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14  structures 339  species 1  interaction 1424  sequences 24  architectures

Family: BK_channel_a (PF03493)

Summary: Calcium-activated BK potassium channel alpha subunit

Pfam includes annotations and additional family information from a range of different sources. These sources can be accessed via the tabs below.

This is the Wikipedia entry entitled "BK channel". More...

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
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 called Maxi-K or slo1, are potassium channels characterized by their large conductance for potassium ions (K+) through cell membranes. These channels are activated (opened) by changes in membrane electrical potential and/or by increases in concentration of intracellular calcium ion (Ca2+).[1][2] Opening of BK channels allows K+ to passively flow through the channel, down the electrochemical gradient. Under typical physiological conditions, this results in an efflux of K+ from the cell, which leads to cell membrane hyperpolarization (an increase in the electrical potential across the cell membrane) and a decrease in cell excitability (a decrease in the probability that the cell will transmit an action potential).[3]

BK channels are essential for the regulation of several key physiological processes including smooth muscle tone and neuronal excitability.[4] They control the contraction of smooth muscle and are involved with the electrical tuning of hair cells in the cochlea. BK channels also contribute to the behavioral effects of ethanol in the worm C. elegans under high exogenous doses (> 100 mM) [5] that have been shown to correspond to biologically relevant internal ethanol concentrations.[6] It remains to be determined if BK channels contribute to intoxication in humans.

Structure

As with most other voltage-gated potassium channels, BK channels have a tetrameric structure. Each monomer of the channel-forming alpha subunit is the product of the KCNMA1 gene. Modulatory beta subunits (encoded by KCNMB1, KCNMB2, KCNMB3, or KCNMB4) can associate with the tetrametic channel.

BK channels are a prime example of modular protein evolution. Each BK channel alpha subunit consists of (from N- to C-terminal):

  1. A unique transmembrane domain (S0)[7] that precedes the 6 transmembrane domains (S1-S6) conserved in all voltage-dependent K+ channels.
  2. A voltage sensing domain (S1-S4).
  3. A K+ channel pore domain (S5, selectivity filter, and S6).
  4. A cytoplasmic C-terminal domain (CTD) consisting of a pair of RCK (Regulator of Conductance of K+) domains that assemble into an octameric gating ring on the intracellular side of the tetrameric channel.[8][9][10][11][12] The CTD contains four primary binding sites for Ca2+, called "calcium bowls", encoded within the second RCK domain of each monomer.[2][8][12][13]

Available X-ray structures:

  • 3MT5​ - Crystal Structure of the Human BK Gating Apparatus[2]
  • 3NAF​ - Structure of the Intracellular Gating Ring from the Human High-conductance Ca2+ gated K+ Channel (BK Channel)[8]
  • 3U6N​ - Open Structure of the BK channel Gating Ring[13]

Pharmacology

BK channels are pharmacological targets for the treatment of several medical disorders including stroke[14] and overactive bladder.[15] Although pharmaceutical companies have attempted to develop synthetic molecules targeting BK channels,[16] their efforts have proved largely ineffective. For instance, BMS-204352, a molecule developed by Bristol-Myers Squibb, failed to improve clinical outcome in stroke patients compared to placebo.[17] However, BKCa channels are reduced in patients suffering from the Fragile X syndrome[18] and the agonist, BMS-204352, corrects some of the deficits observed in Fmr1 knockout mice, a model of Fragile X syndrome.[19]

BK channels have also been found to be activated by exogenous pollutants and endogenous gasotransmitters carbon monoxide[20][21] and hydrogen sulphide.[22]

BK channels can be readily inhibited by a range of compounds including tetraethylammonium (TEA), paxilline,[23] Limbatustoxin, and iberiotoxin.[24]

The BKCa-channel blocker GAL-021 has been investigated for potential use in inhibiting opioid induced respiratory depression without affecting analgesia.[25][26]

See also

References

  1. ^ Miller C (2000). "An overview of the potassium channel family". Genome Biology. 1 (4): REVIEWS0004. PMC 138870 Freely accessible. PMID 11178249. doi:10.1186/gb-2000-1-4-reviews0004. 
  2. ^ a b c Yuan P, Leonetti MD, Pico AR, Hsiung Y, MacKinnon R (Jul 2010). "Structure of the human BK channel Ca2+-activation apparatus at 3.0 A resolution". Science. 329 (5988): 182–6. PMC 3022345 Freely accessible. PMID 20508092. doi:10.1126/science.1190414. 
  3. ^ Kyle BD (Aug 2014). "Ion Channels of the Mammalian Urethra". Channels. 8 (5): 393–401. PMC 4594508 Freely accessible. PMID 25483582. doi:10.4161/19336950.2014.954224. 
  4. ^ EntrezGene 3778
  5. ^ Davies AG, Pierce-Shimomura JT, Kim H, VanHoven MK, Thiele TR, Bonci A, Bargmann CI, McIntire SL (Dec 2003). "A central role of the BK potassium channel in behavioral responses to ethanol in C. elegans". Cell. 115 (6): 655–66. PMID 14675531. doi:10.1016/S0092-8674(03)00979-6. 
  6. ^ Alaimo JT, Davis SJ, Song SS, Burnette CR, Grotewiel M, Shelton KL, Pierce-Shimomura JT, Davies AG, Bettinger JC (Nov 2012). "Ethanol metabolism and osmolarity modify behavioral responses to ethanol in C. elegans". Alcoholism: Clinical and Experimental Research. 36 (11): 1840–50. PMC 3396773 Freely accessible. PMID 22486589. doi:10.1111/j.1530-0277.2012.01799.x. 
  7. ^ Wallner M, Meera P, Toro L (Dec 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 26238 Freely accessible. PMID 8962157. doi:10.1073/pnas.93.25.14922. 
  8. ^ a b c Wu Y, Yang Y, Ye S, Jiang Y (Jul 2010). "Structure of the gating ring from the human large-conductance Ca(2+)-gated K(+) channel". Nature. 466 (7304): 393–7. PMC 2910425 Freely accessible. PMID 20574420. doi:10.1038/nature09252. 
  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. PMID 11301020. doi:10.1016/S0896-6273(01)00236-7. 
  10. ^ Pico AR (2003). RCK domain model of calcium activation in BK channels (PhD thesis). New York: The Rockfeller University. 
  11. ^ Yusifov T, Savalli N, Gandhi CS, Ottolia M, Olcese R (Jan 2008). "The RCK2 domain of the human BKCa channel is a calcium sensor". Proceedings of the National Academy of Sciences of the United States of America. 105 (1): 376–381. PMC 2224220 Freely accessible. PMID 18162557. doi:10.1073/pnas.0705261105. 
  12. ^ a b Schreiber M, Salkoff L (Sep 1997). "A novel calcium-sensing domain in the BK channel". Biophysical Journal. 73 (3): 1355–63. PMC 1181035 Freely accessible. PMID 9284303. doi:10.1016/S0006-3495(97)78168-2. 
  13. ^ a b Yuan P, Leonetti MD, Hsiung Y, MacKinnon R (Jan 2012). "Open structure of the Ca2+ gating ring in the high-conductance Ca2+-activated K+ channel". Nature. 481 (7379): 94–7. PMC 3319005 Freely accessible. PMID 22139424. doi:10.1038/nature10670. 
  14. ^ 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. PMID 11496927. doi:10.1177/107385840100700211. 
  15. ^ 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. PMC 2828174 Freely accessible. PMID 19923353. doi:10.1152/ajpregu.00458.2009. 
  16. ^ 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. PMID 15926865. doi:10.1517/13543784.14.5.579. 
  17. ^ Jensen BS (2002). "BMS-204352: a potassium channel opener developed for the treatment of stroke". CNS Drug Reviews. 8 (4): 353–60. PMID 12481191. doi:10.1111/j.1527-3458.2002.tb00233.x. 
  18. ^ 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. PMID 16946189. doi:10.1176/ajp.2006.163.9.1622. 
  19. ^ 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. PMC 4237919 Freely accessible. PMID 25079250. doi:10.1186/s13023-014-0124-6. 
  20. ^ Dubuis E, Potier M, Wang R, Vandier C (Feb 2005). "Continuous inhalation of carbon monoxide attenuates hypoxic pulmonary hypertension development presumably through activation of BKCa channels". Cardiovascular Research. 65 (3): 751–61. PMID 15664403. doi:10.1016/j.cardiores.2004.11.007. 
  21. ^ 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. PMC 2268785 Freely accessible. PMID 18316727. doi:10.1073/pnas.0800304105. 
  22. ^ 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. PMID 19802723. doi:10.1007/s00424-009-0737-0. 
  23. ^ "Paxilline, from Fermentek". Archived from the original on 2008-05-17. 
  24. ^ Candia S, Garcia ML, Latorre R (Aug 1992). "Mode of action of iberiotoxin, a potent blocker of the large conductance Ca(2+)-activated K+ channel". Biophysical Journal. 63 (2): 583–90. PMC 1262182 Freely accessible. PMID 1384740. doi:10.1016/S0006-3495(92)81630-2. 
  25. ^ McLeod JF, Leempoels JM, Peng SX, Dax SL, Myers LJ, Golder FJ (Nov 2014). "GAL-021, a new intravenous BKCa-channel blocker, is well tolerated and stimulates ventilation in healthy volunteers". Br J Anaesth. 113 (5): 875–83. PMID 24989775. doi:10.1093/bja/aeu182. 
  26. ^ Golder, Francis J.; Dax, Scott; Baby, Santhosh M.; Gruber, Ryan; Hoshi, Toshinori; Ideo, Courtney; Kennedy, Andrew; Peng, Sean; Puskovic, Veljko; Ritchie, David; Woodward, Richard; Wardle, Robert L.; Van Scott, Michael R.; Mannion, James C.; MacIntyre, D. Euan (2015). "Identification and Characterization of GAL-021 as a Novel Breathing Control Modulator". Anesthesiology. 123 (5): 1093–1104. ISSN 0003-3022. PMID 26352381. doi:10.1097/ALN.0000000000000844. 

External links

This page is based on a Wikipedia article. The text is available under the Creative Commons Attribution/Share-Alike License.

This tab holds the annotation information that is stored in the Pfam database. As we move to using Wikipedia as our main source of annotation, the contents of this tab will be gradually replaced by the Wikipedia tab.

Calcium-activated BK potassium channel alpha subunit Provide feedback

No Pfam abstract.

This tab holds annotation information from the InterPro database.

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.

Ca2+-activated K+ channels are a diverse group of channels that are activated by an increase in intracellular Ca2+ concentration. They are found in the majority of nerve cells, where they modulate cell excitability and action potential. Three types of Ca2+-activated K+ channel have been characterised, termed small-conductance (SK), intermediate conductance (IK) and large conductance (BK) respectively [PUBMED:9687354].

BK channels (also referred to as maxi-K channels) 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.

Gene Ontology

The mapping between Pfam and Gene Ontology is provided by InterPro. If you use this data please cite InterPro.

Cellular component membrane (GO:0016020)
Molecular function calcium-activated potassium channel activity (GO:0015269)
Biological process potassium ion transport (GO:0006813)

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

Alignments

We store a range of different sequence alignments for families. As well as the seed alignment from which the family is built, we provide the full alignment, generated by searching the sequence database (reference proteomes) using the family HMM. We also generate alignments using four representative proteomes (RP) sets, the UniProtKB sequence database, the NCBI sequence database, and our metagenomics sequence database. More...

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  Seed
(93)		 Full
(1424)		 Representative proteomes UniProt
(2168)		 NCBI
(7456)		 Meta
(7)
RP15
(349)		 RP35
(565)		 RP55
(813)		 RP75
(997)
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  Seed
(93)		 Full
(1424)		 Representative proteomes UniProt
(2168)		 NCBI
(7456)		 Meta
(7)
RP15
(349)		 RP35
(565)		 RP55
(813)		 RP75
(997)
Alignment:
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  Seed
(93)		 Full
(1424)		 Representative proteomes UniProt
(2168)		 NCBI
(7456)		 Meta
(7)
RP15
(349)		 RP35
(565)		 RP55
(813)		 RP75
(997)
Raw Stockholm Download   Download   Download   Download   Download   Download   Download   Download   Download  
Gzipped Download   Download   Download   Download   Download   Download   Download   Download   Download  

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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.

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Curation and family details

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Seed source: PRINTS
Previous IDs: none
Type: Family
Author: Griffiths-Jones SR
Number in seed: 93
Number in full: 1424
Average length of the domain: 96.90 aa
Average identity of full alignment: 36 %
Average coverage of the sequence by the domain: 9.31 %

HMM information View help on HMM parameters

HMM build commands:
build method: hmmbuild -o /dev/null HMM SEED
search method: hmmsearch -Z 26740544 -E 1000 --cpu 4 HMM pfamseq
Model details:
Parameter Sequence Domain
Gathering cut-off 26.8 26.8
Trusted cut-off 27.1 26.9
Noise cut-off 26.6 26.7
Model length: 99
Family (HMM) version: 17
Download: download the raw HMM for this family

Species distribution

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Archea Archea Eukaryota Eukaryota
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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 14 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 seqence.

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