pH, mechanical stretch, and G-proteins. Their name is derived from the fact that the α subunits consist of four transmembrane segments, each containing two pore loops. As such, they structurally correspond to two inward-rectifier α subunits and thus form dimers in the membrane.
  • Chloride channels: This superfamily of poorly understood channels consists of approximately 13 members. Chloride channels are important for setting cell resting membrane potential and maintaining proper cell volume. These channels conduct Cl- as well as other anions such as HCO3-, I-, SCN-, and NO3-. The structure of these channels is also not other known channels. Chloride channel subunits contain between 1 and 12 transmembrane segments. Some members of this family are activated by voltage, while others are activated by Ca2+, extracellular ligands, and pH among other modulators.[2]
  • Transient receptor potential channels: This group of channels, normally referred to simply as TRP channels, is named after their role in Drosophila phototransduction. This family, containing at least 28 members, is incredibly diverse in its method of activation. Some TRP channels seem to be constitutively open, while others are gated by voltage, intracellular Ca2+, pH, redox state, osmolarity, and mechanical stretch. These channels also vary according to the ion(s) they pass, some being selective for Ca2+ while others are less selective, acting as cation channels. This family is subdivided into 6 subfamilies based on homology: classical (TRPC), 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.
  • 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.
  • Cation channels of sperm: This small family of channels, normally referred to as Catsper channels, is related to the two-pore channels and distantly related to TRP channels. The 4 members of this family form voltage-gated Ca2+ channels that seem to be specific to sperm. These channels are required form proper fertilization. The study of these channels has been slow because they do not traffick to the cell membrane in many heterologous systems.
  • Two-pore channels: This small family of 2 members putatively forms cation-selective ion channels. These channels are related to catsper channels channels and, more distantly, TRP channels.
  • Light-gated channels like channelrhodopsin are directly opened by the action of light.

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. 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 Channelopathies. See Category:Channelopathy for a full list.

Chemicals

Genetic

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.

The Nobel Prize in chemistry for 2003 was awarded to two American scientist; to Roderick MacKinnon for his studies on the physico-chemical properties of ion channel function, including x-ray crystallographic structure studies; and to Peter Agre for his similar work on aquaporins.

Reference:

References

  1. ^ Two textbooks that discuss ion channels are: Neuroscience (2nd edition) Dale Purves, George J. Augustine, David Fitzpatrick, Lawrence. C. Katz, Anthony-Samuel LaMantia, James O. McNamara, S. Mark Williams, editors. Published by Sinauer Associates, Inc. (2001) online textbook and Basic Neurochemistry: Molecular, Cellular, and Medical Aspects (6th edition) by George J Siegel, Bernard W Agranoff, R. W Albers, Stephen K Fisher and Michael D Uhler published by Lippincott, Williams & Wilkins (1999): online textbook
  2. ^ Suzuki M., Morita T. and Iwamoto, T. (2006) Diversity of Cl(-) channels. Cell Mol Life Sci. 63(1):12-24. Entrez PubMed 16314923

See also

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