Calcium-activated potassium channel

Last updated

Calcium-activated potassium channels are potassium channels gated by calcium, [1] or that are structurally or phylogenetically related to calcium gated channels. They were first discovered in 1958 by Gardos who saw that calcium levels inside of a cell could affect the permeability of potassium through that cell membrane. Then in 1970, Meech was the first to observe that intracellular calcium could trigger potassium currents. In humans they are divided into three subtypes: large conductance or BK channels, which have very high conductance which range from 100 to 300 pS, intermediate conductance or IK channels, with intermediate conductance ranging from 25 to 100 pS, and small conductance or SK channels with small conductances from 2-25 pS. [2]

Contents

This family of ion channels is, for the most part, activated by intracellular Ca2+ and contains 8 members in the human genome. However, some of these channels (the KCa4 and KCa5 channels) are responsive instead to other intracellular ligands, such as Na+, Cl−, and pH. Furthermore, multiple members of family are both ligand and voltage activated, further complicating the description of this family. The KCa channel α subunits have six or seven transmembrane segments, similar to the KV channels but occasionally with an additional N-terminal transmembrane helix. The α subunits make homo- and hetero-tetrameric complexes. The calcium binding domain may be contained in the α subunit sequence, as in KCa1, or may be through an additional calcium binding protein such as calmodulin.

Structure

Simple diagram of a Large Conductance calcium-activated potassium channel (BK). A similar structure can be hypothesized for the other subtypes in this family of channels. BK Channel Diagram.jpg
Simple diagram of a Large Conductance calcium-activated potassium channel (BK). A similar structure can be hypothesized for the other subtypes in this family of channels.

Knowing the structure of these channels can provide insight into their function and mechanism of gating. They are made up of two different subunits, alpha and beta. The alpha subunit is a tetramer which forms the pore, the voltage sensor, and the calcium sensing region. This subunit of the channel is made up of seven trans-membrane units, and a large intracellular region. The voltage sensor is made by the S4 transmembrane region, which has several Arginine residues which act to ‘sense’ the changes in charge and move in a very similar way to other voltage gated potassium channels. As they move in response to the voltage changes they open and close the gate. The linker between the S5 and S6 region serves to form the pore of the channel. Inside of the cell, the main portion to note is the calcium bowl. This bowl is thought to be the site of calcium binding. [3]

The beta subunit of the channel is thought to be a regulatory subunit of the channel. There are four different kinds of the beta subunit, 1, 2, 3, and, 4. Beta 2 and 3 are inhibitory, while beta 1 and 4 are excitatory, or they cause the channel to be more open than not open. The excitatory beta subunits affect the alpha subunits in such a way that the channel seldom inactivates. [4]

Homology Classification and Descriptions

Human KCa Channels

Below is a list of the 8 known human calcium-activated potassium channel grouped according to sequence homology of transmembrane hydrophobic cores: [5]

BK channel

Though not implied in the name, but implied by the structure these channels can also be activated by voltage. The different modes of activation in these channels are thought to be independent of one another. This feature of the channel allows them to participate in many different physiologic functions. The physiological effects of BK channels have been studied extensively using knockout mice. In doing so it was observed that there were changes in the blood vessels of the mice. The animals without the BK channels showed increased mean arterial pressure and vascular tone. These findings indicate that BK channels are involved in the relaxation of smooth muscle cells. In any muscle cell, increased intracellular calcium causes contraction. In smooth muscle cells the elevated levels of intracellular calcium cause the opening of BK channels which in turn allow potassium ions to flow out of the cell. This causes further hyperpolarization and closing of voltage gated calcium channels, relaxation can then occur. The knockout mice also experienced intention tremors, shorter stride length, and slower swim speed. All of these are symptoms of ataxia, indicating that BK channels are highly important in the cerebellum. [6]

Subtypes of BK Channels

IK channel

Intermediate conductance channels seem to be the least studied of all of the channels. Structurally they are thought to be very similar to BK channels with the main differences being conductance, and the methods of modulation. It is known that IK channels are modulated by calmodulin, whereas BK channels are not.

IK channels have shown a strong connection to calcification in vasculature, as inhibition of the channel causes a decrease in vascular calcification. Over-expression of these channels has quite a different effect on the body. Studies have shown that this treatment causes proliferation of vascular smooth muscle cells. This finding has sparked further exploration surrounding these channels and researchers have found that IK channels regulate the cell cycle in cancer cells, B and T lymphocytes, and stem cells. These discoveries show promise for future treatments surrounding IK Channels.

Subtypes of IK Channels

SK channel

Small conductance calcium activate potassium channels are quite different from their relatives with larger conductance. The main and most intriguing difference in SK Channels is that they are voltage insensitive. These channels can only be opened by increased levels of intracellular calcium. This trait of SK channels suggests that they have a slightly different structure than the BK and IK channels.

Like other potassium channels they are involved in hyperpolarization of cells after an action potential. The calcium activated property of these channels allows them to participate in vaso-regulation, auditory tuning of hair cells, and also the circadian rhythm. Researchers were trying to figure out which channels were responsible for the re-polarization and after-hyperpolarization of action potentials. They did this by voltage clamping cells, treating them with different BK, and SK channel blockers and then stimulating the cell to create a current. The researchers found that the re-polarization of cells happens because of BK channels and that a part of the after-hyperpolarization occurs because of current through SK channels. They also found that with blocking SK channels, current during after-hyperpolarization still occurred. It was concluded that there was a different unknown type of potassium channel allowing these currents. [7]

It is clear that SK channels are involved in AHP. It is not clear exactly how this happens. There are three different ideas on how this is done. 1) Simple diffusion of Calcium accounts for the slow kinetics of these currents, 2) The slow kinetics is due to other channels with slow activations, or 3) The Calcium simply activates a second messenger system to activate the SK channels. Simple diffusion has been shown to be an unlikely mechanism because the current is temperature sensitive, and a diffusive mechanism would not be temperature sensitive. This is also unlikely because only the amplitude of the current is changed with concentration of Calcium, not the kinetics of the channel activation.

Subtypes of SK Channels

Other subfamilies

Prokaryotic KCa Channels

A number of prokaryotic KCa channels have been described, both structurally and functionally. All are either gated by calcium or other ligands and are homologous to the human KCa channels, in particular the KCa1.1 gating ring. These structures have served as templates for ligand gating.

ProteinSpeciesLigandFunctionReference
Kch Escherichia coli UnknownChannel [8] [9]
MthK Methanothermobacter thermautotrophicus Calcium, Cadmium, Barium, pH Channel [10] [11] [12] [13] [14]
TrkA/TrkH Vibrio parahaemolyticus ATP, ADP Channel [15] [16]
KtrAB Bacillus subtilis ATP, ADPTransporter [17]
GsuK Geobacter sulfurreducens Calcium, ADP, NAD Channel [18]
TM1088 Thermotoga maritima UnknownUnknown [19]

See also

Related Research Articles

<span class="mw-page-title-main">Ion channel</span> Pore-forming membrane protein

Ion channels are pore-forming membrane proteins that allow ions to pass through the channel pore. Their functions include establishing a resting membrane potential, shaping action potentials and other electrical signals by gating the flow of ions across the cell membrane, controlling the flow of ions across secretory and epithelial cells, and regulating cell volume. Ion channels are present in the membranes of all cells. Ion channels are one of the two classes of ionophoric proteins, the other being ion transporters.

<span class="mw-page-title-main">BK channel</span> Family of transport proteins

BK channels (big potassium), are large conductance calcium-activated potassium channels, also known as Maxi-K, slo1, or Kca1.1. BK channels are voltage-gated potassium channels that conduct large amounts of potassium ions (K+) across the cell membrane, hence their name, big potassium. These channels can be activated (opened) by either electrical means, or by increasing Ca2+ concentrations in the cell. BK channels help regulate physiological processes, such as circadian behavioral rhythms and neuronal excitability. BK channels are also involved in many processes in the body, as it is a ubiquitous channel. They have a tetrameric structure that is composed of a transmembrane domain, voltage sensing domain, potassium channel domain, and a cytoplasmic C-terminal domain, with many X-ray structures for reference. Their function is to repolarize the membrane potential by allowing for potassium to flow outward, in response to a depolarization or increase in calcium levels.

<span class="mw-page-title-main">Potassium channel</span> Ion channel that selectively passes K+

Potassium channels are the most widely distributed type of ion channel found in virtually all organisms. 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.

<span class="mw-page-title-main">Voltage-gated ion channel</span> Type of ion channel transmembrane protein

Voltage-gated ion channels are a class of transmembrane proteins that form ion channels that are activated by changes in the electrical membrane potential near the channel. The membrane potential alters the conformation of the channel proteins, regulating their opening and closing. Cell membranes are generally impermeable to ions, thus they must diffuse through the membrane through transmembrane protein channels. They have a crucial role in excitable cells such as neuronal and muscle tissues, allowing a rapid and co-ordinated depolarization in response to triggering voltage change. Found along the axon and at the synapse, voltage-gated ion channels directionally propagate electrical signals. Voltage-gated ion-channels are usually ion-specific, and channels specific to sodium (Na+), potassium (K+), calcium (Ca2+), and chloride (Cl−) ions have been identified. The opening and closing of the channels are triggered by changing ion concentration, and hence charge gradient, between the sides of the cell membrane.

<span class="mw-page-title-main">Cyclic nucleotide–gated ion channel</span>

Cyclic nucleotide–gated ion channels or CNG channels are ion channels that function in response to the binding of cyclic nucleotides. CNG channels are nonselective cation channels that are found in the membranes of various tissue and cell types, and are significant in sensory transduction as well as cellular development. Their function can be the result of a combination of the binding of cyclic nucleotides and either a depolarization or a hyperpolarization event. Initially discovered in the cells that make up the retina of the eye, CNG channels have been found in many different cell types across both the animal and the plant kingdoms. CNG channels have a very complex structure with various subunits and domains that play a critical role in their function. CNG channels are significant in the function of various sensory pathways including vision and olfaction, as well as in other key cellular functions such as hormone release and chemotaxis. CNG channels have also been found to exist in prokaryotes, including many spirochaeta, though their precise role in bacterial physiology remains unknown.

Voltage-gated calcium channels (VGCCs), also known as voltage-dependent calcium channels (VDCCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (e.g., muscle, glial cells, neurons, etc.) with a permeability to the calcium ion Ca2+. These channels are slightly permeable to sodium ions, so they are also called Ca2+–Na+ channels, but their permeability to calcium is about 1000-fold greater than to sodium under normal physiological conditions.

<span class="mw-page-title-main">G protein-gated ion channel</span>

G protein-gated ion channels are a family of transmembrane ion channels in neurons and atrial myocytes that are directly gated by G proteins.

<span class="mw-page-title-main">SK channel</span> Protein subfamily of calcium-activated potassium channels

SK channels are a subfamily of calcium-activated potassium channels. They are so called because of their small single channel conductance in the order of 10 pS. SK channels are a type of ion channel allowing potassium cations to cross the cell membrane and are activated (opened) by an increase in the concentration of intracellular calcium through N-type calcium channels. Their activation limits the firing frequency of action potentials and is important for regulating afterhyperpolarization in the neurons of the central nervous system as well as many other types of electrically excitable cells. This is accomplished through the hyperpolarizing leak of positively charged potassium ions along their concentration gradient into the extracellular space. This hyperpolarization causes the membrane potential to become more negative. SK channels are thought to be involved in synaptic plasticity and therefore play important roles in learning and memory.

T-type calcium channels are low voltage activated calcium channels that become inactivated during cell membrane hyperpolarization but then open to depolarization. The entry of calcium into various cells has many different physiological responses associated with it. Within cardiac muscle cell and smooth muscle cells voltage-gated calcium channel activation initiates contraction directly by allowing the cytosolic concentration to increase. Not only are T-type calcium channels known to be present within cardiac and smooth muscle, but they also are present in many neuronal cells within the central nervous system. Different experimental studies within the 1970s allowed for the distinction of T-type calcium channels from the already well-known L-type calcium channels. The new T-type channels were much different from the L-type calcium channels due to their ability to be activated by more negative membrane potentials, had small single channel conductance, and also were unresponsive to calcium antagonist drugs that were present. These distinct calcium channels are generally located within the brain, peripheral nervous system, heart, smooth muscle, bone, and endocrine system.

<span class="mw-page-title-main">SK3</span> Protein-coding gene

SK3 also known as KCa2.3 is a protein that in humans is encoded by the KCNN3 gene.

<span class="mw-page-title-main">Cation channel superfamily</span> Family of ion channel proteins

The transmembrane cation channel superfamily was defined in InterPro and Pfam as the family of tetrameric ion channels. These include the sodium, potassium, calcium, ryanodine receptor, HCN, CNG, CatSper, and TRP channels. This large group of ion channels apparently includes families 1.A.1, 1.A.2, 1.A.3, and 1.A.4 of the TCDB transporter classification.

<span class="mw-page-title-main">Calcium-activated potassium channel subunit alpha-1</span> Voltage-gated potassium channel protein

Calcium-activated potassium channel subunit alpha-1 also known as large conductance calcium-activated potassium channel, subfamily M, alpha member 1 (KCa1.1), or BK channel alpha subunit, is a voltage gated potassium channel encoded by the KCNMA1 gene and characterized by their large conductance of potassium ions (K+) through cell membranes.

<span class="mw-page-title-main">KCNMB1</span> Protein-coding gene in the species Homo sapiens

Calcium-activated potassium channel subunit beta-1 is a protein that in humans is encoded by the KCNMB1 gene.

<span class="mw-page-title-main">KCNB1</span> Protein-coding gene in the species Homo sapiens

Potassium voltage-gated channel, Shab-related subfamily, member 1, also known as KCNB1 or Kv2.1, is a protein that, in humans, is encoded by the KCNB1 gene.

<span class="mw-page-title-main">KCNMB2</span> Protein-coding gene in the species Homo sapiens

Calcium-activated potassium channel subunit beta-2 is a protein that in humans is encoded by the KCNMB2 gene.

<span class="mw-page-title-main">KCNMB3</span> Protein-coding gene in the species Homo sapiens

Calcium-activated potassium channel subunit beta-3 is a protein that in humans is encoded by the KCNMB3 gene.

<span class="mw-page-title-main">KCNN1</span> Protein-coding gene in the species Homo sapiens

Potassium intermediate/small conductance calcium-activated channel, subfamily N, member 1 , also known as KCNN1 is a human gene encoding the KCa2.1 protein.

<span class="mw-page-title-main">KCNMB4</span> Protein-coding gene in humans

Calcium-activated potassium channel subunit beta-4 is a protein that in humans is encoded by the KCNMB4 gene.

<span class="mw-page-title-main">Tertiapin</span>

Tertiapin is a 21-amino acid peptide isolated from venom of the European honey bee. It blocks two different types of potassium channels, inward rectifier potassium channels (Kir) and calcium activated large conductance potassium channels (BK).

<span class="mw-page-title-main">Isopimaric acid</span> Chemical compound

Isopimaric acid (IPA) is a toxin which acts as a large conductance Ca2+-activated K+ channel (BK channel) opener.

References

  1. ↑ Vergara, C.; Latorre, R.; Marrion, N. V.; Adelman, J. P. (1998). "Calcium-activated potassium channels". Current Opinion in Neurobiology. 8 (3): 321–329. doi:10.1016/s0959-4388(98)80056-1. ISSN   0959-4388. PMID   9687354. S2CID   40840564.
  2. ↑ WEAVER, AMY K.; BOMBEN, VALERIE C.; SONTHEIMER, HARALD (2006-08-15). "Expression and Function of Calcium-Activated Potassium Channels in Human Glioma Cells". Glia. 54 (3): 223–233. doi:10.1002/glia.20364. ISSN   0894-1491. PMC   2562223 . PMID   16817201.
  3. ↑ Ghatta, Srinivas; Nimmagadda, Deepthi; Xu, Xiaoping; O'Rourke, Stephen T. (2006-04-01). "Large-conductance, calcium-activated potassium channels: Structural and functional implications". Pharmacology & Therapeutics. 110 (1): 103–116. doi:10.1016/j.pharmthera.2005.10.007. PMID   16356551.
  4. ↑ "Calcium- and sodium-activated potassium channels | Introduction | BPS/IUPHAR Guide to PHARMACOLOGY". www.guidetopharmacology.org. Retrieved 2019-04-22.
  5. ↑ Wei AD, Gutman GA, Aldrich R, Chandy KG, Grissmer S, Wulff H (Dec 2005). "International Union of Pharmacology. LII. Nomenclature and molecular relationships of calcium-activated potassium channels". Pharmacological Reviews. 57 (4): 463–72. doi:10.1124/pr.57.4.9. PMID   16382103. S2CID   8290401.
  6. ↑ Brenner, R (2000). "Cloning and functional characterization of novel large conductance calcium-activated potassium channel beta subunits, hKCNMB3 and hKCNMB4". J Biol Chem. 275 (9): 6453–6461. doi: 10.1074/jbc.275.9.6453 . PMID   10692449.
  7. ↑ Sah, Pankaj (1996). "Ca2+ activated K+ Currents in Neurones: Types, physiological roles and modulation". Trends in Neurosciences. 19 (4): 150–154. doi:10.1016/s0166-2236(96)80026-9. PMID   8658599. S2CID   9504595.
  8. ↑ Milkman R (Apr 1994). "An Escherichia coli homologue of eukaryotic potassium channel proteins". Proceedings of the National Academy of Sciences of the United States of America. 91 (9): 3510–4. Bibcode:1994PNAS...91.3510M. doi: 10.1073/pnas.91.9.3510 . PMC   43609 . PMID   8170937.
  9. ↑ Jiang Y, Pico A, Cadene M, Chait BT, MacKinnon R (Mar 2001). "Structure of the RCK domain from the E. coli K+ channel and demonstration of its presence in the human BK channel". Neuron. 29 (3): 593–601. doi: 10.1016/s0896-6273(01)00236-7 . PMID   11301020.
  10. ↑ Jiang Y, Lee A, Chen J, Cadene M, Chait BT, MacKinnon R (May 2002). "Crystal structure and mechanism of a calcium-gated potassium channel". Nature. 417 (6888): 515–22. Bibcode:2002Natur.417..515J. doi:10.1038/417515a. PMID   12037559. S2CID   205029269.
  11. ↑ Smith FJ, Pau VP, Cingolani G, Rothberg BS (2013). "Structural basis of allosteric interactions among Ca2+-binding sites in a K+ channel RCK domain". Nature Communications. 4: 2621. Bibcode:2013NatCo...4.2621S. doi: 10.1038/ncomms3621 . PMID   24126388.
  12. ↑ Ye S, Li Y, Chen L, Jiang Y (Sep 2006). "Crystal structures of a ligand-free MthK gating ring: insights into the ligand gating mechanism of K+ channels". Cell. 126 (6): 1161–73. doi: 10.1016/j.cell.2006.08.029 . PMID   16990139.
  13. ↑ Dvir H, Valera E, Choe S (Aug 2010). "Structure of the MthK RCK in complex with cadmium". Journal of Structural Biology. 171 (2): 231–7. doi:10.1016/j.jsb.2010.03.020. PMC   2956275 . PMID   20371380.
  14. ↑ Smith FJ, Pau VP, Cingolani G, Rothberg BS (Dec 2012). "Crystal structure of a Ba(2+)-bound gating ring reveals elementary steps in RCK domain activation". Structure. 20 (12): 2038–47. doi:10.1016/j.str.2012.09.014. PMC   3518701 . PMID   23085076.
  15. ↑ Cao Y, Jin X, Huang H, Derebe MG, Levin EJ, Kabaleeswaran V, Pan Y, Punta M, Love J, Weng J, Quick M, Ye S, Kloss B, Bruni R, Martinez-Hackert E, Hendrickson WA, Rost B, Javitch JA, Rajashankar KR, Jiang Y, Zhou M (Mar 2011). "Crystal structure of a potassium ion transporter, TrkH". Nature. 471 (7338): 336–40. Bibcode:2011Natur.471..336C. doi:10.1038/nature09731. PMC   3077569 . PMID   21317882.
  16. ↑ Cao Y, Pan Y, Huang H, Jin X, Levin EJ, Kloss B, Zhou M (Apr 2013). "Gating of the TrkH ion channel by its associated RCK protein TrkA". Nature. 496 (7445): 317–22. Bibcode:2013Natur.496..317C. doi:10.1038/nature12056. PMC   3726529 . PMID   23598339.
  17. ↑ Vieira-Pires RS, Szollosi A, Morais-Cabral JH (Apr 2013). "The structure of the KtrAB potassium transporter". Nature. 496 (7445): 323–8. Bibcode:2013Natur.496..323V. doi:10.1038/nature12055. hdl: 10216/110345 . PMID   23598340. S2CID   205233489.
  18. ↑ Kong C, Zeng W, Ye S, Chen L, Sauer DB, Lam Y, Derebe MG, Jiang Y (2012). "Distinct gating mechanisms revealed by the structures of a multi-ligand gated K(+) channel". eLife. 1: e00184. doi: 10.7554/eLife.00184 . PMC   3510474 . PMID   23240087.
  19. ↑ Deller MC, Johnson HA, Miller MD, Spraggon G, Elsliger MA, Wilson IA, Lesley SA (2015). "Crystal Structure of a Two-Subunit TrkA Octameric Gating Ring Assembly". PLOS ONE. 10 (3): e0122512. Bibcode:2015PLoSO..1022512D. doi: 10.1371/journal.pone.0122512 . PMC   4380455 . PMID   25826626.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.