BK channel

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The domain structure of BK channels
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
Identifiers
Symbol KCNMB1
Entrez 3779
HUGO 6285
OMIM 603951
RefSeq NM_004137
UniProt Q16558
Other data
Locus Chr. 5 q34
Identifiers
Symbol KCNMB2
Entrez 10242
HUGO 6286
OMIM 605214
RefSeq NM_181361
UniProt Q9Y691
Other data
Locus Chr. 3 q26.32
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
potassium large conductance calcium-activated channel, subfamily M, beta member 3-like
Identifiers
Symbol KCNMB3L
Alt. Symbols KCNMB2L, KCNMBLP
Entrez 27093
HUGO 6288
RefSeq NG_002679
Other data
Locus Chr. 22 q11.1
Identifiers
Symbol KCNMB4
Entrez 27345
HUGO 6289
OMIM 605223
RefSeq NM_014505
UniProt Q86W47
Other data
Locus Chr. 12 q15

BK channels, also called Maxi-K or slo1 channels, are large conductance Ca2+ and voltage-activated K+ channels, which allow K+ to leave the cytoplasm under physiological conditions when activated by membrane potential and/or intracellular Ca2+.[1][2] This results in hyperpolarization or a decrease in cell excitability. BK channels are essential for key physiological processes. They are important for controlling the contraction of smooth muscle and are also for electrical tuning of hair cells in the cochlea. BK channels are important for very high concentration (> 100 mM) behavioral effects of ethanol in the worm C. elegans.[3] It remains to be determined if, and how much, BK channels contribute to low intoxicating doses of ethanol (legal driving limit in most US states is 17.4 mM blood alcohol).

MaxiK channels are large conductance, voltage and calcium-sensitive potassium channels which are fundamental to the control of smooth muscle tone and neuronal excitability. MaxiK channels can be formed by 2 subunits: the pore-forming alpha subunit, which is the product of this gene, and the modulatory beta subunit. Intracellular calcium regulates the physical association between the alpha and beta subunits. Alternatively spliced transcript variants encoding different isoforms have been identified.[4]

Contents

[edit] Structure

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]


[edit] 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 paxilline[11] and iberiotoxin.[12]

[edit] 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. ^ 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. 
  4. ^ Entrez Gene: KCNMA1 potassium large conductance calcium-activated channel, subfamily M, alpha member 1.
  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. PMID 9284303. 
  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. 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.
  12. ^ Candia S, Garcia ML, Latorre R (August 1992). "Mode of action of iberiotoxin, a potent blocker of the large conductance Ca(2+)-activated K+ channel". Biophys. J. 63 (2): 583–90. PMID 1384740. 

[edit] See also

[edit] External links

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Membrane transport protein: ion channels
Ca2+: Calcium channel
Na+: Sodium channel
Navα (1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.9, 7A) • Navβ (1, 2, 3, 4) • Epithelial sodium channel
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