BK channel: Wikis

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KCNMA1
Bkchannel.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

In the field of molecular biology, BK channels, also called Maxi-K or slo1, are ion channels which conduct potassium (K+) ions through cell membranes. These channels are activated (opened) by changes in membrane electrical potential and/or by increases in concentrations of intracellular Ca2+.[1][2] Opening of BK channels results in cell membrane hyperpolarization (an increase in the electrical potential across the cell membrane) and a decrease in cell excitability (that is a decrease in the probability that the cell will transmit an action potential).

BK channels are essential for the regulation of several key physiological processes including smooth muscle tone and neuronal excitability.[3] They control the contraction of smooth muscle and are involved with the electrical tuning of hair cells in the cochlea. BK channels are also responsible for the very high concentration (> 100 mM) behavioral effects of ethanol in the worm C. elegans.[4] It remains to be determined if BK channels contribute to low intoxicating doses of ethanol.

Contents

Structure

As with other potassium channels, MaxiK channels have a tetrameric structure. Each of the monomers in turn is formed by the association of 2 subunits: the pore-forming alpha subunit, which is the product of the KCNMA1 gene, and one of four modulatory beta subunits (encoded by KCNMB1, KCNMB2, KCNMB3, or KCNMB4). Hence the overall structure is composed of eight subunits with the stoichiometry of α4β4. Intracellular calcium regulates the physical association between the alpha and beta subunits.

BK channels are a prime example of modular evolutionary protein design. The pore forming α-subunit consists of:

  1. The K+ permeable pore domain.
  2. The voltage sensing domain that are found in all other voltage gated K+ channels.
  3. A pair of RCK domains involved in the Ca2+-activated regulation the K+ conductance.[2][5][6]
  4. A unique N-terminal transmembrane domain that is in addition to the usually 6 transmembrane domains in voltage dependent K+ channels.
  5. A unique large intracellular domain that acts as a sensor for the intracellular Ca2+ concentration.[7]

Pharmacology

BK channels are pharmacological targets for the treatment of stroke. Various pharmaceutical companies developed synthetic molecules activating these channels[8] in order to prevent excessive neurotoxic calcium entry in neurons.[9] But BMS-204352 (MaxiPost) a molecule developed by Bristol-Myers Squibb failed to improve clinical outcome in stroke patients compared to placebo.[10]
BK channels are blocked by tetraethylammonium (TEA), paxilline[11 ] and iberiotoxin.[12]

References

  1. ^ Miller C (2000). "An overview of the potassium channel family". Genome Biol. 1 (4): REVIEWS0004. doi:10.1186/gb-2000-1-4-reviews0004. PMID 11178249.  
  2. ^ a b Jiang Y, Pico A, Cadene M, Chait BT, MacKinnon R (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.  
  3. ^ "Entrez Gene: KCNMA1 potassium large conductance calcium-activated channel, subfamily M, alpha member 1". http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3778.  
  4. ^ Davies AG, Pierce-Shimomura JT, Kim H, VanHoven MK, Thiele TR, Bonci A, Bargmann CI, McIntire SL (2003). "A central role of the BK potassium channel in behavioral responses to ethanol in C. elegans". Cell 115 (6): 655–66. doi:10.1016/S0092-8674(03)00979-6. PMID 14675531.  
  5. ^ Pico A. 2003. RCK domain model of calcium activation in BK channels. PhD thesis. The Rockfeller University, New York.
  6. ^ Yusifov T, Savalli N, Gandhi CS, Ottolia M, Olcese R (2008). "The RCK2 domain of the human BKCa channel is a calcium sensor". PNAS 105 (1): 376–381. doi:10.1073/pnas.0705261105. PMID 18162557.  
  7. ^ Schreiber M, Salkoff L (1997). "A novel calcium-sensing domain in the BK channel". Biophys. J. 73 (3): 1355–63. doi:10.1016/S0006-3495(97)78168-2. PMID 9284303. http://www.biophysj.org/cgi/content/abstract/73/3/1355.  
  8. ^ Gribkoff VK, Winquist RJ (May 2005). "Voltage-gated cation channel modulators for the treatment of stroke". Expert Opin Investig Drugs 14 (5): 579–92. doi:10.1517/13543784.14.5.579. PMID 15926865.  
  9. ^ Gribkoff VK, Starrett JE, Dworetzky SI (April 2001). "Maxi-K potassium channels: form, function, and modulation of a class of endogenous regulators of intracellular calcium". Neuroscientist 7 (2): 166–77. doi:10.1177/107385840100700211. PMID 11496927. http://nro.sagepub.com/cgi/pmidlookup?view=long&pmid=11496927.  
  10. ^ Jensen BS (2002). "BMS-204352: a potassium channel opener developed for the treatment of stroke". CNS Drug Rev 8 (4): 353–60. PMID 12481191.  
  11. ^ "Paxilline, from Fermentek". http://www.fermentek.co.il/paxilline.htm.  
  12. ^ Candia S, Garcia ML, Latorre R (August 1992). "Mode of action of iberiotoxin, a potent blocker of the large conductance Ca2+-activated K+ channel". Biophys. J. 63 (2): 583–90. doi:10.1016/S0006-3495(92)81630-2. PMID 1384740. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1262182.  

See also

External links

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