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
electrochemical gradient, which is a function of ion concentration and membrane potential, "downhill", without the input (or help) of metabolic energy (e.g.
ATP,
co-transport mechanisms, or
active transport mechanisms).
Ion channels are located within the
membrane of all excitable cells,[3] and of many intracellular
organelles. They are often described as narrow, water-filled tunnels that allow only ions of a certain size and/or charge to pass through. This characteristic is called
selective permeability. The archetypal channel pore is just one or two atoms wide at its narrowest point and is selective for specific species of ion, such as
sodium or
potassium. However, some channels may be permeable to the passage of more than one type of ion, typically sharing a common charge: positive (
cations) or negative (
anions). Ions often move through the segments of the channel pore in a single file nearly as quickly as the ions move through the free solution. In many ion channels, passage through the pore is governed by a "gate", which may be opened or closed in response to chemical or electrical signals, temperature, or mechanical force.
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
nerve impulse and because "transmitter-activated" channels mediate conduction across the
synapses, channels are especially prominent components of the
nervous system. Indeed,
numerous 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 modulating ion channel conductance and/or kinetics. In addition, ion channels are key components in a wide variety of biological processes that involve rapid changes in cells, such as
cardiac,
skeletal, and
smooth musclecontraction,
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 frequent target.[8][9][10]
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 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.
Voltage-gated potassium channels (KV): 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.
Some
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).
Hyperpolarization-activated
cyclic nucleotide-gated channels: The opening of these channels is due to
hyperpolarization rather than the depolarization required for other cyclic nucleotide-gated 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.
Voltage-gated proton channels: Voltage-gated proton channels open with depolarization, but in a strongly pH-sensitive manner. The result is that these channels open only when the electrochemical gradient is outward, such that their opening will only allow protons to leave cells. Their function thus appears to be acid extrusion from cells. Another important function occurs in phagocytes (e.g.
eosinophils,
neutrophils,
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.
Also known as ionotropic
receptors, this group of channels open in response to specific ligand molecules binding to the extracellular domain of the receptor protein.[13] 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 such channels include the cation-permeable
nicotinic acetylcholine receptors,
ionotropic glutamate-gated receptors, acid sensing ion channels (
ASICs),[14]ATP-gated P2X receptors, and the anion-permeable γ-aminobutyric acid-gated
GABAA receptor.
Ion channels activated by second messengers may also be categorized in this group, although
ligands and second messengers are otherwise distinguished from each other.
This group of channels opens in response to specific
lipid molecules binding to the channel's transmembrane domain typically near the inner leaflet of the plasma membrane.[15] Phosphatidylinositol 4,5-bisphosphate (
PIP2) and phosphatidic acid (
PA) are the best-characterized lipids to gate these channels.[16][17][18] Many of the leak potassium channels are gated by lipids including the
inward-rectifier potassium channels and two pore domain potassium channels TREK-1 and TRAAK.
KCNQ potassium channel family are gated by PIP2.[19] The voltage activated potassium channel (Kv) is regulated by PA. Its midpoint of activation shifts +50 mV upon PA hydrolysis, near resting membrane potentials.[20] This suggests Kv could be opened by lipid hydrolysis independent of voltage and may qualify this channel as dual lipid and voltage gated channel.
Other gating
Gating also includes activation and inactivation by
second messengers from the inside of the
cell membrane – rather than from outside the cell, as in the case for ligands.
Some potassium channels:
Inward-rectifier potassium channels: These channels allow potassium ions to flow into the cell in an "inwardly rectifying" manner: potassium flows more efficiently into than out of the cell. This family is composed of 15 official and 1 unofficial member 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 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 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]
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.
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.
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
endoplasmic reticulum,
Golgi apparatus, and
mitochondria. On the basis of localization, ion channels are classified as:
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:
Transient receptor potential channels: This group of channels, normally referred to simply as TRP channels, is named after their role in Drosophila visual phototransduction. This family, containing at least 28 members, is diverse in its mechanisms of activation. Some TRP channels remain 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 cation channels. This family is subdivided into 6 subfamilies based on homology: canonical TRP (
TRPC), vanilloid receptors (
TRPV), melastatin (
TRPM), polycystins (
TRPP), mucolipins (
TRPML), and ankyrin transmembrane protein 1 (
TRPA).
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.[29] Channels belonging to the largest class, which includes the voltage-gated channels that underlie the nerve impulse, consists of four or sometimes five [30] 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 late 1960s by
Bertil Hille and
Clay Armstrong.[31][32][33][34][35] The idea of the ionic selectivity for potassium channels was that the carbonyl oxygens of the protein backbones of the "selectivity filter" (named by
Bertil Hille) could efficiently replace the water molecules that normally shield potassium ions, but that sodium ions were smaller and cannot be completely dehydrated to allow such shielding, and therefore could not pass through. This mechanism was finally confirmed when the first structure of an ion channel was elucidated. A bacterial potassium channel KcsA, consisting of just the selectivity filter, "P" loop, and two transmembrane helices was used as a model to study the permeability and the selectivity of ion channels in the Mackinnon lab. The determination of the molecular structure of KcsA by
Roderick MacKinnon using
X-ray crystallography won a share of the 2003
Nobel Prize in Chemistry.[36]
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.
A variety of
ion channel blockers (inorganic and organic molecules) can modulate ion channel activity and conductance.
Some commonly used blockers include:
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 gene mutations cause a defect in the voltage gated ion channels, slowing down the repolarization of the cell.
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.
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
biophysicistsAlan 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 crystallographicstructure 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.
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^Doyle DA, Morais Cabral J, Pfuetzner RA, Kuo A, Gulbis JM, Cohen SL, et al. (April 1998). "The structure of the potassium channel: molecular basis of K+ conduction and selectivity". Science. 280 (5360): 69–77.
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^
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.
doi:
10.1085/jgp.24.6.771.
PMC2238007.
PMID19873252. Describes what happens when you stick a
giant squid axon 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