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Functions of SK Channels in Central Neurons

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Functions of SK Channels in Central Neurons Proceedings of the Australian Physiological Society (2007) 38: 25-34 http://www.aups.org.au/Proceedings/38/25-34 ©E.S.L. Faber 2007 Functions of SK channels in central neurons E.S. Louise Faber and Pankaj Sah Queensland Brain Institute,University of Queensland, St Lucia, QLD 4072, Australia Summary only share significant homology with voltage-gated potassium channels in the pore region3 (Figure 1b). SK 1. SK channels are small conductance calcium- channels lack an obvious calcium-binding domain and their activated potassium channels that are widely expressed in calcium sensitivity is conferred by calmodulin, which is neurons. The traditional viewofthe functional role of SK constitutively bound to the C terminus of the channel and channels is in mediating one component of the causes channel opening upon binding of calcium.9-11 afterhyperpolarisation that follows action potentials. In situ hybridisation3,12,13 and Calcium influx via voltage-gated calcium channels active immunohistochemistry14,15 have shown that SK channels during action potentials opens SK channels and the are widely expressed throughout the central nervous resultant hyperpolarisation lowers the firing frequencyof system. SK1 and SK2 subunits are expressed at their action potentials in manyneurons. highest density in the hippocampus and cortex, whereas 2. Recent advances have shown that in addition to SK3 subunits are expressed at their highest levels in regions controlling action potential firing frequency, SKchannels such as the hypothalamus, thalamus and midbrain. When are also important in regulating dendritic excitability, expressed as homomultimers,3 SK channel subunits form synaptic transmission and synaptic plasticity. ion channels that have functional characteristics typical of 3. In accordance with their role in modulating apamin-sensitive currents in neurons. Thus, theyrespond synaptic plasticity,SKchannels are also important in rapidly to calcium and are voltage-independent.16 While SK regulating several learning and memory tasks, and may also channels can assemble as heteromultimers in expression play a role in a number of neurological disorders. systems,17,18 immunoprecipitation studies suggest that 4. The present reviewwill discuss recent findings on native channels are homomultimers.15,19,20 the role of SK channels in central neurons. Several types of calcium-activated potassium channels are known to be present in neurons21 and SK Introduction channels were initially distinguished by their potent block 1,22,23 SK channels are calcium-activated potassium by the bee venom apamin. The measured IC50 of SK channels that have been termed as such due to their channels for apamin is 63 pM for SK2,3 2nMfor SK3,24 relatively small single channel conductance of and between 3.3 nM and 12 nM for SK1 channels25,26 approximately 10 pS.1,2 Three types of SK channels have (Table 1). SK channels are also blocked by the scorpion been cloned from mammalian systems: SK1, SK2, and toxin scyllatoxin,27-29 tubocurarine, quaternary salts of SK3, encoded for by KCNN1, KCNN2 and KCNN3, bicuculline,30,31 dequalinium, UCL1848 and a large set of respectively3 (Figure 1). Each of these genes has splice related bis-quinolinium cyclophanes25,32-34 (See Table 1 for variants. 20 SK1 splice variants have been detected in IC50 values). Recently SK2 channels have been found to be mouse brains.4 Tw o isoforms of SK2 protein have been selectively blocked by the scorpion toxin tamapin35 and by described in the mouse brain, a short isoform and a long Lei-Dab36 (Table 1). Conversely SK channel-mediated isoform with an extended N terminus.5 SK3 is reported to currents can be enhanced by 1-ethyl-2-benzimidazolinone have two splice variants in human brain, with the truncated (EBIO), which enhances their calcium sensitivity and open SK3 channel protein behaving as a dominant negative toSK probability37,40 and by NS30941 (Table 2). channels.6 However, other than the truncated form of SK3, Modulation of SK channels the functional roles and locations of the other SK channel splice variants are unknown. Manyion channels contain consensus SK channels are insensitive tochanges in membrane phosphorylation sites for protein kinases and potential but are activated by rises in cytosolic calcium with phosphorylation of some of these has been found to 1,7 ahalf maximal activation in the 300–800 nM range. modulate function or trafficking of channels. To date there These channels are structurally similar to voltage-dependent have been fewdemonstrations of modulation of SK potassium channels with six putative transmembrane channels. Despite containing several potential spanning regions and cytoplasmic carboxy and amino phosphorylation sites for protein kinase A and protein terminals (Figure 1a), and are thought to assemble as kinase C, biophysical evidence for modulation of SK 8 tetramers. Their primary structure shows approximately channels by these kinases has been lacking. Interestingly, 60% sequence homology with each other but SK channels SK2 channels have been shown to co-assemble with casein Proceedings of the Australian Physiological Society (2007) 38 25 SK channels in neurons A extracellular S1 S2 S3 S4 S5 S6 intracellular NH2 COOH B 1 - - - - - - - - - - - - - - - M P G P R A A C S - - - - - - - E - - - - - - - - - - - - - - - - - - P - - - - - - - N - KCNN1 1 - - - - - - - - - - - - - - - - - - - M S S C R Y N G G - V M R - - - - - - - - - - - - - - - - - - P - - - - - - - L S KCNN2 1 M D T S G H F H D S G V G D L D E D P K C P C P S S G D E Q Q Q Q Q Q Q Q Q Q Q Q P P P P A P P A A P Q Q P L G P S L Q KCNN3 13 - - - P C T Q V V M N S H S Y N G S V G R P L G S G P G A L G R D P P - - - - - - D P E A G H P P Q P P H S P G L Q V V KCNN1 16 N L S A S R R N L H E M D S E A Q P L Q P P A S V G G G G G A S S - P - - - - - - - S A D A A A A A A V S S S A P E I V KCNN2 61 P Q P P Q L Q Q Q Q Q Q Q Q Q Q Q Q Q Q P P H P L S Q L A Q L Q S Q P V H P G L L H S S P T A F R A P P S S N S T A I L KCNN3 64 V A K S E P A R P S P G S P R G Q P Q D Q D D D E D D E E D E A G R Q R A S G - - - - - - - - - - - - - - - - - - - - - KCNN1 68 V S K P E H N N S N N L A L Y G T G G G - G S T G G G G G G G G S G H G S S S - - - - - - - - - - - - - - - - - - - - - KCNN2 121 H P S S R Q G S Q L N L N D H L L G H S P S S T A T S G P G G G S R H R Q A S P L V H R R D S N P F T E I A M S S C K Y KCNN3 103 - - - K P S - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - KCNN1 106 - - - G T K - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - KCNN2 181 S G G V M K P L S R L S A S R R N L I E A E T E G Q P L Q L F S P S N P P E I V I S S R E D N H A H Q T L L H H P N A T KCNN3 106 - - - - - - - - - - - - - - - - - - - - - - - - N V G H R L G H R R A L F E K R K R L S D Y A L I F G M F G I V V M V T KCNN1 109 - - - - - - - - - - - - S - - - - - S K K K N Q N I G Y K L G H R R A L F E K R K R L S D Y A L I F G M F G I V V M V I KCNN2 241 H N H Q H A G T T A S S T T F P K A N K R K N Q N I G Y K L G H R R A L F E K R K R L S D Y A L I F G M F G I V V M V I KCNN3 142 E T E L S W G V Y T K E S L Y S F A L K C L I S L S T A I L L G L V V L Y H A R E I Q L F M V D N G A D D W R I A M T C KCNN1 152 E T E L S W G A Y D K A S L Y S L A L K C L I S L S T I I L L G L I I V Y H A R E I Q L F M V D N G A D D W R I A M T Y KCNN2 301 E T E L S W G L Y S K D S M F S L A L K C L I S L S T I I L L G L I I A Y H T R E V Q L F V I D N G A D D W R I A M T Y KCNN3 202 E R V F L I S L E L A V C A I H P V P G H Y R F T W T A R L A F T Y A P S V A E A D V D V L L S I P M F L R L Y L L G R KCNN1 212 E R I F F I C L E I L V C A I H P I P G N Y T F T W T A R L A F S Y A P S T T T A D V D I I L S I P M F L R L Y L I A R KCNN2 361 E R I L Y I S L E M L V C A I H P I P G E Y K F F W T A R L A F S Y T P S R A E A D V D I I L S I P M F L R L Y L I A R KCNN3 262 V M L L H S K I F T D A S S R S I G A L N K I T F N T R F V M K T L M T I C P G T V L L V F S I S S W I I A A W T V R V KCNN1 272 V M L L H S K L F T D A S S R S I G A L N K I N F N T R F V M K T L M T I C P G T V L L V F S I S L W I I A A W T V R A KCNN2 421 V M L L H S K L F T D A S S R S I G A L N K I N F N T R F V M K T L M T I C P G T V L L V F S I S L W I I A A W T V R V KCNN3 322 C E R Y H D K Q E V T S N F L G A M W L I S I T F L S I G Y G D M V P H T Y C G K G V C L L T G I M G A G C T A L V V A KCNN1 332 C E R Y H D Q Q D V T S N F L G A M W L I S I T F L S I G Y G D M V P N T Y C G K G V C L L T G I M G A G C T A L V V A KCNN2 481 C E R Y H D Q Q D V T S N F L G A M W L I S I T F L S I G Y G D M V P H T Y C G K G V C L L T G I M G A G C T A L V V A KCNN3 382 V V A R K L E L T K A E K H V H N F M M D T Q L T K R V K N A A A N V L R E T W L I Y K H T R L V K K P D Q A R V R K H KCNN1 392 V V A R K L E L T K A E K H V H N F M M D T Q L T K R V K N A A A N V L R E T W L I Y K N T K L V K K I D H A K V R K H KCNN2 541 V V A R K L E L T K A E K H V H N F M M D T Q L T K R I K N A A A N V L R E T W L I Y K H T K L L K K I D H A K V R K H KCNN3 442 Q R K F L Q A I H Q A Q K L R S V K I E Q G K L N D Q A N T L T D L A K T Q T V M Y D L V S E L H A Q H E E L E A R L A KCNN1 452 Q R K F L Q A I H Q - - - L R S V K M E Q R K L N D Q A N T L V D L A K T Q N I M Y D M I S D L N E R S E D F E K R I V KCNN2 601 Q R K F L Q A I H Q - - - L R S V K M E Q R K L S D Q A N T L V D L S K M Q N V M Y D L I T E L N D R S E D L E K Q I G KCNN3 502 T L E S R L D A L G A S L Q A L P G L I A Q A I R P P P P P L P P - - - - - - - R - P G P G P Q D Q A A R S S P C R W T KCNN1 509 T L E T K L E T L I G S I H A L P G L I S Q T I R Q Q Q R D F I E A Q M E S Y D K H V T Y N A E R S R S S S R R R R S S KCNN2 658 S L E S K L E H L T A S F N S L P L L I A D T L R Q Q Q Q Q L L S A I I E A R G V S V A V G T T H T P I S D S P I G V S KCNN3 554 P V A P S D C G KCNN1 569 S T A P P T S S E S S KCNN2 718 S T S F P T P Y T S S S S C KCNN3 Figure 1.
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