Ion channel
Ion channels are pore-forming
The study of ion channels often involves
Basic features
There are two distinctive features of ion channels that differentiate them from other types of ion transporter proteins:[4]
- The rate of ion transport through the channel is very high (often 106 ions per second or greater).
- Ions pass through channels down their co-transport mechanisms, or active transportmechanisms).
Ion channels are located within the
Ion channels are integral membrane proteins, typically formed as assemblies of several individual 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.[6][7] For most voltage-gated ion channels, the pore-forming subunit(s) are called the α subunit, while the auxiliary subunits are denoted β, γ, and so on.
Biological role
Because channels underlie the
Diversity
There are over 300 types of ion channels just in the cells of the inner ear.[11] Ion channels may be classified by the nature of their gating, the species of ions passing through those gates, the number of gates (pores), and localization of proteins.
Further heterogeneity of ion channels arises when channels with different constitutive subunits give rise to a specific kind of current.[12] Absence or mutation of one or more of the contributing types of channel subunits can result in loss of function and, potentially, underlie neurologic diseases.
Classification by gating
Ion channels may be classified by gating, i.e. what opens and closes the channels. For example, voltage-gated ion channels open or close depending on the voltage gradient across the plasma membrane, while ligand-gated ion channels open or close depending on binding of ligands to the channel.
Voltage-gated
Voltage-gated ion channels open and close in response to membrane potential.
- Voltage-gated sodium channels: 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: This family contains 10 members, though these 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.
- TRP channels.
- tetramersto produce a functioning channel.
- Some TRPA).
- Hyperpolarization-activated SA node.
- macrophages) during the "respiratory burst." When bacteria or other microbes are engulfed by phagocytes, the enzyme NADPH oxidase assembles in the membrane and begins to produce reactive oxygen species(ROS) that help kill bacteria. NADPH oxidase is electrogenic, moving electrons across the membrane, and proton channels open to allow proton flux to balance the electron movement electrically.
Ligand-gated (neurotransmitter)
Also known as ionotropic
Ion channels activated by second messengers may also be categorized in this group, although ligands and second messengers are otherwise distinguished from each other.
Lipid-gated
This group of channels opens in response to specific
Other gating
Gating also includes activation and inactivation by
- Some potassium channels:
- G-protein βγ subunits. They are involved in important physiological processes such as 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.
- Calcium-activated potassium channels: This family of channels is activated by intracellular Ca2+ and contains 8 members.
- Goldman-Hodgkin-Katz (open) rectification. Contrary to their common name of 'Two-pore-domain potassium channels', these channels have only one pore but two pore domains per subunit.[21][22]
- Two-pore channels include ligand-gated and voltage-gated cation channels, so-named because they contain two pore-forming subunits. As their name suggests, they have two pores.[23][24][25][26][27]
- Light-gated channels like channelrhodopsin are directly opened by photons.
- Mechanosensitive ion channelsopen under the influence of stretch, pressure, shear, and displacement.
- 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. This grouping is functional rather than evolutionary.
- Cyclic nucleotide-gated channels: This family of channels is characterized by activation by either intracellular cAMP or cGMP. 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
- Temperature-gated channels: Members of the , are opened either by hot or cold temperatures.
Classification by type of ions
- Chloride channels: This superfamily of channels consists of approximately 13 members. They include ClCs, CLICs, Bestrophins and CFTRs. These channels are non-selective for small anions; however chloride is the most abundant anion, and hence they are known as chloride channels.
- Potassium channels
- Voltage-gated potassium channels e.g., Kvs, Kirs etc.
- Calcium-activated potassium channels e.g., BKCa or MaxiK, SK, etc.
- Inward-rectifier potassium channels
- Goldman-Hodgkin-Katz (open) rectification.
- Sodium channels
- Voltage-gated sodium channels (NaVs)
- Epithelial sodium channels (ENaCs)[28]
- Calcium channels (CaVs)
- Proton channels
- Voltage-gated proton channels
- Non-selective cation channels: These non-selectively allow many types of cations, mainly Na+, K+ and Ca2+, through the channel.
- Most transient receptor potential channels
- Most
Classification by cellular localization
Ion channels are also classified according to their subcellular localization. The plasma membrane accounts for around 2% of the total membrane in the cell, whereas intracellular organelles contain 98% of the cell's membrane. The major intracellular compartments are
- Plasma membrane channels
- Examples: Voltage-gated potassium channels (Kv), Sodium channels (Nav), Calcium channels (Cav) and Chloride channels (ClC)
- Intracellular channels, which are further classified into different organelles
- Endoplasmic reticulum channels: RyR, SERCA, ORAi
- Mitochondrial channels: mPTP, KATP, BK, IK, CLIC5, Kv7.4 at the inner membrane and VDAC and CLIC4 as outer membrane channels.
Other classifications
Some ion channels are classified by the duration of their response to stimuli:
- TRPA).
Detailed structure
Channels differ with respect to the ion they let pass (for example,
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.[37][38] 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.
Channels can have single (CLICs) to multiple transmembrane (K channels, P2X receptors, Na channels) domains which span plasma membrane to form pores. Pore can determine the selectivity of the channel. Gate can be formed either inside or outside the pore region.
Pharmacology
Chemical substances can modulate the activity of ion channels, for example by blocking or activating them.
Ion channel blockers
A variety of
- newtsfor defense. It blocks sodium channels.
- red tide". It blocks voltage-dependent sodium channels.
- cone snailsto hunt prey.
- local anestheticswhich block sodium ion channels.
- snakes, and blocks potassium channels.
- Iberiotoxin is produced by the Hottentotta tamulus (Eastern Indian scorpion) and blocks potassium channels.
- Heteropodatoxin is produced by Heteropoda venatoria (brown huntsman spider or laya) and blocks potassium channels.
Ion channel activators
Several compounds are known to promote the opening or activation of specific ion channels. These are classified by the channel on which they act:
- Calcium channel openers, such as Bay K8644
- phenanthroline
- Potassium channel openers, such as minoxidil
- Sodium channel openers, such as DDT
Diseases
There are a number of disorders which disrupt normal functioning of ion channels and have disastrous consequences for the organism. Genetic and autoimmune disorders of ion channels and their modifiers are known as channelopathies. See Category:Channelopathies for a full list.
- Shaker genemutations cause a defect in the voltage gated ion channels, slowing down the repolarization of the cell.
- human hyperkalaemic periodic paralysis(HyperPP) are caused by a defect in voltage-dependent sodium channels.
- potassium-aggravated myotonias(PAM)
- Generalized epilepsy with febrile seizures plus (GEFS+)
- Episodic ataxia (EA), characterized by sporadic bouts of severe discoordination with or without myokymia, and can be provoked by stress, startle, or heavy exertion such as exercise.
- Familial hemiplegic migraine (FHM)
- Spinocerebellar ataxia type 13
- arrhythmia syndrome caused by mutations in one or more of presently ten different genes, most of which are potassium channels and all of which affect cardiac repolarization.
- Brugada syndrome is another ventricular arrhythmia caused by voltage-gated sodium channel gene mutations.
- Polymicrogyria is a developmental brain malformation caused by voltage-gated sodium channel and NMDA receptor gene mutations.[39]
- Cystic fibrosis is caused by mutations in the CFTR gene, which is a chloride channel.
- TRPML1channel
- Mutations in and overexpression of ion channels are important events in cancer cells. In Glioblastoma multiforme, upregulation of gBK potassium channels and ClC-3 chloride channels enables glioblastoma cells to migrate within the brain, which may lead to the diffuse growth patterns of these tumors.[40]
History
The fundamental properties of currents mediated by ion channels were analyzed by the British biophysicists Alan Hodgkin and Andrew Huxley as part of their Nobel Prize-winning research on the action potential, published in 1952. They built on the work of other physiologists, such as Cole and Baker's research into voltage-gated membrane pores from 1941.[41][42] The existence of ion channels was confirmed in the 1970s by Bernard Katz and Ricardo Miledi using noise analysis [citation needed]. It was then shown more directly 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 significantly the throughput in ion channel screening.
The Nobel Prize in Chemistry for 2003 was awarded to Roderick MacKinnon for his studies on the physico-chemical properties of ion channel structure and function, including x-ray crystallographic structure studies.
Culture
Roderick MacKinnon commissioned Birth of an Idea, a 5-foot (1.5 m) tall sculpture based on the KcsA potassium channel.[43] The artwork contains a wire object representing the channel's interior with a blown glass object representing the main cavity of the channel structure.
See also
- Alpha helix
- Babycurus toxin 1
- Ki Database
- Lipid bilayer ion channels
- Magnesium transport
- Neurotoxin
- Passive transport
- Synthetic ion channels
- Transmembrane receptor
References
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Other than Ca2+ and Na+ channels that are formed by four intramolecular repeats, together forming the tetrameric channel's pore, the new channel had just two Shaker-like repeats, each of which was equipped with one pore domain. Because of this unusual topology, this channel, present in animals as well as plants, was named Two Pore Channel1 (TPC1).
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The best candidate for a vacuolar Ca2+ release channel is TPC1, a homolog of a mammalian voltage-gated Ca2+ channel that possesses two pores and twelve membrane spans.
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Organellar two-pore channels (TPCs) are an interesting type of channel that, as the name suggests, has two pores.
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The Arabidopsis two‐pore channel (AtTPC1) has been predicted to have 12 transmembrane helices and two pores (red lines).
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It is believed that TPCs, with their two pores, dimerise to form a functional channel.
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An expansive review of bioelectrical characteristics from 1987. ... the observation of an inductance (negative capacitance) by Cole and Baker (1941) during measurements of the AC electrical properties of squid axons led directly to the concept of voltage-gated membrane pores, as embodied in the celebrated Hodgkin-Huxley (1952) treatment (Cole 1972, Jack er a1 1975), as the crucial mechanism of neurotransmission.
- ^
Cole KS, Baker RF (July 1941). "Longitudinal Impedance of the Squid Giant Axon". The Journal of General Physiology. 24 (6). The Rockefeller University Press: 771–88. PMID 19873252.with electrodes and pass through an alternating current, and then notice that sometimes the voltage rises with time, and sometimes it decreases. The inductive reactance is a property of the axon and requires that it contain an inductive structure. The variation of the impedance with interpolar distance indicates that the inductance is in the membrane
Describes what happens when you stick a giant squid axon
- ^ Ball P (March 2008). "The crucible: Art inspired by science should be more than just a pretty picture". Chemistry World. 5 (3): 42–43. Retrieved 2009-01-12.
External links
- "The Weiss Lab". The Weiss Lab is investigating the molecular and cellular mechanisms underlying human diseases caused by dysfunction of ion channels.
- "Voltage-Gated Ion Channels". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
- "TRIP Database". a manually curated database of protein-protein interactions for mammalian TRP channels.
- Ion Channels at the U.S. National Library of Medicine Medical Subject Headings (MeSH)