Potassium channels

The "potassium channel" is a large group of transmembrane ion channels that allow potassium ions to pass through the cell membrane in a specific way. Potassium channels can be activated either voltage-dependent, via free cytosolic Ca2+ ions or via a ligand (e.g. ATP).

The transport of the ions through the potassium channel takes place passively by diffusion. In human cells an inward rectifying potassium channel is almost always expressed. However,the direction of the potassium ion flow is not inward,but along the potassium concentration gradient. When the channel is opened,there is usually an outflow of K+ from the cell and thus a hyperpolarisation of the membrane.

K+ channels consist of glycoprotein complexes consisting of four alpha-subunits and four accessory beta-subunits. The alpha-protein complexes form the actual pore.

There is a large variety of K+-channels. They are activated in very different ways and affect different cell systems. Accordingly, completely different processes are induced (muscle contraction, stímulation of renin release, inhibition of insulin release, excitation of mechanoreceptors in stereocilia, activation of hair growth).

K+ channels show a high selectivity. This is based on a special filter that works by forming binding sites within the pore that mimic the hydration shell of potassium ions and can preserve the hydration energy after the ion enters the pore. The potassium ion diffuses into the pore channel with loss of its hydrate envelope, while sodium ions are excluded because the more energy-consuming dehydration process cannot take place.

Basically one can distinguish between:

• outward rectifying potassium channels (Kor=outward rectifier)
• and
• inward rectifying potassium channels (Kir=inward rectifier)

can be distinguished. The transport of ions through the potassium channel occurs passively by diffusion. In human cells, an inward rectifying potassium channel is almost always expressed. However, the direction of the potassium ion flow is not inward but along the potassium concentration gradient. When the channel opens, there is usually an outflow of K+ from the cell and thus a hyperpolarization of the membrane.

Furthermore, K+channels can be divided into 3 groups according to their biophysical properties:

• Voltage-dependent K+ channels (Kv channels).
• Inwardly rectifying K+ channels (_{Kir channels})
• Two-pore K+ channels (2P-K+ channels)

Kv channels (voltage-dependent K+ channels). Kv channels are composed of a pore-forming α- and a regulatory β-subunit. The channels can be activated by an increase in calcium concentration and in a voltage-dependent manner by depolarization, with the β-subunit predominantly influencing calcium sensitivity (Orio P et al (2002).

BKCa++ channels: In smooth muscle, BKCa++ channels are important determinants of the contractile state. BKCa++ channels are functionally coupled with voltage-gated calcium channels and calcium release from the endoplasmic reticulum. Activation of voltage-gated calcium channels results in depolarization and localized increases in Ca2+ concentration to a range of concentrations (3 - 10 µmol/l) (Jaggar J H et al. 2000). These brief localized increases in calcium concentration are called Ca2+ sparks and result from calcium-dependent activation of endoplasmic reticulum ryanodine receptors and a calcium release. Both events, calcium influx and calcium release, cause activation of BKCa++ channels. This leads to spontaneous transient outward currents (STOCs) and thus to the hyperpolarization of smooth muscle cells (Porter VA et al. (1998).

Kv channels are responsible for afterhyperpolarization following an action potential in many cells. They limit Ca++ influx via voltage-gated Ca++ channels (Jackson W F (2005). Class III -Antiarrhythmic drugs block versch. Kv channels(Kv channel blockers).

SKCa and IKCa: The other subtypes of KCa channels, SKCa and IKCa, are predominantly expressed in the endothelium and are characterized by lower conductance. Furthermore, unlike BKCa, these channels cannot be activated in a voltage-dependent manner. The IKCa and/or SKCa channels mediate the hyperpolarization of endothelial cells triggered by various substances, such as ACh, bradykinin, and histamine. Thus, these channels have a central role in dilations induced by these endothelium-dependent stimuli (Busse R et al.2002; Sharma NR et al.1994). The SKCa channel can be selectively inhibited by the bee toxin apamin as well as by the compound UCL1684, whereas the scorpion toxin charybdotoxin inhibits IKCa but also BKCa and KV channels.

_Kir ( inward rectifying potassium channels = inward rectifier anomalous rectifier ) can be considered as potassium sensors, since their activation can already occur by a moderate increase of the extracellular potassium concentration (6 - 15 mmol/l). Although their name suggests an inward current, physiologically channel activation always results in an outward current of potassium ions, because the direction of the potassium current is not dependent on the channel itself, but only on the current membrane potential and the chemical gradient (extracellular/intracellular). Consequently, activation leads to hyperpolarization and thus dilation of the cell (Nelson MT et al. 1995)._{Kir channels} can be inhibited relatively selectively by barium ions in a concentration-dependent manner (≤ 100µmol/l) (Sobey C G 2001); however, extracellular barium also inhibits other channels at higher concentrations. The_{Kir 4.1} potassium channel is found on glial cells in the central nervous system (astrocytes, oligodendrocytes, and others). Its function is to maintain axonal conduction of stimuli. IgG autoantibodies to the potassium channel have been found in certain patients with multiple sclerosis. Mutations in the_{Kir 4.1} coding gene KCNJ10 are associated with the very rare autosomal recessive EAST/SeSAME syndrome, which is associated with epilepsy, ataxia, renal tubulopathy, and deafness.

KATP channels (ATP-sensitive K+ channels): Constructed of a pore-forming (KIR6_.1) and a regulatory subunit (sulfonylurea receptor), ATP-sensitive potassium channels (KATP) are a group of K+ channels. Members of this K+ channel group function as sites of action for several drugs. KATP channels are activated by a decrease in ATP levels. Furthermore, by protein kinases A and G (Jackson W F 1993) and by NO (Nelson MT et al 1995). KATP channels are inactivated by an increase in the intracellular ATP concentration (this is the origin of their name); furthermore by an increase in the intracellular calcium concentration.
An important physiological role is played by KATP channels in pancreatic β-cells in the release of insulin.

KATP channel blockers(sulfonylureas and glinides) bind to and close the SR unit of KATP channel proteins. This explains their effect. They only act on cells in which the K+channels are normally open. This is true for B cells of the islets of Langerhans (antidiabetic effect), but not for cardiac muscle cells and vascular muscle cells. KATP channel blockers belong to the group of antidiabetic drugs.

KATP channel openers are minoxidil and diazoxide. They also bind intracellularly to the SHR subunit. The promotion of hair growth is probably also due to the opening of KATP channels at the hair roots.

_{Gi/o protein} controlled K+ channels: A potassium channel subunit is additionally controlled by ATP (adenosine triphosphate) or a G protein.

2P-K+ channels (two -pores (tandem pores) These K+ channels are composed of a dimeric protein complex in which each of the two subunits has adjacent pore-forming domains. These channels are mainly found in the CNS. They play an important role in stabilizing the resting membrane potential in many neurons. The channels contribute to the control of the frequency of action potentials. Because their activation threshold is close to the resting potential of most cells, they are activated by even small depolarizations, but are also deactivated very quickly (opening time <100 ms). Versch. Anesthetics (e.g. halothane) act via activation of 2P-K+ channels.

Second messenger-gated K+ channels: The so-called M channels in nerve cells belong to this class of K+ channels (second messenger-gated ion channels). On the one hand, they are opened by depolarization and then act as a brake on further neuronal excitation. On the other hand, the activation of certain neurotransmitter receptors (e.g. muscarinic acetylcholine receptor) also leads to the closure of the M-channels via the mediation of G-proteins and other messenger substances. For example, the transmitter acetylcholine can excite sympathetic neurons in two ways: on the one hand via activation of nicotinic acetylcholine receptor channels, and on the other hand via inhibition of the M channels.

All known potassium channels belong to a large protein family whose subfamilies and subtypes differ in different mechanisms of channel activation. Both in endothelial cells and in smooth muscle cells, voltage-dependent potassium channels (_KV), inward rectifying potassium channels (KIR), ATP sensitive potassium channels (KATP) and calcium2+-dependent potassium channels (KCa) can be expressed (Jackson W F 2005). Within this group, different subtypes are distinguished according to their conductivity in BKCa (high conductivity), IKCa (medium conductivity) and SKCa (low conductivity) (Nelson MT et al. 1995). The involvement of these different channels in the regulation of vascular tone or other functions can be demonstrated and investigated by using specific blockers.

The importance of an intact potassium channel results from the following casuistry: An 82-year-old female patient is admitted to hospital with pneumonia. She is first treated with the antibiotic erythromycin. After improvement of the symptoms and stabilization of the general condition, the antibiotic clarithromycin is used. After two applications of clarithromycin, the patient first develops ventricular extrasystoles, later ventricular flutter and then ventricular fibrillation. The emergency situation could be eliminated by defibrillation. The cause of this ADR was a mutation of a protein of the potassium channel in the heart. The mutated channel was blocked by the antibiotic clarithromycin, resulting in the disturbed excitation of the myocardium.

Overview of common potassium channels:

• KA (A channel), channel blocker: α-Dendrotoxin; Affected genes: Kv1, Kv2, Kv3, Kv4
• _KV (delayed rectifying K+ channel)
  • _KV (delayed rectifying K+ channel), channel blocker= β-dendrotoxin; affected genes: Kv1, Kv2, Kv3, Kv4
  • _KV(r ) (fast delayed rectifying K+ channel) channel blocker=doufetilide; affected genes: Kbv1, Kv2, Kv3, Kv4
  • _KV(s) (slowly delayed rectifying K+ channel), affected genes: Kv1, Kv2, Kv3, Kv4
• KSR (channel in the sarcoplasmic reticulum), channel blocker: decamethonium; affected genes: Kv1, Kv2, Kv3, Kv4 (Note: this channel is a strongly voltage-dependent K+ channel, but has only a low selectivity for K+ or Na+ ions (sodium)). –
• Calcium-sensitive K+channels:
  • BKCA (High conductance Ca2+-sensitive channel) Channel blocker: Iberiotoxin; affected genes: SK
  • IKCA (intermediate conductance Ca2+-sensitive channel); channel blocker: Ceteidil; affected genes: SK
  • SKCA (small conductance Ca2+-sensitive channel); channel blocker: UCL1684; affected genes:SK
• KM (M channel); channel blocker: Linopirdin; affected genes: KCNQ2, KCNQ3
• KACh (atrial muscarin-activated channel); channel blocker: Ba2+; affected gene: Kir3
• KIR (inward rectifying channel); channel blocker: poison of the Gabon viper; affected genes: Kir1, Kir2; KATP (ATP sensitive channel) channel blocker: glibenclamide; affected genes: Kir6, SUR
• KNA (Na+ activated channel); channel blocker: Ba2+; affected genes: unknown
• _KVol (cell volume sensitive channel); channel blocker: quinidine; affected genes: unknown

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