The SK2-long isoform directs synaptic localization and function of SK2-containing channels

Article metrics


SK2-containing channels are expressed in the postsynaptic density (PSD) of dendritic spines on mouse hippocampal area CA1 pyramidal neurons and influence synaptic responses, plasticity and learning. The Sk2 gene (also known as Kcnn2) encodes two isoforms that differ only in the length of their N-terminal domains. SK2-long (SK2-L) and SK2-short (SK2-S) are coexpressed in CA1 pyramidal neurons and likely form heteromeric channels. In mice lacking SK2-L (SK2-S only mice), SK2-S–containing channels were expressed in the extrasynaptic membrane, but were excluded from the PSD. The SK channel contribution to excitatory postsynaptic potentials was absent in SK2-S only mice and was restored by SK2-L re-expression. Blocking SK channels increased the amount of long-term potentiation induced in area CA1 in slices from wild-type mice but had no effect in slices from SK2-S only mice. Furthermore, SK2-S only mice outperformed wild-type mice in the novel object recognition task. These results indicate that SK2-L directs synaptic SK2-containing channel expression and is important for normal synaptic signaling, plasticity and learning.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1: Subcellular localization of SK2-L in dendritic spines of wild-type CA1 pyramidal neurons.
Figure 2: Sk2 gene locus and western blot.
Figure 3: Subcellular localization of SK2 in wild-type and SK2-S only CA1 pyramidal neurons.
Figure 4: SK2-containing channels are expressed in the plasma membrane of SK2-S only CA1 pyramidal neurons.
Figure 5: SK2-L re-expression re-instates apamin sensitivity to synaptically evoked glutamatergic EPSPs.
Figure 6: SK channel activity affects LTP in wild-type, but not SK2-S only, mice.
Figure 7: Spatial memory is impaired in SK2-S only mice.


  1. 1

    Bredt, D.S. & Nicoll, R.A. AMPA receptor trafficking at excitatory synapses. Neuron 40, 361–379 (2003).

  2. 2

    Petralia, R.S. & Wenthold, R.J. Light and electron immunocytochemical localization of AMPA-selective glutamate receptors in the rat brain. J. Comp. Neurol. 318, 329–354 (1992).

  3. 3

    Carroll, R.C. & Zukin, R.S. NMDA-receptor trafficking and targeting: implications for synaptic transmission and plasticity. Trends Neurosci. 25, 571–577 (2002).

  4. 4

    Adesnik, H., Nicoll, R.A. & England, P.M. Photoinactivation of native AMPA receptors reveals their real-time trafficking. Neuron 48, 977–985 (2005).

  5. 5

    Harris, A.Z. & Pettit, D.L. Recruiting extrasynaptic NMDA receptors augments synaptic signaling. J. Neurophysiol. 99, 524–533 (2008).

  6. 6

    Makino, H. & Malinow, R. AMPA receptor incorporation into synapses during LTP: the role of lateral movement and exocytosis. Neuron 64, 381–390 (2009).

  7. 7

    Derkach, V.A., Oh, M.C., Guire, E.S. & Soderling, T.R. Regulatory mechanisms of AMPA receptors in synaptic plasticity. Nat. Rev. Neurosci. 8, 101–113 (2007).

  8. 8

    van Zundert, B., Yoshii, A. & Constantine-Paton, M. Receptor compartmentalization and trafficking at glutamate synapses: a developmental proposal. Trends Neurosci. 27, 428–437 (2004).

  9. 9

    Bellone, C. & Nicoll, R.A. Rapid bidirectional switching of synaptic NMDA receptors. Neuron 55, 779–785 (2007).

  10. 10

    Köhler, M. et al. Small-conductance, calcium-activated potassium channels from mammalian brain. Science 273, 1709–1714 (1996).

  11. 11

    Lin, M.T., Lujan, R., Watanabe, M., Adelman, J.P. & Maylie, J. SK2 channel plasticity contributes to LTP at Schaffer collateral-CA1 synapses. Nat. Neurosci. 11, 170–177 (2008).

  12. 12

    Ngo-Anh, T.J. et al. SK channels and NMDA receptors form a Ca2+-mediated feedback loop in dendritic spines. Nat. Neurosci. 8, 642–649 (2005).

  13. 13

    Bloodgood, B.L. & Sabatini, B.L. Nonlinear regulation of unitary synaptic signals by CaV(2.3) voltage-sensitive calcium channels located in dendritic spines. Neuron 53, 249–260 (2007).

  14. 14

    Stackman, R.W. et al. Small conductance Ca2+-activated K+ channels modulate synaptic plasticity and memory encoding. J. Neurosci. 22, 10163–10171 (2002).

  15. 15

    Hammond, R.S. et al. Small-conductance Ca2+-activated K+ channel type 2 (SK2) modulates hippocampal learning, memory, and synaptic plasticity. J. Neurosci. 26, 1844–1853 (2006).

  16. 16

    Stackman, R.W. Jr., Bond, C.T. & Adelman, J.P. Contextual memory deficits observed in mice overexpressing small conductance Ca2+-activated K+ type 2 (KCa2.2, SK2) channels are caused by an encoding deficit. Learn. Mem. 15, 208–213 (2008).

  17. 17

    Vick, K.A. IV, Guidi, M. & Stackman, R.W. Jr. In vivo pharmacological manipulation of small conductance Ca2+-activated K+ channels influences motor behavior, object memory and fear conditioning. Neuropharmacology 58, 650–659 (2010).

  18. 18

    Lin, M.T. et al. Coupled activity-dependent trafficking of synaptic SK2 channels and AMPA receptors. J. Neurosci. 30, 11726–11734 (2010).

  19. 19

    Strassmaier, T. et al. A novel isoform of SK2 assembles with other SK subunits in mouse brain. J. Biol. Chem. 280, 21231–21236 (2005).

  20. 20

    Bond, C.T. et al. Small conductance Ca2+-activated K+ channel knock-out mice reveal the identity of calcium-dependent afterhyperpolarization currents. J. Neurosci. 24, 5301–5306 (2004).

  21. 21

    Bond, C.T. et al. Respiration and parturition affected by conditional overexpression of the Ca2+-activated K+ channel subunit, SK3. Science 289, 1942–1946 (2000).

  22. 22

    Stocker, M., Krause, M. & Pedarzani, P. An apamin-sensitive Ca2+-activated K+ current in hippocampal pyramidal neurons. Proc. Natl. Acad. Sci. USA 96, 4662–4667 (1999).

  23. 23

    Kye, M.J., Spiess, J. & Blank, T. Transcriptional regulation of intronic calcium-activated potassium channel SK2 promoters by nuclear factor-kappa B and glucocorticoids. Mol. Cell. Biochem. 300, 9–17 (2007).

  24. 24

    Davuluri, R.V., Suzuki, Y., Sugano, S., Plass, C. & Huang, T.H. The functional consequences of alternative promoter use in mammalian genomes. Trends Genet. 24, 167–177 (2008).

  25. 25

    Stocker, M. & Pedarzani, P. Differential distribution of three Ca2+-activated K+ channel subunits, SK1, SK2, and SK3, in the adult rat central nervous system. Mol. Cell. Neurosci. 15, 476–493 (2000).

  26. 26

    Lu, W., Isozaki, K., Roche, K.W. & Nicoll, R.A. Synaptic targeting of AMPA receptors is regulated by a CaMKII site in the first intracellular loop of GluA1. Proc. Natl. Acad. Sci. USA 107, 22266–22271 (2010).

  27. 27

    Luján, R., Nusser, Z., Roberts, J.D., Shigemoto, R. & Somogyi, P. Perisynaptic location of metabotropic glutamate receptors mGluR1 and mGluR5 on dendrites and dendritic spines in the rat hippocampus. Eur. J. Neurosci. 8, 1488–1500 (1996).

  28. 28

    Fujimoto, K. Freeze-fracture replica electron microscopy combined with SDS digestion for cytochemical labeling of integral membrane proteins. Application to the immunogold labeling of intercellular junctional complexes. J. Cell Sci. 108, 3443–3449 (1995).

Download references


We thank K. Vick, C. Christakis and K. Smith (all from FAU) for their expert assistance with the behavioral testing. This work was supported by US National Institutes of Health grants NS038880 (J.P.A.), MH081860-01 (J.M.), F32MH080480 (M.T.L.) and MH0876591-01 (R.W.S.), National Science Foundation grant IBN 0630522 (R.W.S.), and grants from the Spanish Ministry of Education and Science (CONSOLIDER CSD2008-00005) and Consejería de Educación y Ciencia, Junta de Comunidades de Castilla-La Mancha (PPII11-0284-9301) and Spanish Ministry of Education and Science (BFU-2009-08404/BFI) to R.L.

Author information

D.A., M.T.L., K.W. and N.K. performed the electrophysiology. C.T.B. performed molecular biology and biochemistry. R.L., C.B.-M. and R.S. were responsible for iEM. M.W. provided the antibodies. R.W.S. was responsible for the behavioral testing. J.P.A. and J.M. wrote the manuscript.

Correspondence to James Maylie or John P Adelman.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–5 (PDF 976 kb)

Rights and permissions

Reprints and Permissions

About this article

Further reading