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An evolutionarily conserved dileucine motif in Shal K+ channels mediates dendritic targeting

Nature Neuroscience volume 6, pages 243–250 (2003)Cite this article

A Corrigendum to this article was published on 01 August 2003

Abstract

The molecular mechanisms underlying polarized sorting of proteins in neurons are poorly understood. Here we report the identification of a 16 amino-acid, dileucine-containing motif that mediates dendritic targeting in a variety of neuronal cell types in slices of rat brain. This motif is present in the carboxy (C) termini of Shal-family K+ channels and is highly conserved from C. elegans to humans. It is necessary for dendritic targeting of potassium channel Kv4.2 and is sufficient to target the axonally localized channels Kv1.3 and Kv1.4 to the dendrites. It can also mediate dendritic targeting of a non-channel protein, CD8.

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Figure 1: Characterization of tagged K+ channel constructs.
Figure 2: Subcellular localization of K+ channel constructs in cortical pyramidal cells in slices.
Figure 3: Alignment of Shal K+ channels reveals a conserved C-terminal dileucine-containing motif that is necessary for dendritic localization.
Figure 4: The dileucine-containing motif is sufficient to mediate dendritic localization in cortical pyramidal neurons.
Figure 5: The dileucine-containing motif mediates dendritic localization of CD8 in cortical pyramidal neurons.
Figure 6: The dileucine-containing motif functions in multiple cell types.
Figure 7: Mutation of the dileucine-containing motif does not affect the rate of endocytosis.

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References

  1. Doyle, D.A. et al. The structure of the potassium channel: molecular basis of K+ conduction and selectivity. Science 280, 69–77 (1998).

    Article  CAS  Google Scholar 

  2. Veh, R.W. et al. Immunohistochemical localization of five members of the Kv1 channel subunits: contrasting subcellular locations and neuron-specific co- localizations in rat brain. Eur. J. Neurosci. 7, 2189–2205 (1995).

    Article  CAS  Google Scholar 

  3. Smart, S.L. et al. Deletion of the K(V)1.1 potassium channel causes epilepsy in mice. Neuron 20, 809–819 (1998).

    Article  CAS  Google Scholar 

  4. Sheng, M., Tsaur, M.L., Jan, Y.N. & Jan, L.Y. Subcellular segregation of two A-type K+ channel proteins in rat central neurons. Neuron 9, 271–284 (1992).

    Article  CAS  Google Scholar 

  5. Baro, D.J. et al. Molecular underpinnings of motor pattern generation: differential targeting of shal and shaker in the pyloric motor system. J. Neurosci. 20, 6619–6630 (2000).

    Article  CAS  Google Scholar 

  6. Song, W.J. et al. Somatodendritic depolarization-activated potassium currents in rat neostriatal cholinergic interneurons are predominantly of the A type and attributable to coexpression of Kv4.2 and Kv4.1 subunits. J. Neurosci. 18, 3124–3137 (1998).

    Article  CAS  Google Scholar 

  7. Cooper, E.C., Milroy, A., Jan, Y.N., Jan, L.Y. & Lowenstein, D.H. Presynaptic localization of Kv1.4-containing A-type potassium channels near excitatory synapses in the hippocampus. J. Neurosci. 18, 965–974 (1998).

    Article  CAS  Google Scholar 

  8. Tsunoda, S., Sun, Y., Suzuki, E. & Zuker, C. Independent anchoring and assembly mechanisms of INAD signaling complexes in Drosophila photoreceptors. J. Neurosci. 21, 150–158 (2001).

    Article  CAS  Google Scholar 

  9. Lim, S.T., Antonucci, D.E., Scannevin, R.H. & Trimmer, J.S. A novel targeting signal for proximal clustering of the Kv2.1 K+ channel in hippocampal neurons. Neuron 25, 385–397 (2000).

    Article  CAS  Google Scholar 

  10. Garrido, J.J. et al. Identification of an axonal determinant in the C-terminus of the sodium channel Na(v)1.2. EMBO J. 20, 5950–5961 (2001).

    Article  CAS  Google Scholar 

  11. Burack, M.A., Silverman, M.A. & Banker, G. The role of selective transport in neuronal protein sorting. Neuron 26, 465–472 (2000).

    Article  CAS  Google Scholar 

  12. Hunziker, W., Harter, C., Matter, K. & Mellman, I. Basolateral sorting in MDCK cells requires a distinct cytoplasmic domain determinant. Cell 66, 907–920 (1991).

    Article  CAS  Google Scholar 

  13. Matter, K. & Mellman, I. Mechanisms of cell polarity: sorting and transport in epithelial cells. Curr. Opin. Cell Biol. 6, 545–554 (1994).

    Article  CAS  Google Scholar 

  14. Dotti, C.G. & Simons, K. Polarized sorting of viral glycoproteins to the axon and dendrites of hippocampal neurons in culture. Cell 62, 63–72 (1990).

    Article  CAS  Google Scholar 

  15. Casanova, J.E., Apodaca, G. & Mostov, K.E. An autonomous signal for basolateral sorting in the cytoplasmic domain of the polymeric immunoglobulin receptor. Cell 66, 65–75 (1991).

    Article  CAS  Google Scholar 

  16. Matter, K., Yamamoto, E.M. & Mellman, I. Structural requirements and sequence motifs for polarized sorting and endocytosis of LDL and Fc receptors in MDCK cells. J. Cell Biol. 126, 991–1004 (1994).

    Article  CAS  Google Scholar 

  17. Odorizzi, G. & Trowbridge, I.S. Structural requirements for basolateral sorting of the human transferrin receptor in the biosynthetic and endocytic pathways of Madin-Darby canine kidney cells. J. Cell Biol. 137, 1255–1264 (1997).

    Article  CAS  Google Scholar 

  18. Kundu, A. & Nayak, D.P. Analysis of the signals for polarized transport of influenza virus (A/WSN/33) neuraminidase and human transferrin receptor, type II transmembrane proteins. J. Virol. 68, 1812–1818 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Jareb, M. & Banker, G. The polarized sorting of membrane proteins expressed in cultured hippocampal neurons using viral vectors. Neuron 20, 855–867 (1998).

    Article  CAS  Google Scholar 

  20. Stowell, J.N. & Craig, A.M. Axon/dendrite targeting of metabotropic glutamate receptors by their cytoplasmic carboxy-terminal domains [see comments]. Neuron 22, 525–536 (1999).

    Article  CAS  Google Scholar 

  21. Francesconi, A. & Duvoisin, R.M. Alternative splicing unmasks dendritic and axonal targeting signals in metabotropic glutamate receptor 1. J. Neurosci. 22, 2196–2205 (2002).

    Article  CAS  Google Scholar 

  22. Ruberti, F. & Dotti, C.G. Involvement of the proximal C terminus of the AMPA receptor subunit GluR1 in dendritic sorting. J. Neurosci. 20, RC78 (2000).

    Article  CAS  Google Scholar 

  23. Arnold, D., Feng, L., Kim, J. & Heintz, N. A strategy for the analysis of gene expression during neural development. Proc. Natl. Acad. Sci. USA 91, 9970–9974 (1994).

    Article  CAS  Google Scholar 

  24. Moriyoshi, K., Richards, L.J., Akazawa, C., O'Leary, D.D. & Nakanishi, S. Labeling neural cells using adenoviral gene transfer of membrane-targeted GFP. Neuron 16, 255–260 (1996).

    Article  CAS  Google Scholar 

  25. Yellen, G. The voltage-gated potassium channels and their relatives. Nature 419, 35–42 (2002).

    Article  CAS  Google Scholar 

  26. Letourneur, F. & Klausner, R.D. A novel di-leucine motif and a tyrosine-based motif independently mediate lysosomal targeting and endocytosis of CD3 chains. Cell 69, 1143–1157 (1992).

    Article  CAS  Google Scholar 

  27. Matter, K., Hunziker, W. & Mellman, I. Basolateral sorting of LDL receptor in MDCK cells: the cytoplasmic domain contains two tyrosine-dependent targeting determinants. Cell 71, 741–753 (1992).

    Article  CAS  Google Scholar 

  28. Craig, A.M., Wyborski, R.J. & Banker, G. Preferential addition of newly synthesized membrane protein at axonal growth cones. Nature 375, 592–594 (1995).

    Article  CAS  Google Scholar 

  29. Hoffman, D.A., Magee, J.C., Colbert, C.M. & Johnston, D. K+ channel regulation of signal propagation in dendrites of hippocampal pyramidal neurons. Nature 387, 869–875 (1997).

    Article  CAS  Google Scholar 

  30. Hoffman, D.A. & Johnston, D. Downregulation of transient K+ channels in dendrites of hippocampal CA1 pyramidal neurons by activation of PKA and PKC. J. Neurosci. 18, 3521–3528 (1998).

    Article  CAS  Google Scholar 

  31. Ohno, H. et al. Interaction of tyrosine-based sorting signals with clathrin-associated proteins. Science 269, 1872–1875 (1995).

    Article  CAS  Google Scholar 

  32. Rapoport, I., Chen, Y.C., Cupers, P., Shoelson, S.E. & Kirchhausen, T. Dileucine-based sorting signals bind to the beta chain of AP-1 at a site distinct and regulated differently from the tyrosine-based motif binding site. EMBO J. 17, 2148–2155 (1998).

    Article  CAS  Google Scholar 

  33. Dwyer, N.D., Adler, C.E., Crump, J.G., L'Etoile, N.D. & Bargmann, C.I. Polarized dendritic transport and the AP-1 mu1 clathrin adaptor UNC-101 localize odorant receptors to olfactory cilia. Neuron 31, 277–287 (2001).

    Article  CAS  Google Scholar 

  34. Nakagawa, T. et al. A novel motor, KIF13A, transports mannose-6-phosphate receptor to plasma membrane through direct interaction with AP-1 complex. Cell 103, 569–581 (2000).

    Article  CAS  Google Scholar 

  35. Hanlon, D.W., Yang, Z. & Goldstein, L.S. Characterization of KIFC2, a neuronal kinesin superfamily member in mouse. Neuron 18, 439–451 (1997).

    Article  CAS  Google Scholar 

  36. Saito, N. et al. KIFC2 is a novel neuron-specific C-terminal type kinesin superfamily motor for dendritic transport of multivesicular body-like organelles. Neuron 18, 425–438 (1997).

    Article  CAS  Google Scholar 

  37. Setou, M., Nakagawa, T., Seog, D.H. & Hirokawa, N. Kinesin superfamily motor protein KIF17 and mLin-10 in NMDA receptor-containing vesicle transport. Science 288, 1796–1802 (2000).

    Article  CAS  Google Scholar 

  38. Marszalek, J.R., Weiner, J.A., Farlow, S.J., Chun, J. & Goldstein, L.S. Novel dendritic kinesin sorting identified by different process targeting of two related kinesins: KIF21A and KIF21B. J. Cell Biol. 145, 469–479 (1999).

    Article  CAS  Google Scholar 

  39. Setou, M. et al. Glutamate-receptor-interacting protein GRIP1 directly steers kinesin to dendrites. Nature 417, 83–87 (2002).

    Article  CAS  Google Scholar 

  40. Arnold, D.B. & Clapham, D.E. Molecular determinants for subcellular localization of PSD-95 with an interacting K+ channel. Neuron 23, 149–157 (1999).

    Article  CAS  Google Scholar 

  41. Serodio, P. & Rudy, B. Differential expression of Kv4 K+ channel subunits mediating subthreshold transient K+ (A-type) currents in rat brain. J. Neurophysiol. 79, 1081–1091 (1998).

    Article  CAS  Google Scholar 

  42. Whitworth, T.L. & Quick, M.W. Substrate-induced regulation of gamma-aminobutyric acid transporter trafficking requires tyrosine phosphorylation. J. Biol. Chem. 276, 42932–42937 (2001).

    Article  CAS  Google Scholar 

  43. Koren, G., Liman, E.R., Logothetis, D.E., Nadal-Ginard, B. & Hess, P. Gating mechanism of a cloned potassium channel expressed in frog oocytes and mammalian cells. Neuron 4, 39–51 (1990).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank D. Liu for technical assistance, G. Banker for the CD8 expression construct, K. Moriyoshi for pCA–GAP–GFP and C-P. Ko and S. Bottjer for helpful suggestions on the manuscript. This work was supported by National Institutes of Health grants NS41963 (D.B.A.) and DC04213 (E.R.L.) and a grant from the Whitehall foundation (D.B.A.).

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Authors and Affiliations

  1. Program in Molecular Biology, University of Southern California, 835 W. 37th Street, Los Angeles, 90089-1340, California, USA

    Jacqueline F. Rivera, Shoeb Ahmad, Michael W. Quick, Emily R. Liman & Don B. Arnold

  2. Program in Neuroscience, University of Southern California, 835 W. 37th Street, Los Angeles, 90089-1340, California, USA

    Michael W. Quick, Emily R. Liman & Don B. Arnold

  3. Department of Biological Sciences, University of Southern California, 835 W. 37th Street, Los Angeles, 90089-1340, California, USA

    Jacqueline F. Rivera, Shoeb Ahmad, Michael W. Quick, Emily R. Liman & Don B. Arnold

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Correspondence to Don B. Arnold.

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Rivera, J., Ahmad, S., Quick, M. et al. An evolutionarily conserved dileucine motif in Shal K+ channels mediates dendritic targeting. Nat Neurosci 6, 243–250 (2003). https://doi.org/10.1038/nn1020

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