Potassium

channel
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Potassium channel Kv1.2, structure in a membrane-like environment.

Calculated hydrocarbon boundaries of the lipid bilayer are indicated by red
and blue lines.

Potassium channels are the most widely distributed type of ion

channel and are found in virtually all living organisms.[1] They

form potassium-selective pores that span cell membranes.
Potassium channels are found in most cell types and control a

wide variety of cell functions.[2][3]

Contents

1
Function

2
Types

3
Structure
3.1
Selectivity filter
3.1.1
Selectivity mechanism

3.2
Hydrophobic region

3.3
Central cavity

4
Regulation

5
Pharmacology
5.1
Blockers

5.2
Activators

6
Muscarinic potassium channel

7
In fine art

8
See also

9
References

10
External links

Function[edit]
Potassium channels function to conduct potassium ions down
their electrochemical gradient, doing so both rapidly (up to the

diffusion rate of K+ ions in bulk water) and selectively (excluding,

most notably, sodium despite the sub-angstrom difference in

ionic radius).[4] Biologically, these channels act to set or reset the

resting potential in many cells. In excitable cells, such as
neurons, the delayed counterflow of potassium ions shapes the
action potential.

By contributing to the regulation of the action potential duration in

cardiac muscle, malfunction of potassium channels may cause
life-threatening arrhythmias. Potassium channels may also be
involved in maintaining vascular tone.

They also regulate cellular processes such as the secretion of

hormones (e.g., insulin release from beta-cells in the pancreas)
so their malfunction can lead to diseases (such as diabetes).

Types[edit]
There are four major classes of potassium channels:

● Calcium-activated potassium channel - open in

response to the presence of calcium ions or other
signalling molecules.
● Inwardly rectifying potassium channel - passes current
(positive charge) more easily in the inward direction
(into the cell).
● Tandem pore domain potassium channel - are
constitutively open or possess high basal activation,
such as the "resting potassium channels" or "leak
channels" that set the negative membrane potential of
neurons.
● Voltage-gated potassium channel - are voltage-gated
ion channels that open or close in response to
changes in the transmembrane voltage.
 The following table contains a comparison of the major classes of
potassium channels with representative examples (for a
complete list of channels within each class, see the respective
class pages).

For more examples of pharmacological modulators of potassium

channels, see potassium channel blocker and potassium channel
opener.

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Structure[edit]
 Top view of a potassium channel with potassium ions (purple) moving through
the pore (in the center). (PDB: 1BL8)

Potassium channels have a tetrameric structure in which four

identical protein subunits associate to form a fourfold symmetric

(C4) complex arranged around a central ion conducting pore (i.e.,

a homotetramer). Alternatively four related but not identical
protein subunits may associate to form heterotetrameric

complexes with pseudo C4 symmetry. All potassium channel

subunits have a distinctive pore-loop structure that lines the top
of the pore and is responsible for potassium selective
permeability.

There are over 80 mammalian genes that encode potassium

channel subunits. However potassium channels found in bacteria
are amongst the most studied of ion channels, in terms of their

molecular structure. Using X-ray crystallography,[49][50] profound

insights have been gained into how potassium ions pass through

these channels and why (smaller) sodium ions do not.[51] The

2003 Nobel Prize for Chemistry was awarded to Rod MacKinnon

for his pioneering work in this area. [52]

Selectivity filter[edit]

Crystallographic structure of the bacterial KcsA potassium channel

[53]
(PDB: 1K4C). In this figure, only two of the four subunits of the tetramer
are displayed for the sake of clarity. The protein is displayed as a green
cartoon diagram. In addition backbone carbonyl groups and threonine
sidechain protein atoms (oxygen = red, carbon = green) are displayed. Finally
potassium ions (occupying the S2 and S4 sites) and the oxygen atoms of
water molecules (S1 and S3) are depicted as purple and red spheres
respectively.

Potassium ion channels remove the hydration shell from the ion
when it enters the selectivity filter. The selectivity filter is formed
by a five residue sequence, TVGYG, termed the signature
sequence, within each of the four subunits. This signature
sequence is within a loop between the pore helix and TM2/6,
historically termed the P-loop. This signature sequence is highly
conserved, with the exception that a valine residue in prokaryotic
potassium channels is often substituted with an isoleucine
residue in eukaryotic channels. This sequence adopts a unique
main chain structure, structurally analogous to a nest protein
structural motif. The four sets of electronegative carbonyl oxygen
atoms are aligned toward the center of the filter pore and form a
square anti-prism similar to a water-solvating shell around each
potassium binding site. The distance between the carbonyl
oxygens and potassium ions in the binding sites of the selectivity
filter is the same as between water oxygens in the first hydration
shell and a potassium ion in water solution, providing an
energetically-favorable route for de-solvation of the ions. Sodium
ions, however, are too small to fill the space between the
carbonyl oxygen atoms. Thus, it is energetically favorable for
sodium ions to remain bound with water molecules in the
extracellular space than to pass through the potassium-selective

ion pore.[54] This width appears to be maintained by hydrogen

bonding and van der Waals forces within a sheet of aromatic

amino acid residues surrounding the selectivity filter. [49][55] The

selectivity filter opens towards the extracellular solution, exposing
four carbonyl oxygens in a glycine residue (Gly79 in KcsA). The
next residue toward the extracellular side of the protein is the
negatively charged Asp80 (KcsA). This residue together with the
five filter residues form the pore that connects the water-filled
cavity in the center of the protein with the extracellular solution.
[56]

Selectivity mechanism[edit]

The mechanism of potassium channel selectivity remains under

continued debate. The carbonyl oxygens are strongly electro-
negative and cation-attractive. The filter can accommodate
potassium ions at 4 sites usually labelled S1 to S4 starting at the
extracellular side. In addition, one ion can bind in the cavity at a
site called SC or one or more ions at the extracellular side at
more or less well-defined sites called S0 or Sext. Several
different occupancies of these sites are possible. Since the X-ray
structures are averages over many molecules, it is, however, not
possible to deduce the actual occupancies directly from such a
structure. In general, there is some disadvantage due to
electrostatic repulsion to have two neighboring sites occupied by
ions. Proposals for the mechanism of selectivity have been made

based on molecular dynamics simulations,[57] toy models of ion

binding,[58] thermodynamic calculations,[59] topological

considerations,[60][61] and structural differences[62] between

selective and non-selective channels.

The mechanism for ion translocation in KcsA has been studied

extensively by theoretical calculations and simulation. [56][63] The

prediction of an ion conduction mechanism in which the two
doubly occupied states (S1, S3) and (S2, S4) play an essential
role has been affirmed by both techniques. Molecular dynamics

(MD) simulations suggest the two extracellular states, S ext and

S0, reflecting ions entering and leaving the filter, also are
important actors in ion conduction.

Hydrophobic region[edit]
This region is used to neutralize the environment around the
potassium ion so that it is not attracted to any charges. In turn, it
speeds up the reaction.

Central cavity[edit]
A central pore, 10 Å wide, is located near the center of the
transmembrane channel, where the energy barrier is highest for
the transversing ion due to the hydrophobity of the channel wall.
The water-filled cavity and the polar C-terminus of the pore
helices ease the energetic barrier for the ion. Repulsion by
preceding multiple potassium ions is thought to aid the
throughput of the ions. The presence of the cavity can be
understood intuitively as one of the channel's mechanisms for
overcoming the dielectric barrier, or repulsion by the low-

dielectric membrane, by keeping the K+ ion in a watery, high-

dielectric environment.

Regulation[edit]

Graphical representation of open and shut potassium channels (PDB: 1lnq

and PDB: 1k4c). Two simple bacterial channels are shown to compare the
"open" channel structure on the right with the "closed" structure on the left. At
top is the filter (selects potassium ions), and at bottom is the gating domain
(controls opening and closing of channel).

The flux of ions through the potassium channel pore is regulated

by two related processes, termed gating and inactivation. Gating
is the opening or closing of the channel in response to stimuli,
while inactivation is the rapid cessation of current from an open
potassium channel and the suppression of the channel's ability to
resume conducting. While both processes serve to regulate
channel conductance, each process may be mediated by a
number of mechanisms.

Generally, gating is thought to be mediated by additional

structural domains which sense stimuli and in turn open the
channel pore. These domains include the RCK domains of BK

channels,[64][65][66] and voltage sensor domains of voltage gated

K+ channels. These domains are thought to respond to the

stimuli by physically opening the intracellular gate of the pore
domain, thereby allowing potassium ions to traverse the
membrane. Some channels have multiple regulatory domains or
accessory proteins, which can act to modulate the response to
stimulus. While the mechanisms continue to be debated, there
are known structures of a number of these regulatory domains,

including RCK domains of prokaryotic[67][68][69] and eukaryotic[64]

[65][66]
channels, pH gating domain of KcsA, [70] cyclic nucleotide

gating domains,[71] and voltage gated potassium channels. [72][73]

N-type inactivation is typically the faster inactivation mechanism,

and is termed the "ball and chain" model.[74] N-type inactivation

involves interaction of the N-terminus of the channel, or an
associated protein, which interacts with the pore domain and
occludes the ion conduction pathway like a "ball". Alternatively,
C-type inactivation is thought to occur within the selectivity filter
itself, where structural changes within the filter render it non-
conductive. There are a number of structural models of C-type

inactivated K+ channel filters,[75][76][77] although the precise

mechanism remains unclear.
Pharmacology[edit]

Blockers[edit]
Main article: Potassium channel blocker

Potassium channel blockers inhibit the flow of potassium ions

through the channel. They either compete with potassium binding
within the selectivity filter or bind outside the filter to occlude ion
conduction. An example of one of these competitors is
quaternary ammonium ions, which bind at the extracellular face
[78][79]
or central cavity of the channel.[80] For blocking from the
central cavity quaternary ammonium ions are also known as
open channel blockers, as binding classically requires the prior

opening of the cytoplasmic gate.[81]

Barium ions can also block potassium channel currents, [82][83] by

binding with high affinity within the selectivity filter. [84][85][86][87] This
tight binding is thought to underlie barium toxicity by inhibiting
potassium channel activity in excitable cells.

Medically potassium channel blockers, such as 4-aminopyridine

and 3,4-diaminopyridine, have been investigated for the

treatment of conditions such as multiple sclerosis.[88] Off target

drug effects can lead to drug induced Long QT syndrome, a
potentially life-threatening condition. This is most frequently due
to action on the hERG potassium channel in the heart.
Accordingly, all new drugs are preclinically tested for cardiac
safety.

Activators[edit]
Main article: Potassium channel opener
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Muscarinic potassium channel[edit]

 Birth of an Idea (2007) by Julian Voss-Andreae. The sculpture was
commissioned by Roderick MacKinnon based on the molecule's atomic
coordinates that were determined by MacKinnon's group in 2001.

See also: G protein-coupled inwardly-rectifying potassium

channel

Some types of potassium channels are activated by muscarinic

receptors and these are called muscarinic potassium channels

(IKACh). These channels are a heterotetramer composed of two

GIRK1 and two GIRK4 subunits.[89][90] Examples are potassium

channels in the heart, which, when activated by parasympathetic
signals through M2 muscarinic receptors, cause an outward

current of potassium, which slows down the heart rate.[91][92]

In fine art[edit]
Roderick MacKinnon commissioned Birth of an Idea, a 5-foot (1.5

m) tall sculpture based on the KcsA potassium channel. [93] 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[edit]
● Inward-rectifier potassium ion channel
● Potassium transporter (Trk) family
● Potassium uptake permease
● Sodium ion channel
● Calcium channel

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External links[edit]
● Proteopedia channel Potassium channel in 3D
● Potassium+Channels at the US National Library of
Medicine Medical Subject Headings (MeSH)
● Neuromuscular Disease Center (2008-03-04).
"Potassium Channels". Washington University in St.
Louis. Retrieved 2008-03-10.
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Membrane transport protein: ion channels (TC

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