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18  structures 450  species 1  interaction 2335  sequences 28  architectures

Family: BK_channel_a (PF03493)

Summary: Calcium-activated BK potassium channel alpha subunit

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BK channel Edit Wikipedia article

KCNMA1
BK-cartoon wp.jpg
The domain structure of BK channels
Identifiers
Symbol KCNMA1
Alt. symbols SLO
Entrez 3778
HUGO 6284
OMIM 600150
RefSeq NM_002247
UniProt Q12791
Other data
Locus Chr. 10 q22
KCNMB1
Identifiers
Symbol KCNMB1
Entrez 3779
HUGO 6285
OMIM 603951
RefSeq NM_004137
UniProt Q16558
Other data
Locus Chr. 5 q34
KCNMB2
Identifiers
Symbol KCNMB2
Entrez 10242
HUGO 6286
OMIM 605214
RefSeq NM_181361
UniProt Q9Y691
Other data
Locus Chr. 3 q26.32
BK Channel Structure
KCNMB3
Identifiers
Symbol KCNMB3
Alt. symbols KCNMB2, KCNMBL
Entrez 27094
HUGO 6287
OMIM 605222
RefSeq NM_171828
UniProt Q9NPA1
Other data
Locus Chr. 3 q26.3-q27
KCNMB3L
Identifiers
Symbol KCNMB3L
Alt. symbols KCNMB2L, KCNMBLP
Entrez 27093
HUGO 6288
RefSeq NG_002679
Other data
Locus Chr. 22 q11.1
KCNMB4
Identifiers
Symbol KCNMB4
Entrez 27345
HUGO 6289
OMIM 605223
RefSeq NM_014505
UniProt Q86W47
Other data
Locus Chr. 12 q15
Calcium-activated BK potassium channel alpha subunit
Identifiers
Symbol BK_channel_a
Pfam PF03493
InterPro IPR003929

BK channels (Big Potassium), also known as Maxi-K, slo1, or Kcal.1, 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 calcium concentrations in the cell.[1] [2]BK channels help regulate physiological processes, such as circadian behavioral rhythms and neuronal excitability.[3] 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.

Structure

Structurally, BK channels are homologous to voltage- and ligand-gated potassium channels, having a voltage sensor and pore as the membrane-spanning domain and a cytosolic domain for the binding of intracellular calcium and magnesium.[4] Each monomer of the channel-forming alpha subunit is the product of the KCNMA1 gene (also known as Slo1). The Slo1 subunit has three main structural domains, each with a distinct function: the vvoltage sensing domain (VSD) senses membrane potential across the membrane, the cytosolic domain (senses calcium concentration, Ca²⁺ ions), and the pore-gate domain (PGD) which opens and closes to regulate potassium permeation. The activation gate resides in the PGD, which is located at either the cytosolic side of S6 or the selectivity filter (selectivity is the preference of a channel to conduct a specific ion).[4] The Voltage sensing domain and pore-gated domain are collectively referred as the membrane-spanning domains and are formed by transmembrane segments S1-S4 and S5-S6, respectively. Within the S4 helix contains a series of positively charged residues which serve as the primary voltage sensor.[5]

BK channels are quite similar to voltage gated K⁺ channels, however, in BK channels only one positively charged residue (Arg213) is involved in voltage sensing across the membrane.[4] Also unique to BK channels is an additional S0 segment, this segment is required for β subunit modulation.[6][7] and voltage sensitivity.[8]

The Cytosolic domain is composed of two RCK (regulator of potassium conductance) domains, RCK1 and RCK2. These domains contain two high affinity Ca²⁺ binding sites: one in the RCK1 domain and the other in a region termed the Ca²⁺ bowl that consists of a series of Aspartic acid (Asp) residues that are located in the RCK2 domain. The Mg²⁺ binding site is located between the VSD and the cytosolic domain, which is formed by: Asp residues within the S0-S1 loop, Asparagine residues in the cytosolic end of S2, and Glutamine residues in RCK1.[4] In forming the Mg²⁺ binding site, two residues come from the RCK1 of one Slo1 subunit and the other two residues come from the VSD of the neighboring subunit. In order for these residues to coordinate the Mg²⁺ ion, the VSD and cytosolic domain from neighboring subunits must be in close proximity.[4] Modulatory beta subunits (encoded by KCNMB1, KCNMB2, KCNMB3, or KCNMB4) can associate with the tetrameric channel. There are four types of β subunits (β1-4), each of which have different expression patterns that modify the gating properties of the BK channel. The β1 subunit is primarily responsible for smooth muscle cell expression, both β2 and β3 subunits are neuronally expressed, while β4 is expressed within the brain.[4] The VSD associates with the PGD via three major interactions:

  1. Physical connection between the VSD and PGD through the S4-S5 linker.
  2. Interactions between the S4-S5 linker and the cytosolic side of S6.
  3. Interactions between S4 and S5 of a neighboring subunit.

Regulation

BK channels are associated and modulated by a wide variety of intra- and extracellular factors, such as auxiliary subunits (β, γ), Slobs (slo binding protein), phosphorylation, membrane voltage, chemical ligands (Ca²⁺, Mg²⁺), PKC, The BK α-subunits assemble 1:1 with four different auxiliary types of β-subunits (β1, β2, β3 or β4).[9]

Trafficking to and expression of BK channels in the plasma membrane has been found to be regulated by distinct splicing motifs located within the intracellular C-terminal RCK domains. In particular a splice variant that excluded these motifs prevented cell surface expression of BK channels and suggests that such a mechanism impacts physiology and pathophysiology.[9]

BK channels in the vascular system are modulated by agents naturally produced in the body, such as angiotensin II (Ang II), high glucose or arachidonic acid (AA) which is modulated in diabetes by oxidative stress (ROS).[9]

A weaker voltage sensitivity allows BK channels to function in a wide range of membrane potentials. This ensures that the channel can properly perform its physiological function.[10]

Inhibition of BK channel activity by phosphorylation of S695 by protein kinase C (PKC) is dependent on the phosphorylation of S1151 in C terminus of channel alpha-subunit. Only one of these phosphorylations in the tetrameric structure needs to occur for inhibition to be successful. Protein phosphatase 1 counteracts phosphorylation of S695. PKC decreases channel opening probability by shortening the channel open time and prolonging the closed state of the channel. PKC does not affect the single-channel conductance, voltage dependence, or the calcium sensitivity of BK channels.[10]

Activation mechanism

BK channels are synergistically activated through the binding of calcium and magnesium ions, but can also be activated via voltage dependence.[9] Ca²⁺ - dependent activation occurs when intracellular Ca²⁺ binds to two high affinity binding sites: one located in the C-terminus of the RCK2 domain (Ca²⁺ bowl), and the other located in the RCK1 domain.[4] The binding site within the RCK1 domain has somewhat of a lower affinity for calcium than the Ca²⁺ bowl, but is responsible for a larger portion of the Ca²⁺ sensitivity.[11] Voltage and calcium activate BK channels using two parallel mechanisms, with the voltage sensors and the Ca²⁺ bindings sites coupling to the activation gate independently, except for a weak interaction between the two mechanisms. The Ca²⁺ bowl accelerates activation kinetics at low Ca²⁺ concentrations while RCK1 site influences both activation and deactivation kinetics.[10] One mechanism model was originally proposed by Monod, Wyman, and Changeux, known as the MWC model. The MWC model for BK channels explains that a conformational change of the activation gate in channel opening is accompanied by a conformational change to the Ca²⁺ binding site, which increases the affinity of Ca²⁺ binding.[11]

Magnesium-dependent activation of BK channels activates via a low-affinity metal binding site that is independent from Ca²⁺-dependent activation. The Mg²⁺ sensor activates BK channels by shifting the activation voltage to a more negative range. Mg²⁺ activates the channel only when the voltage sensor domain stays in the activated state. The cytosolic tail domain (CTD) is a chemical sensor that has multiple binding sites for different ligands. The CTD activates the BK channel when bound with intracellular Mg²⁺ to allow for interaction with the voltage sensor domain (VSD).[10] Magnesium is predominantly coordinated by six oxygen atoms from the side chains of oxygen-containing residues, main chain carbonyl groups in proteins, or water molecules.[11] D99 at the C-terminus of the S0-S1 loop and N172 in the S2-S3 loop contain side chain oxygens in the voltage sensor domain that are essential for Mg²⁺ binding. Much like the Ca²⁺-dependent activation model, Mg²⁺-dependent activation can also be described by an allosteric MCW gating model. While calcium activates the channel largely independent of the voltage sensor, magnesium activates the channel by channel by an electrostatic interaction with the voltage sensor.[11] This is also known as the Nudging model, in which Magnesium activates the channel by pushing the voltage sensor via electrostatic interactions and involves the interactions among side chains in different structural domains.[4] Energy provided by voltage, Ca²⁺, and Mg²⁺ binding will propagate to the activation gate of BK channels to initiate ion conduction through the pore.[4]

Effects on the neuron, organ, body as a whole

Cellular level

BK channels help regulate both the firing of neurons and neurotransmitter release.[12] This modulation of synaptic transmission and electrical discharge at the cellular level is due to BK channel expression in conjunction with other potassium-calcium channels.[9] The opening of these channels causes a drive towards the potassium equilibrium potential and thus play a role in speeding up the repolarization of action potentials.[9] This would effectively allow for more rapid stimulation.[9] There is also a role played in shaping the general repolarization of cells, and thus after hyperpolarization (AHP) of action potentials.[13] The role that BK channels have in the fast phase of AHP has been studied extensively in the hippocampus.[13] It can also play a role in inhibiting the release of neurotransmitters.[14] There are many BK channels in Purkinje cells in the cerebellum, thus highlighting their role in motor coordination and function.[13] Furthermore, BK channels play a role in modulating the activity of dendrites as well as astrocytes and microglia.[14] They not only play a role in the CNS (central nervous system) but also in smooth muscle contractions, the secretion of endocrine cells, and the proliferation of cells.[12] Various γ subunits during early brain development are involved in neuronal excitability and in non-excitable cells they often are responsible as a driving force of calcium.[9] Therefore, these subunits can be targets for therapeutic treatments as BK channel activators.[9] There is further evidence that inhibiting BK channels would prevent the efflux of potassium and thus reduce the usage of ATP, in effect allowing for neuronal survival in low oxygen environments.[9] BK channels can also function as a neuronal protectant in terms such as limiting calcium entry into the cells through methionine oxidation.[9]

Organ level

BK channels also play a role in hearing.[13] This was found when the BK ɑ-subunit was knocked out in mice and progressive loss of cochlear hair cells, and thus hearing loss, was observed.[13] BK channels are not only involved in hearing, but also circadian rhythms. Slo binding proteins (Slobs) can modulate BK channels as a function of circadian rhythms in neurons.[9] BK channels are expressed in the suprachiasmatic nucleus (SCN), which is characterized to influence the pathophysiology of sleep.[13] BK channel openers can also have a protective effect on the cardiovascular system.[9] At a low concentration of calcium BK channels have a greater impact on vascular tone.[9] Furthermore, the signaling system of BK channels in the cardiovascular system have an influence on the functioning of coronary blood flow.[9] One of the functions of the β subunit in the brain includes inhibition of the BK channels, allowing for the slowing of channel properties as well as the ability to aid in prevention of seizures in the temporal lobe.[9]

Bodily function level

Mutations of BK channels, resulting in a lower amount of expression in mRNA, is more common in people who are mentally challenged (via hypofunction [14]), schizophrenic or autistic.[9] Moreover, increased repolarization caused by BK channel mutations may lead to dependency of alcohol initiation of dyskinesias, epilepsy or paroxysmal movement disorders.[9] Not only are BK channels important in many cellular processes in the adult it also is crucial for proper nutrition supply to a developing fetus.[9] Thus, estrogen can cause an increase in the density of BK channels in the uterus.[9] However, increased expression of BK channels have been found in tumor cells, and this could influence future cancer therapy, discussed more in the pharmacology section.[9] BK channels are ubiquitous throughout the body and thus have a large and vast impact on the body as a whole and at a more cellular level, as discussed.

Pharmacology

Potential issues

Several issues arise when there is a deficit in BK channels. Consequences of the malfunctioning BK channel can affect the functioning of a person in many ways, some more life threatening than others. BK channels can be activated by exogenous pollutants and endogenous gasotransmitters carbon monoxide,[15][16] nitric oxide, and hydrogen sulphide.[17] Mutations in the proteins involved with BK channels or genes encoding BK channels are involved in many diseases. A malfunction of BK channels can proliferate in many disorders such as: epilepsy, cancer, diabetes, asthma, and hypertension.[12] Specifically, β1 defect can increase blood pressure and hydrosaline retention in the kidney.[12] Both loss of function and gain of function mutations have been found to be involved in disorders such as epilepsy and chronic pain.[14] Furthermore, increases in BK channel activation, through gain-of-function mutants and amplification, has links to epilepsy and cancer.[12] Moreover, BK channels play a role in tumors as well as cancers. In certain cancers gBK, a variant ion channel called glioma BK channel, can be found.[13] It is known that BK channels do in some way influence the division of cells during replication, which when unregulated can lead to cancers and tumors.[13] Moreover, an aspect studied includes the migration of cancer cells and the role in which BK channels can facilitate this migration, though much is still unknown.[13] Another reason why BK channel understanding is important involves its role in organ transplant surgery. This is due to the activation of BK channels influencing repolarization of the resting membrane potential.[9] Thus, understanding is crucial for safety in effective transplantation.

Current developments

BK channels can be used as pharmacological targets for the treatment of several medical disorders including stroke[18] and overactive bladder.[19] There have been attempts to develop synthetic molecules targeting BK channels,[20] however their efforts have proven largely ineffective thus far. For instance, BMS-204352, a molecule developed by Bristol-Myers Squibb, failed to improve clinical outcome in stroke patients compared to placebo.[21] However, there have been some success from the agonist to BKCa channels, BMS-204352, in treating deficits observed in Fmr1 knockout mice, a model of Fragile X syndrome.[22] [23] BK channels also function as a blocker in ischemia and are a focus in investigating its use as a therapy for stroke.[9]

Future directions

There are many applications for therapeutic strategies involving BK channels. There has been research displaying that a blockage of BK channels results in an increase in neurotransmitter release, effectively indicating future therapeutic possibilities in cognition enhancement, improved memory, and relieving depression.[12] A behavioral response to alcohol is also modulated by BK channels,[9] therefore further understanding of this relationship can aid treatment in patients who are alcoholics. Oxidative stress on BK channels can lead to the negative impairments of lowering blood pressure through cardiovascular relaxation have on both aging and disease.[9] Thus, the signaling system can be involved in treating hypertension and atherosclerosis[9] through targeting of the ɑ subunit to prevent these detrimental effects. Furthermore, the known role that BK channels can play in cancer and tumors is limited. Thus, there is not a lot of current knowledge regarding specific aspects of BK channels that can influence tumors and cancers.[13] Further study is crucial, as this could lead to immense development in treatments for those suffering from cancer and tumors. It is known that epilepsies are due to over-excitability of neurons, which BK channels have a large impact on controlling hyperexcitability.[3] Therefore, understanding could influence the treatment of epilepsy. Overall, BK channels are a target for future pharmacological agents that can be used for benevolent treatments of disease.

See also

References

  1. ^ Miller, C. (2000). Genome Biology, 1(4), reviews0004.1. https://dx.doi.org/10.1186/gb-2000-1-4-reviews0004
  2. ^ Yuan, P., Leonetti, M., Pico, A., Hsiung, Y., & MacKinnon, R. (2010). Structure of the Human BK Channel Ca2+-Activation Apparatus at 3.0 A Resolution. Science, 329(5988), 182-186. https://dx.doi.org/10.1126/science.1190414
  3. ^ a b N'Gouemo P (November 2011). "Targeting BK (big potassium) channels in epilepsy". Expert Opinion on Therapeutic Targets. 15 (11): 1283–95. doi:10.1517/14728222.2011.620607. PMC 3219529Freely accessible. PMID 21923633. 
  4. ^ a b c d e f g h i Lee US, Cui J (September 2010). "BK channel activation: structural and functional insights". Trends in Neurosciences. 33 (9): 415–23. doi:10.1016/j.tins.2010.06.004. PMC 2929326Freely accessible. PMID 20663573. 
  5. ^ Atkinson NS, Robertson GA, Ganetzky B (August 1991). "A component of calcium-activated potassium channels encoded by the Drosophila slo locus". Science. 253 (5019): 551–5. doi:10.1126/science.1857984. PMID 1857984. 
  6. ^ Morrow JP, Zakharov SI, Liu G, Yang L, Sok AJ, Marx SO (March 2006). "Defining the BK channel domains required for beta1-subunit modulation". Proceedings of the National Academy of Sciences of the United States of America. 103 (13): 5096–101. doi:10.1073/pnas.0600907103. PMC 1458800Freely accessible. PMID 16549765. 
  7. ^ Wallner M, Meera P, Toro L (December 1996). "Determinant for beta-subunit regulation in high-conductance voltage-activated and Ca(2+)-sensitive K+ channels: an additional transmembrane region at the N terminus". Proceedings of the National Academy of Sciences of the United States of America. 93 (25): 14922–7. PMC 26238Freely accessible. PMID 8962157. 
  8. ^ Koval OM, Fan Y, Rothberg BS (March 2007). "A role for the S0 transmembrane segment in voltage-dependent gating of BK channels". The Journal of General Physiology. 129 (3): 209–20. doi:10.1085/jgp.200609662. PMC 2151615Freely accessible. PMID 17296928. 
  9. ^ a b c d e f g h i j k l m n o p q r s t u v w x y z Hermann A, Sitdikova GF, Weiger TM (August 2015). "Oxidative Stress and Maxi Calcium-Activated Potassium (BK) Channels". Biomolecules. 5 (3): 1870–911. doi:10.3390/biom5031870. PMC 4598779Freely accessible. PMID 26287261. 
  10. ^ a b c d Yang H, Zhang G, Cui J (2015). "BK channels: multiple sensors, one activation gate". Frontiers in Physiology. 6: 29. doi:10.3389/fphys.2015.00029. PMC 4319557Freely accessible. PMID 25705194. 
  11. ^ a b c d Cui J, Yang H, Lee US (March 2009). "Molecular mechanisms of BK channel activation". Cellular and Molecular Life Sciences : CMLS. 66 (5): 852–75. doi:10.1007/s00018-008-8609-x. PMC 2694844Freely accessible. PMID 19099186. 
  12. ^ a b c d e f Yu M, Liu SL, Sun PB, Pan H, Tian CL, Zhang LH (January 2016). "Peptide toxins and small-molecule blockers of BK channels". Acta Pharmacologica Sinica. 37 (1): 56–66. doi:10.1038/aps.2015.139. PMC 4722972Freely accessible. PMID 26725735. 
  13. ^ a b c d e f g h i j Bentzen BH, Olesen SP, Rønn LC, Grunnet M (2014). "BK channel activators and their therapeutic perspectives". Frontiers in Physiology. 5: 389. doi:10.3389/fphys.2014.00389. PMC 4191079Freely accessible. PMID 25346695. 
  14. ^ a b c d Contet C, Goulding SP, Kuljis DA, Barth AL (2016). "BK Channels in the Central Nervous System". International Review of Neurobiology. 128: 281–342. doi:10.1016/bs.irn.2016.04.001. PMC 4902275Freely accessible. PMID 27238267. 
  15. ^ Dubuis E, Potier M, Wang R, Vandier C (Feb 2005). "hypoxic". Cardiovascular Research. 65 (3): 751–61. doi:10.1016/j.cardiores.2004.11.007. PMID 15664403. 
  16. ^ Hou S, Xu R, Heinemann SH, Hoshi T (Mar 2008). "The RCK1 high-affinity Ca2+ sensor confers carbon monoxide sensitivity to Slo1 BK channels". Proceedings of the National Academy of Sciences of the United States of America. 105 (10): 4039–43. doi:10.1073/pnas.0800304105. PMC 2268785Freely accessible. PMID 18316727. 
  17. ^ Sitdikova GF, Weiger TM, Hermann A (Feb 2010). "Hydrogen sulfide increases calcium-activated potassium (BK) channel activity of rat pituitary tumor cells". Pflügers Archiv. 459 (3): 389–97. doi:10.1007/s00424-009-0737-0. PMID 19802723. 
  18. ^ Gribkoff VK, Starrett JE, Dworetzky SI (Apr 2001). "Maxi-K potassium channels: form, function, and modulation of a class of endogenous regulators of intracellular calcium". The Neuroscientist. 7 (2): 166–77. doi:10.1177/107385840100700211. PMID 11496927. 
  19. ^ Layne JJ, Nausch B, Olesen SP, Nelson MT (Feb 2010). "BK channel activation by NS11021 decreases excitability and contractility of urinary bladder smooth muscle". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 298 (2): R378–84. doi:10.1152/ajpregu.00458.2009. PMC 2828174Freely accessible. PMID 19923353. 
  20. ^ Gribkoff VK, Winquist RJ (May 2005). "Voltage-gated cation channel modulators for the treatment of stroke". Expert Opinion on Investigational Drugs. 14 (5): 579–92. doi:10.1517/13543784.14.5.579. PMID 15926865. 
  21. ^ Jensen BS (2002). "BMS-204352: a potassium channel opener developed for the treatment of stroke". CNS Drug Reviews. 8 (4): 353–60. doi:10.1111/j.1527-3458.2002.tb00233.x. PMID 12481191. 
  22. ^ Laumonnier F, Roger S, Guérin P, Molinari F, M'rad R, Cahard D, Belhadj A, Halayem M, Persico AM, Elia M, Romano V, Holbert S, Andres C, Chaabouni H, Colleaux L, Constant J, Le Guennec JY, Briault S (2006). "Association of a functional deficit of the BKCa channel, a synaptic regulator of neuronal excitability, with autism and mental retardation". The American Journal of Psychiatry. 163 (9): 1622–1629. doi:10.1176/ajp.2006.163.9.1622. PMID 16946189. 
  23. ^ Hébert B; Pietropaolo S; Même S; Laudier B; Laugeray A; Doisne N; Quartier A; Lefeuvre S; Got L; Cahard D; Laumonnier F; Crusio WE; Pichon J; Menuet A; Perche O; Briault S (2014). "Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by a BKCa channel opener molecule". Orphanet Journal of Rare Diseases. 9: 124. doi:10.1186/s13023-014-0124-6. PMC 4237919Freely accessible. PMID 25079250. 

Further reading

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Calcium-activated BK potassium channel alpha subunit Provide feedback

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InterPro entry IPR003929

Potassium channels are the most diverse group of the ion channel family [PUBMED:1772658, PUBMED:1879548]. They are important in shaping the action potential, and in neuronal excitability and plasticity [PUBMED:2451788]. The potassium channel family is composed of several functionally distinct isoforms, which can be broadly separated into 2 groups [PUBMED:2555158]: the practically non-inactivating 'delayed' group and the rapidly inactivating 'transient' group.

These are all highly similar proteins, with only small amino acid changes causing the diversity of the voltage-dependent gating mechanism, channel conductance and toxin binding properties. Each type of K+ channel is activated by different signals and conditions depending on their type of regulation: some open in response to depolarisation of the plasma membrane; others in response to hyperpolarisation or an increase in intracellular calcium concentration; some can be regulated by binding of a transmitter, together with intracellular kinases; while others are regulated by GTP-binding proteins or other second messengers [PUBMED:2448635]. In eukaryotic cells, K+ channels are involved in neural signalling and generation of the cardiac rhythm, act as effectors in signal transduction pathways involving G protein-coupled receptors (GPCRs) and may have a role in target cell lysis by cytotoxic T-lymphocytes [PUBMED:1373731]. In prokaryotic cells, they play a role in the maintenance of ionic homeostasis [PUBMED:11178249].

All K+ channels discovered so far possess a core of alpha subunits, each comprising either one or two copies of a highly conserved pore loop domain (P-domain). The P-domain contains the sequence (T/SxxTxGxG), which has been termed the K+ selectivity sequence. In families that contain one P-domain, four subunits assemble to form a selective pathway for K+ across the membrane. However, it remains unclear how the 2 P-domain subunits assemble to form a selective pore. The functional diversity of these families can arise through homo- or hetero-associations of alpha subunits or association with auxiliary cytoplasmic beta subunits. K+ channel subunits containing one pore domain can be assigned into one of two superfamilies: those that possess six transmembrane (TM) domains and those that possess only two TM domains. The six TM domain superfamily can be further subdivided into conserved gene families: the voltage-gated (Kv) channels; the KCNQ channels (originally known as KvLQT channels); the EAG-like K+ channels; and three types of calcium (Ca)-activated K+ channels (BK, IK and SK) [PUBMED:11178249]. The 2TM domain family comprises inward-rectifying K+ channels. In addition, there are K+ channel alpha-subunits that possess two P-domains. These are usually highly regulated K+ selective leak channels.

BK channels (also referred to as high-conductance, maxi-K channels or Slo family channels) [PUBMED:17115074] are widely expressed in the body, being found in glandular tissue, smooth and skeletal muscle, as well as in neural tissues. They have been demonstrated to regulate arteriolar and airway diameter, and also neurotransmitter release. Each channel complex is thought to be composed of 2 types of subunit; the pore-forming (alpha) subunits and smaller accessory (beta) subunits.

The alpha subunit of the BK channel was initially thought to share the characteristic 6TM organisation of the voltage-gated K+ channels. However, the molecule is now thought to possess an additional TM domain, with an extracellular N terminus and intracellular C terminus. This C-terminal region contains 4 predominantly hydrophobic domains, which are also thought to lie intracellularly. The extracellular N terminus and the first TM region are required for modulation by the beta subunit. The precise location of the Ca2+-binding site that modulates channel activation remains unknown, but it is thought to lie within the C-terminal hydrophobic domains.

The sodium-activated potassium channels Slick (Slo2.1, KCNT2) and Slack (Slo2.2, KCNT1) belong to the structurally related high-conductance potassium channels of the Slo family [PUBMED:26587966]. Slo3, also a member of the Slo family, isexclusively expressed in mammalian sperm [PUBMED:23129643].

Gene Ontology

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Domain organisation

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Pfam Clan

This family is a member of clan TrkA_C (CL0582), which has the following description:

This superfamily is characterised by families that form part of voltage-gated ion channels found in a wide range of bacteria, archaea, eukaryotes and viruses.

The clan contains the following 3 members:

BK_channel_a Castor_Poll_mid TrkA_C

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You can also download a FASTA format file containing the full-length sequences for all sequences in the full alignment.

HMM logo

HMM logos is one way of visualising profile HMMs. Logos provide a quick overview of the properties of an HMM in a graphical form. You can see a more detailed description of HMM logos and find out how you can interpret them here. More...

Trees

This page displays the phylogenetic tree for this family's seed alignment. We use FastTree to calculate neighbour join trees with a local bootstrap based on 100 resamples (shown next to the tree nodes). FastTree calculates approximately-maximum-likelihood phylogenetic trees from our seed alignment.

Note: You can also download the data file for the tree.

Curation and family details

This section shows the detailed information about the Pfam family. You can see the definitions of many of the terms in this section in the glossary and a fuller explanation of the scoring system that we use in the scores section of the help pages.

Curation View help on the curation process

Seed source: PRINTS
Previous IDs: none
Type: Family
Sequence Ontology: SO:0100021
Author: Griffiths-Jones SR
Number in seed: 88
Number in full: 2335
Average length of the domain: 96.80 aa
Average identity of full alignment: 40 %
Average coverage of the sequence by the domain: 9.03 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 45638612 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 26.8 26.8
Trusted cut-off 27.1 27.4
Noise cut-off 26.3 26.6
Model length: 98
Family (HMM) version: 18
Download: download the raw HMM for this family

Species distribution

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Colour assignments

Archea Archea Eukaryota Eukaryota
Bacteria Bacteria Other sequences Other sequences
Viruses Viruses Unclassified Unclassified
Viroids Viroids Unclassified sequence Unclassified sequence

Selections

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This visualisation provides a simple graphical representation of the distribution of this family across species. You can find the original interactive tree in the adjacent tab. More...

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Tree controls

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The tree shows the occurrence of this domain across different species. More...

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Interactions

There is 1 interaction for this family. More...

TrkA_N

Structures

For those sequences which have a structure in the Protein DataBank, we use the mapping between UniProt, PDB and Pfam coordinate systems from the PDBe group, to allow us to map Pfam domains onto UniProt sequences and three-dimensional protein structures. The table below shows the structures on which the BK_channel_a domain has been found. There are 18 instances of this domain found in the PDB. Note that there may be multiple copies of the domain in a single PDB structure, since many structures contain multiple copies of the same protein sequence.

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