Ion channel

Not to be confused with: Ion Television or Ion

implantation.

1. The rate of ion transport through the channel is very

high (often 106 ions per second or greater).
2. 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 plasma membrane of

nearly all cells and many intracellular organelles. They
are often described as narrow, water-lled 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 specic
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
Schematic diagram of an ion channel. 1 - channel domains (typ- through the segments of the channel pore in single le
ically four per channel), 2 - outer vestibule, 3 - selectivity lter, nearly as quickly as the ions move through free solution.
4 - diameter of selectivity lter, 5 - phosphorylation site, 6 - cell
In many ion channels, passage through the pore is govmembrane.
erned by a gate, which may be opened or closed in reIon channels are pore-forming membrane proteins sponse to chemical or electrical signals, temperature, or
whose functions include establishing a resting membrane mechanical force.
potential, shaping action potentials and other electrical Ion channels are integral membrane proteins, typically
signals by gating the ow of ions across the cell mem- formed as assemblies of several individual proteins. Such
brane, controlling the ow of ions across secretory and multi-subunit" assemblies usually involve a circular arepithelial cells, and regulating cell volume. Ion channels rangement of identical or homologous proteins closely
are present in the membranes of all cells. Ion channels packed around a water-lled pore through the plane of the
are considered to be one of the two traditional classes membrane or lipid bilayer.[3][4] For most voltage-gated
of ionophoric proteins, with the other class known as ion channels, the pore-forming subunit(s) are called the
ion transporters (including the sodium-potassium pump, subunit, while the auxiliary subunits are denoted , ,
sodium-calcium exchanger, and sodium-glucose trans- and so on.
port proteins, amongst others).[1]
Study of ion channels (channelomics) often includes
biophysics, electrophysiology and pharmacology, utiliz- 2 Biological role
ing techniques including voltage clamp, patch clamp,
immunohistochemistry, X-ray uorescence, and RTBecause channels underlie the nerve impulse and bePCR.
cause transmitter-activated channels mediate conduction across the synapses, channels are especially prominent components of the nervous system.
Indeed,
1 Basic features
numerous toxins that organisms have evolved for shutting down the nervous systems of predators and prey (e.g.,
There are two distinctive features of ion channels that the venoms produced by spiders, scorpions, snakes, sh,
dierentiate them from other types of ion transporter bees, sea snails, and others) work by modulating ion chanproteins:[2]
nel conductance and/or kinetics. In addition, ion channels
1

are key components 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 frequent target.[5][6][7]

Diversity

There are over 300 types of ion channels in a living cell.[8]

Ion channels may be classied 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 dierent constitutive subunits give rise to a specic kind of current.[9] 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.

3.1

Classication by gating

Ion channels may be classied by gating, i.e. what opens

and closes the channels. 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.
3.1.1

Voltage-gated

Main article: Voltage-gated ion 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 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 subunits, each spanning
the membrane once. Both and subunits are extensively glycosylated.
Voltage-gated calcium channels: This family contains 10 members, though these members are known
to coassemble with 2 , , and subunits. These
channels play an important role in both linking muscle excitation with contraction as well as neuronal
excitation with transmitter release. The subunits
have an overall structural resemblance to those of
the sodium channels and are equally large.

DIVERSITY

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.
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 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 channels 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 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

3.2

Classication by type of ions

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 ux to balance
the electron movement electrically.

3.1.2

Ligand-gated

Main article: Ligand-gated ion channel

3
Calcium-activated potassium channels: This
family of channels is, for the most part, activated by intracellular Ca2+ and contains 8
members.
Two-pore-domain potassium channels: This
family of 15 members form what is known
as leak channels, and they follow GoldmanHodgkin-Katz (open) rectication.
Light-gated channels like channelrhodopsin are directly opened by the action of light.

Also known as ionotropic receptors, this group of channels open in response to specic 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 ux
across the plasma membrane. Examples of such channels include the cation-permeable nicotinic Acetylcholine receptor, ionotropic glutamate-gated receptors
and ATP-gated P2X receptors, and the anion-permeable
-aminobutyric acid-gated GABAA receptor.

Mechanosensitive ion channels are opening under

the inuence of stretch, pressure, shear, displacement.

Ion channels activated by second messengers may also

be categorized in this group, although ligands and second
messengers are otherwise distinguished from each other.

Cyclic nucleotide-gated channels: This family of channels is characterized by activation

due to the binding of intracellular cAMP or
cGMP, with specicity 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.

3.1.3

Other gating

Other gating include activation/inactivation by e.g.

second messengers from the inside of the cell membrane,
rather as from outside, as in the case for ligands. Ions
may count to such second messengers, and then causes
direct activation, rather than indirect, as in the case were
the electric potential of ions cause activation/inactivation
of voltage-gated ion channels.
Some potassium channels

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.

Hyperpolarization-activated cyclic nucleotidegated channels

Temperature Gated Channels: Members of the
Transient Receptor Potential ion channel superfamily, such as TRPV1 or TRPM8 are opened either by
hot or cold temperatures.

Inward-rectier potassium channels: These

channels allow potassium to ow into the cell 3.2 Classication by type of ions
in an inwardly rectifying manner, i.e., potas Chloride channels: This superfamily of poorly unsium ows eectively into, but not out of, the
derstood channels consists of approximately 13
cell. This family is composed of 15 ocial
members. They include ClCs, CLICs, Bestrophins
and 1 unocial members and is further suband CFTRs. These channels are non-selective for
divided into 7 subfamilies based on homolsmall anions; however chloride is the most abundant
ogy. These channels are aected by intraanion, and hence they are known as chloride chancellular ATP, PIP2 , and G-protein subnels.
units. They are involved in important physiological processes such as the pacemaker ac Potassium channels
tivity in the heart, insulin release, and potassium uptake in glial cells. They contain only
Voltage-gated potassium channels e.g., Kvs,
two transmembrane segments, corresponding
Kirs etc.
to the core pore-forming segments of the KV
Calcium-activated potassium channels e.g.,
and KC channels. Their subunits form
BKCa or MaxiK, SK, etc.
tetramers.

ION CHANNEL BLOCKERS

Inward-rectier potassium channels

4 Detailed structure
Two-pore-domain potassium channels: This
family of 15 members form what is known Channels dier with respect to the ion they let pass (for
as leak channels, and they follow Goldman- example, Na+ , K+ , Cl ), the ways in which they may be
Hodgkin-Katz (open) rectication.
regulated, the number of subunits of which they are composed and other aspects of structure. Channels belong Sodium channels
ing to the largest class, which includes the voltage-gated
channels that underlie the nerve impulse, consists of four
voltage-gated sodium channels NaVs
subunits with six transmembrane helices each. On acti epithelial sodium channels (ENaC)
vation, these helices move about and open the pore. Two
of these six helices are separated by a loop that lines the
Calcium channels CaVs
pore and is the primary determinant of ion selectivity and
conductance in this channel class and some others. The
Proton channels
existence and mechanism for ion selectivity was rst postulated in the 1960s by Clay Armstrong.[10] He suggested
Voltage-gated proton channels
that the pore lining could eciently replace the water
Non-selective cation channels: These let many types molecules that normally shield potassium ions, but that
of cations, mainly Na+ , K+ and Ca2+ through the sodium ions were too small to allow such shielding, and
therefore could not pass through. This mechanism was
channel.
nally conrmed when the structure of the channel was
Most Transient receptor potential channels
elucidated. 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
3.3 Other classications
structure by Roderick MacKinnon using X-ray crystallography won a share of the 2003 Nobel Prize in ChemThere are other types of ion channel classications that istry.
are based on less normal characteristics, e.g. multiple
Because of their small size and the diculty of cryspores and transient potentials.
tallizing integral membrane proteins for X-ray analysis,
Almost all ion channels have one single pore. However, it is only very recently that scientists have been able
there are also those with two:
to directly examine what channels look like. Particularly in cases where the crystallography required re Two-pore channels: This small family of 2 mem- moving channels from their membranes with detergent,
bers putatively forms cation-selective ion channels. many researchers regard images that have been obtained
They are predicted to contain two KV-style six- as tentative. An example is the long-awaited crystal
transmembrane domains, suggesting they form a structure of a voltage-gated potassium channel, which
dimer in the membrane. These channels are related was reported in May 2003.[11][12] One inevitable ambito catsper channels channels and, more distantly, guity about these structures relates to the strong evidence
TRP channels.
that channels change conformation as they operate (they
open and close, for example), such that the structure in
There are channels that are classied by the duration of the crystal could represent any one of these operational
the response to stimuli:
states. Most of what researchers have deduced about
channel operation so far they have established through
Transient receptor potential channels: This group of electrophysiology, biochemistry, gene sequence comparchannels, normally referred to simply as TRP chan- ison and mutagenesis.
nels, is named after their role in Drosophila phototransduction. This family, containing at least 28 Channels can have single (CLICs) to multiple transmemmembers, is incredibly diverse in its method of ac- brane (K channels, P2X receptors, Na channels) domains
tivation. Some TRP channels seem to be constitu- which span plasma membrane to form pores. Pore can
tively open, while others are gated by voltage, in- determine the selectivity of the channel. Gate can be
tracellular Ca2+ , pH, redox state, osmolarity, and formed either inside or outside the pore region.
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 5 Ion channel blockers
subfamilies based on homology: canonical (TRPC),
vanilloid receptors (TRPV), melastatin (TRPM), A variety of inorganic and organic molecules can modpolycystins (TRPP), mucolipins (TRPML), and ulate ion channel activity and conductance. Some comankyrin transmembrane protein 1 (TRPA).
monly use blockers include:

5
Tetrodotoxin (TTX), used by puer sh and some
types of newts for defense. It blocks sodium channels.

Brugada syndrome is another ventricular arrhythmia

caused by voltage-gated sodium channel gene mutations.

Saxitoxin, is produced by a dinoagellate also

known as "red tide". It blocks voltage dependent
sodium channels.

Cystic brosis is caused by mutations in the CFTR

gene, which is a chloride channel.

Conotoxin, is used by cone snails to hunt prey.

Lidocaine and Novocaine belong to a class of local
anesthetics which block sodium ion channels.
Dendrotoxin is produced by mamba snakes, and
blocks potassium channels.
Iberiotoxin is produced by the Buthus tamulus (Eastern Indian scorpion) and blocks potassium channels.
Heteropodatoxin is produced by Heteropoda venatoria (brown huntsman spider or laya) and blocks
potassium channels.

Diseases

There are a number of genetic disorders which disrupt normal functioning of ion channels and have disastrous consequences for the organism. Genetic disorders of ion channels and their modiers are known as
channelopathies. See Category:Channelopathy for a full
list.
Shaker gene mutations cause a defect in the voltage
gated ion channels, slowing down the repolarization
of the cell.

Mucolipidosis type IV is caused by mutations in the

gene encoding the TRPML1 channel
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 diuse growth patterns of these
tumors.[13]

7 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 Prizewinning research on the action potential, published in
1952. They built on the work of other physiologists,
such as Cole and Bakers research into voltage-gated
membrane pores from 1941.[14][15] The existence of ion
channels was conrmed in the 1970s by Bernard Katz
and Ricardo Miledi using noise analysis. 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 techniques
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.

Equine hyperkalaemic periodic paralysis as well

as Human hyperkalaemic periodic paralysis (HyperPP) are caused by a defect in voltage dependent The Nobel Prize in Chemistry for 2003 was awarded to
sodium channels.
two American scientists: Roderick MacKinnon for his
studies on the physico-chemical properties of ion channel
Paramyotonia congenita (PC) and potassium aggrastructure and function, including x-ray crystallographic
vated myotonias (PAM)
structure studies, and Peter Agre for his similar work on
[16]
Generalized epilepsy with febrile seizures plus aquaporins.
(GEFS+)
Episodic Ataxia (EA), characterized by sporadic 8 Culture
bouts of severe discoordination with or without
myokymia, and can be provoked by stress, startle,
Roderick MacKinnon commissioned Birth of an Idea, a
or heavy exertion such as exercise.
5-foot (1.5 m) tall sculpture based on the KcsA potassium channel.[17] The artwork contains a wire object rep Familial hemiplegic migraine (FHM)
resenting the channels interior with a blown glass object
Spinocerebellar ataxia type 13
representing the main cavity of the channel structure.
Long QT syndrome is a ventricular arrhythmia
syndrome caused by mutations in one or more of
presently ten dierent genes, most of which are
potassium channels and all of which aect cardiac
repolarization.

9 See also
Action potential

10

REFERENCES

10 References
[1] Hille, Bertil (2001) [1984]. Ion Channels of Excitable
Membranes (3rd ed.). Sunderland, Mass: Sinauer Associates, Inc. p. 5. ISBN 0-87893-321-2.
[2] Hille, Bertil (1984). Ionic Channels of Excitable Membranes.
[3] Purves, (2001). Chapter 4: Channels and Transporters.
In Dale Purves, George J. Augustine, David Fitzpatrick,
Lawrence. C. Katz, Anthony-Samuel LaMantia, James
O. McNamara, S. Mark Williams, editors. Neuroscience
(2nd ed.). Sinauer Associates Inc. ISBN 0-87893-741-2.
[4] Hille B, Catterall, WA (1999). Chapter 6: Electrical Excitability and Ion Channels. In George J Siegel, Bernard
W Agrano, R. W Albers, Stephen K Fisher and Michael
D Uhler. Basic neurochemistry: molecular, cellular, and
medical aspects. Philadelphia: Lippincott-Raven. ISBN
0-397-51820-X.
[5] Camerino DC, Tricarico D, Desaphy JF (April 2007).
Ion channel pharmacology.
Neurotherapeutics 4
(2): 18498. doi:10.1016/j.nurt.2007.01.013. PMID
17395128.
Birth of an Idea (2007) by Julian Voss-Andreae. The sculpture was commissioned by Roderick MacKinnon based on the
molecules atomic coordinates that were determined by MacKinnons group in 2001.

Active transport
Alpha helix
Channelome
Channelopathy
Electrochemical gradient
Gating (electrophysiology)
Ion channel family as dened in Pfam and InterPro
Ionophore
K Database
Lipid bilayer ion channels
Magnesium transport
Membrane potential
Neurotoxin
Passive transport
Potassium ion channels
Sodium ion channel
Synthetic ion channels
Transmembrane receptor
MeSH entry for Ion channels

[6] Verkman AS, Galietta LJ (February 2009). Chloride

channels as drug targets. Nat Rev Drug Discov 8 (2):
15371. doi:10.1038/nrd2780. PMC 3601949. PMID
19153558.
[7] Camerino DC, Desaphy JF, Tricarico D, Pierno S, Liantonio A (2008). Therapeutic approaches to ion channel diseases. Adv. Genet. Advances in Genetics 64: 81145.
doi:10.1016/S0065-2660(08)00804-3. ISBN 978-0-12374621-4. PMID 19161833.
[8] Gabashvili IS, Sokolowski BH, Morton CC, Giersch AB
(September 2007). Ion Channel Gene Expression in the
Inner Ear. J. Assoc. Res. Otolaryngol. 8 (3): 30528.
doi:10.1007/s10162-007-0082-y. PMC 2538437. PMID
17541769.
[9] Vicini S (April 1999). New perspectives in the functional
role of GABA(A) channel heterogeneity. Mol. Neurobiol. 19 (2): 97110. doi:10.1007/BF02743656. PMID
10371465.
[10] Bezanilla F, Armstrong CM (November 1972). Negative
Conductance Caused by Entry of Sodium and Cesium Ions into the Potassium Channels of Squid Axons.
J. Gen.
Physiol.
60 (5): 588608.
doi:10.1085/jgp.60.5.588.
PMC 2226091.
PMID
4644327.
[11] Jiang Y, Lee A, Chen J, Ruta V, Cadene M, Chait BT,
MacKinnon R (May 2003). X-ray structure of a voltagedependent K+ channel. Nature 423 (6935): 3341.
Bibcode:2003Natur.423...33J. doi:10.1038/nature01580.
PMID 12721618.
[12] The detailed 3D structure of the magnesium channel from
bacteria can be seen here .

[13] Molenaar, Remco J. (2011).

Ion Channels
in Glioblastoma.
ISRN Neurology 2011:
1.
doi:10.5402/2011/590249. PMC 3263536. PMID
22389824.
[14] Pethig R, Kell DB (1987). The passive electrical properties of biological systems: their signicance in physiology, biophysics and biotechnology. Phys. Med.
Biol. 32 (8): 933970. Bibcode:1987PMB....32..933P.
doi:10.1088/0031-9155/32/8/001. PMID 3306721. 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.
[15] Cole KS, Baker RF (February 1941). Longitudinal
Impedance of the Squid Giant Axon. The Journal of
General Physiology (The Rockefeller University Press) 24
(6): 77188. doi:10.1085/jgp.24.6.771. PMC 2238007.
PMID 19873252. 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
[16] The Nobel Prize in Chemistry 2003 (Press release). The
Royal Swedish Academy of Science. 2003-10-08. Retrieved 2010-01-18.
[17] Ball, Philip (March 2008). The crucible: Art inspired by
science should be more than just a pretty picture. Chemistry World 5 (3): 4243. Retrieved 2009-01-12.

11

External links

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.
AurSCOPE Ion Channels Database

12

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