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SK channels (Small conductance calcium-activated K (potassium) channels) are a subfamily of Ca2+-activated K+ channels.[1] 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. Their activation limits the firing frequency of action potentials and are important for regulating afterhyperpolarization in central neurons and other types of electrically excitable cells.[2] SK channels are thought to be involved in synaptic plasticity and therefore play important roles in memory and learning.[3]

Contents

Structure

SK potassium channels share the same basic architecture with shaker-like voltage-gated potassium channels.[4] Four identical subunits associate to form a symmetric tetramer. Each of the subunits has six hydrophobic alpha helical domains which insert into the cell membrane. A loop between the fifth and sixth trans membrane domain forms the potassium ion selectivity filter.

In addition, SK potassium channels are tightly associated with the protein calmodulin which accounts for the calcium sensitivity of these channels.[4][5]

Classification

The SK channel family contains 4 members - SK1, SK2, SK3, and SK4.

Channel Gene Aliases Associated subunits
SK1 KCNN1 Kca2.1 calmodulin
SK2 KCNN2 Kca2.2 "
SK3 KCNN3 Kca2.3 "
SK4 KCNN4 Kca3.1 "

Blockers

All SK channels can be pharmacologically blocked by quaternary ammonium salts of a plant-derived neurotoxin bicuculline.[6] In addition, SK channels(SK1-SK3) are sensitive to blockade by the bee venom apamin, [7] but SK4 (IK) is not. and the scorpion venom tamapin.[8]

Modulators

Allosteric modulators of SK channels work by changing the apparent calcium sensitivity of the channels. Examples include:

  • Non selective positive modulators of SK channels: EBIO (1-Ethyl-2-BenzimIdazolin One),[9] NS309 (6,7-dichloro-1H-indole-2,3-dione 3-oxime)[10]
  • SK-3 selective positive modulators : CyPPA (NS6277; Cyclohexyl-(2-(3,5-dimethyl-Pyrazol-1-yl)-6-methyl- Pyrimidin-4-yl)-Amine)[11]
Chemical structure of SK ion channel modulators.


References

  1. ^ Bond CT, Maylie J, Adelman JP (1999). "Small-conductance calcium-activated potassium channels". Ann. N. Y. Acad. Sci. 868: 370–8. doi:10.1111/j.1749-6632.1999.tb11298.x. PMID 10414306. http://www.annalsnyas.org/cgi/content/abstract/868/1/370.  
  2. ^ Faber ES, Sah P (2007). "Functions of SK channels in central neurons". Clin. Exp. Pharmacol. Physiol. 34 (10): 1077–83. doi:10.1111/j.1440-1681.2007.04725.x. PMID 17714097.  
  3. ^ Stackman RW, Hammond RS, Linardatos E, Gerlach A, Maylie J, Adelman JP, Tzounopoulos T (2002). "Small conductance Ca2+-activated K+ channels modulate synaptic plasticity and memory encoding". J. Neurosci. 22 (23): 10163–71. PMID 12451117. http://www.jneurosci.org/cgi/content/abstract/22/23/10163.  
  4. ^ a b Maylie J, Bond CT, Herson PS, Lee WS, Adelman JP (2004). "Small conductance Ca2+-activated K+ channels and calmodulin". J. Physiol. (Lond.) 554 (Pt 2): 255–61. doi:10.1113/jphysiol.2003.049072. PMID 14500775.  
  5. ^ Schumacher MA, Rivard AF, Bächinger HP, Adelman JP (2001). "Structure of the gating domain of a Ca2+-activated K+ channel complexed with Ca2+/calmodulin". Nature 410 (6832): 1120–4. doi:10.1038/35074145. PMID 11323678.  
  6. ^ Khawaled R, Bruening-Wright A, Adelman JP, Maylie J (1999). "Bicuculline block of small-conductance calcium-activated potassium channels". Pflugers Arch. 438 (3): 314–21. doi:10.1007/s004240050915. PMID 10398861.  
  7. ^ Blatz AL, Magleby KL (1986). "Single apamin-blocked Ca-activated K+ channels of small conductance in cultured rat skeletal muscle". Nature 323 (6090): 718–20. doi:10.1038/323718a0. PMID 2430185.  
  8. ^ Pedarzani P, D'hoedt D, Doorty KB, Wadsworth JD, Joseph JS, Jeyaseelan K, Kini RM, Gadre SV, Sapatnekar SM, Stocker M, Strong PN (2002). "Tamapin, a venom peptide from the Indian red scorpion (Mesobuthus tamulus) that targets small conductance Ca2+-activated K+ channels and afterhyperpolarization currents in central neurons". J. Biol. Chem. 277 (48): 46101–9. doi:10.1074/jbc.M206465200. PMID 12239213.  
  9. ^ Pedarzani P, Mosbacher J, Rivard A, Cingolani LA, Oliver D, Stocker M, Adelman JP, Fakler B (2001). "Control of electrical activity in central neurons by modulating the gating of small conductance Ca2+-activated K+ channels". J. Biol. Chem. 276 (13): 9762–9. doi:10.1074/jbc.M010001200. PMID 11134030.  
  10. ^ Strøbaek D, Teuber L, Jørgensen TD, Ahring PK, Kjaer K, Hansen RS, Olesen SP, Christophersen P, Skaaning-Jensen B (2004). "Activation of human IK and SK Ca2+-activated K+ channels by NS309 (6,7-dichloro-1H-indole-2,3-dione 3-oxime)". Biochim. Biophys. Acta 1665 (1-2): 1–5. doi:10.1016/j.bbamem.2004.07.006. PMID 15471565.  
  11. ^ Hougaard C, Eriksen BL, Jørgensen S, Johansen TH, Dyhring T, Madsen LS, Strøbaek D, Christophersen P (2007). "Selective positive modulation of the SK3 and SK2 subtypes of small conductance Ca2+-activated K+ channels". Br. J. Pharmacol. 151 (5): 655–65. doi:10.1038/sj.bjp.0707281. PMID 17486140.  

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