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  • Review Article
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The distribution and targeting of neuronal voltage-gated ion channels

Nature Reviews Neuroscience volume 7, pages 548–562 (2006)Cite this article

Key Points

  • Voltage-gated ion channels are targeted to precise locations in polarized neurons that affect the response of the neuron to electrical activity. Neurons can adjust channel activities by modifying channel properties or altering channel densities.

  • In general, voltage-gated sodium (Nav) and voltage-gated potassium (Kv1 and KCNQ) channels are located in the axon, and Kv2, Kv4, and hyperpolarization-activated cyclic nucleotide-gated channels (HCNs) are located in the dendrites. There are exceptions; for example, different types of voltage-gated calcium (Cav) channels and Kv3 channels are distributed in the axon and dendrites.

  • Mechanisms of directed targeting, transcytosis, and selective retention or endocytosis have been proposed for axonal targeting of proteins of the neuronal membrane. A mechanism of selective endocytosis has been proposed for Nav channels.

  • Various structural motifs physically link channels to proteins that can cluster or anchor themselves at the membrane, target channels to their proper neuronal location, or affect the forward trafficking or endocytosis of these channels.

  • Myelin is involved in the clustering of Nav and Kv channels to the nodes of Ranvier by an as-yet-unidentified factor.

Abstract

Voltage-gated ion channels have to be at the right place in the right number to endow individual neurons with their specific character. Their biophysical properties together with their spatial distribution define the signalling characteristics of a neuron. Improper channel localization could cause communication defects in a neuronal network. This review covers recent studies of mechanisms for targeting voltage-gated ion channels to axons and dendrites, including trafficking, retention and endocytosis pathways for the preferential localization of particular ion channels. We also discuss how the spatial localization of these channels might contribute to the electrical excitability of neurons, and consider the need for future work in this emerging field.

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Figure 1: General localization of voltage-gated ion channels in a model neuron.
Figure 2: General structural topology of voltage-gated ion channels.
Figure 3: Voltage-gated sodium channels.
Figure 4: Voltage-gated potassium Kv1 channels.
Figure 5: Hyperpolarization-activated cyclic nucleotide-gated channels.
Figure 6: Voltage-gated potassium Kv2.1 channels.
Figure 7: Voltage-gated potassium Kv4.2 channels.

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References

  1. Hodgkin, A. L. & Huxley, A. F. Currents carried by sodium and potassium ions through the membrane of the giant axon of Loligo. J. Physiol. 116, 449–472 (1952).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Devaux, J. J., Kleopa, K. A., Cooper, E. C. & Scherer, S. S. KCNQ2 is a nodal K+ channel. J. Neurosci. 24, 1236–1244 (2004). First report that KCNQ is at the AIS and nodes of Ranvier, supported by both co-localization with markers and electrophysiological recordings.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hille, B. Ion Channels of Excitable Membranes (Sinauer, Sunderland, Massachusetts, USA, 2001).

    Google Scholar 

  4. Shepherd, G. M. The Synaptic Organization of the Brain (Oxford University, New York, 2004).

    Book  Google Scholar 

  5. Schwarz, J. R. et al. KCNQ channels mediate IKs, a slow K+ current regulating excitability in the rat node of Ranvier. J. Physiol. 573, 17–34 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Magee, J. C. & Johnston, D. Plasticity of dendritic function. Curr. Opin. Neurobiol. 15, 334–342 (2005).

    Article  CAS  PubMed  Google Scholar 

  7. Magee, J. C. & Johnston, D. A synaptically controlled, associative signal for Hebbian plasticity in hippocampal neurons. Science 275, 209–213 (1997).

    Article  CAS  PubMed  Google Scholar 

  8. Sjostrom, P. J. & Nelson, S. B. Spike timing, calcium signals and synaptic plasticity. Curr. Opin. Neurobiol. 12, 305–314 (2002).

    Article  CAS  PubMed  Google Scholar 

  9. Dan, Y. & Poo, M. M. Spike timing-dependent plasticity of neural circuits. Neuron 44, 23–30 (2004).

    Article  CAS  PubMed  Google Scholar 

  10. Helmchen, F., Svoboda, K., Denk, W. & Tank, D. W. In vivo dendritic calcium dynamics in deep-layer cortical pyramidal neurons. Nature Neurosci. 2, 989–996 (1999).

    Article  CAS  PubMed  Google Scholar 

  11. Larkum, M. E. & Zhu, J. J. Signaling of layer 1 and whisker-evoked Ca2+ and Na+ action potentials in distal and terminal dendrites of rat neocortical pyramidal neurons in vitro and in vivo. J. Neurosci. 22, 6991–7005 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Schiller, J., Schiller, Y., Stuart, G. & Sakmann, B. Calcium action potentials restricted to distal apical dendrites of rat neocortical pyramidal neurons. J. Physiol. 505, 605–616 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Svoboda, K., Helmchen, F., Denk, W. & Tank, D. W. Spread of dendritic excitation in layer 2/3 pyramidal neurons in rat barrel cortex in vivo. Nature Neurosci. 2, 65–73 (1999).

    Article  CAS  PubMed  Google Scholar 

  14. Oakley, J. C., Schwindt, P. C. & Crill, W. E. Initiation and propagation of regenerative Ca2+-dependent potentials in dendrites of layer 5 pyramidal neurons. J. Neurophysiol. 86, 503–513 (2001).

    Article  CAS  PubMed  Google Scholar 

  15. Catterall, W. A., Goldin, A. L. & Waxman, S. G. International union of pharmacology. XLVII. Nomenclature and structure–function relationships of voltage-gated sodium channels. Pharmacol. Rev. 57, 397–409 (2005).

    Article  CAS  PubMed  Google Scholar 

  16. Goldin, A. L. et al. Nomenclature of voltage-gated sodium channels. Neuron 28, 365–368 (2000).

    Article  CAS  PubMed  Google Scholar 

  17. Goldin, A. L. Resurgence of sodium channel research. Annu. Rev. Physiol. 63, 871–894 (2001).

    Article  CAS  PubMed  Google Scholar 

  18. Yu, F. H., Yarov-Yarovoy, V., Gutman, G. A. & Catterall, W. A. Overview of molecular relationships in the voltage-gated ion channel superfamily. Pharmacol. Rev. 57, 387–395 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Catterall, W. A. From ionic currents to molecular mechanisms: the structure and function of voltage-gated sodium channels. Neuron 26, 13–25 (2000).

    Article  CAS  PubMed  Google Scholar 

  20. Vaughn, D. E. & Bjorkman, P. J. The (Greek) key to structures of neural adhesion molecules. Neuron 16, 261–273 (1996).

    Article  CAS  PubMed  Google Scholar 

  21. Gutman, G. A. et al. International union of pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels. Pharmacol. Rev. 57, 473–508 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Gulbis, J. M., Zhou, M., Mann, S. & MacKinnon, R. Structure of the cytoplasmic β subunit–T1 assembly of voltage-dependent K+ channels. Science 289, 123–127 (2000).

    Article  CAS  PubMed  Google Scholar 

  23. Scannevin, R. H. et al. Two N-terminal domains of Kv4 K+ channels regulate binding to and modulation by KChIP1. Neuron 41, 587–598 (2004).

    Article  CAS  PubMed  Google Scholar 

  24. Kim, L. A. et al. Three-dimensional structure of Ito: Kv4.2–KChIP2 ion channels by electron microscopy at 21 Å resolution. Neuron 41, 513–519 (2004).

    Article  CAS  PubMed  Google Scholar 

  25. Zhou, W., Qian, Y., Kunjilwar, K., Pfaffinger, P. J. & Choe, S. Structural insights into the functional interaction of KChIP1 with Shal-type K+ channels. Neuron 41, 573–586 (2004).

    Article  CAS  PubMed  Google Scholar 

  26. Nadal, M. S. et al. The CD26-related dipeptidyl aminopeptidase-like protein DPPX is a critical component of neuronal A-type K+ channels. Neuron 37, 449–461 (2003).

    Article  CAS  PubMed  Google Scholar 

  27. Robinson, R. B. & Siegelbaum, S. A. Hyperpolarization-activated cation currents: from molecules to physiological function. Annu. Rev. Physiol. 65, 453–480 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Catterall, W. A. Structure and regulation of voltage-gated Ca2+ channels. Annu. Rev. Cell Dev. Biol. 16, 521–555 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Catterall, W. A., Perez-Reyes, E., Snutch, T. P. & Striessnig, J. International union of pharmacology. XLVIII. Nomenclature and structure–function relationships of voltage-gated calcium channels. Pharmacol. Rev. 57, 411–425 (2005).

    Article  CAS  PubMed  Google Scholar 

  30. Trimmer, J. S. & Rhodes, K. J. Localization of voltage-gated ion channels in mammalian brain. Annu. Rev. Physiol. 66, 477–519 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Rasband, M. N. et al. Potassium channel distribution, clustering, and function in remyelinating rat axons. J. Neurosci. 18, 36–47 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Chiu, S. Y. & Ritchie, J. M. Evidence for the presence of potassium channels in the paranodal region of acutely demyelinated mammalian single nerve fibres. J. Physiol. 313, 415–437 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Rudy, B. et al. Contributions of Kv3 channels to neuronal excitability. Ann. NY Acad. Sci. 868, 304–343 (1999).

    Article  CAS  PubMed  Google Scholar 

  34. Baranauskas, G., Tkatch, T., Nagata, K., Yeh, J. Z. & Surmeier, D. J. Kv3.4 subunits enhance the repolarizing efficiency of Kv3.1 channels in fast-spiking neurons. Nature Neurosci. 6, 258–266 (2003).

    Article  CAS  PubMed  Google Scholar 

  35. Lien, C. C. & Jonas, P. Kv3 potassium conductance is necessary and kinetically optimized for high-frequency action potential generation in hippocampal interneurons. J. Neurosci. 23, 2058–2068 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wisco, D. et al. Uncovering multiple axonal targeting pathways in hippocampal neurons. J. Cell Biol. 162, 1317–1328 (2003). Proposes mechanisms of directed targeting or transcytosis for the axonal cell adhesion molecule, NgCAM.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Sampo, B., Kaech, S., Kunz, S. & Banker, G. Two distinct mechanisms target membrane proteins to the axonal surface. Neuron 37, 611–624 (2003). Proposes a selective endocytosis mechanism for the axonal protein, VAMP2.

    Article  CAS  PubMed  Google Scholar 

  38. 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  PubMed  Google Scholar 

  39. Poyatos, I. et al. Polarized distribution of glycine transporter isoforms in epithelial and neuronal cells. Mol. Cell. Neurosci. 15, 99–111 (2000).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  41. Owen, D. J. & Evans, P. R. A structural explanation for the recognition of tyrosine-based endocytotic signals. Science 282, 1327–1332 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Rapoport, I., Chen, Y. C., Cupers, P., Shoelson, S. E. & Kirchhausen, T. Dileucine-based sorting signals bind to the β 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  PubMed  PubMed Central  Google Scholar 

  43. West, A. E., Neve, R. L. & Buckley, K. M. Identification of a somatodendritic targeting signal in the cytoplasmic domain of the transferrin receptor. J. Neurosci. 17, 6038–6047 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  45. 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).

  46. Colbert, C. M. & Pan, E. Ion channel properties underlying axonal action potential initiation in pyramidal neurons. Nature Neurosci. 5, 533–538 (2002).

    Article  CAS  PubMed  Google Scholar 

  47. Westenbroek, R. E., Merrick, D. K. & Catterall, W. A. Differential subcellular localization of the RI and RII Na+ channel subtypes in central neurons. Neuron 3, 695–704 (1989).

    Article  CAS  PubMed  Google Scholar 

  48. Caldwell, J. H., Schaller, K. L., Lasher, R. S., Peles, E. & Levinson, S. R. Sodium channel Nav1.6 is localized at nodes of ranvier, dendrites, and synapses. Proc. Natl Acad. Sci. USA 97, 5616–5620 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Salzer, J. L. Polarized domains of myelinated axons. Neuron 40, 297–318 (2003).

    Article  CAS  PubMed  Google Scholar 

  50. Poliak, S. & Peles, E. The local differentiation of myelinated axons at nodes of Ranvier. Nature Rev. Neurosci. 4, 968–980 (2003).

    Article  CAS  Google Scholar 

  51. Ratcliffe, C. F., Westenbroek, R. E., Curtis, R. & Catterall, W. A. Sodium channel β1 and β3 subunits associate with neurofascin through their extracellular immunoglobulin-like domain. J. Cell Biol. 154, 427–434 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Garver, T. D., Ren, Q., Tuvia, S. & Bennett, V. Tyrosine phosphorylation at a site highly conserved in the L1 family of cell adhesion molecules abolishes ankyrin binding and increases lateral mobility of neurofascin. J. Cell Biol. 137, 703–714 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Liu, C. J. et al. Direct interaction with contactin targets voltage-gated sodium channel Nav1.9/NaN to the cell membrane. J. Biol. Chem. 276, 46553–46561 (2001).

    Article  CAS  PubMed  Google Scholar 

  54. Kazarinova-Noyes, K. et al. Contactin associates with Na+ channels and increases their functional expression. J. Neurosci. 21, 7517–7525 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Shah, B. S. et al. Contactin associates with sodium channel Nav1.3 in native tissues and increases channel density at the cell surface. J. Neurosci. 24, 7387–7399 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Srinivasan, J., Schachner, M. & Catterall, W. A. Interaction of voltage-gated sodium channels with the extracellular matrix molecules tenascin-C-and tenascin-R. Proc. Natl Acad. Sci. USA 95, 15753–15757 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Xiao, Z. C. et al. Tenascin-R is a functional modulator of sodium channel β subunits. J. Biol. Chem. 274, 26511–26517 (1999).

    Article  CAS  PubMed  Google Scholar 

  58. Ratcliffe, C. F. et al. A sodium channel signaling complex: modulation by associated receptor protein tyrosine phosphatase β. Nature Neurosci. 3, 437–444 (2000).

    Article  CAS  PubMed  Google Scholar 

  59. Kordeli, E., Lambert, S. & Bennett, V. AnkyrinG. A new ankyrin gene with neural-specific isoforms localized at the axonal initial segment and node of Ranvier. J. Biol. Chem. 270, 2352–2359 (1995).

    Article  CAS  PubMed  Google Scholar 

  60. Bennett, V. & Baines, A. J. Spectrin and ankyrin-based pathways: metazoan inventions for integrating cells into tissues. Physiol. Rev. 81, 1353–1392 (2001).

    Article  CAS  PubMed  Google Scholar 

  61. Jenkins, S. M. & Bennett, V. Ankyrin-G coordinates assembly of the spectrin-based membrane skeleton, voltage-gated sodium channels, and L1 CAMs at Purkinje neuron initial segments. J. Cell Biol. 155, 739–746 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Lambert, S., Davis, J. Q. & Bennett, V. Morphogenesis of the node of Ranvier: co-clusters of ankyrin and ankyrin-binding integral proteins define early developmental intermediates. J. Neurosci. 17, 7025–7036 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Zhou, D. et al. AnkyrinG is required for clustering of voltage-gated Na channels at axon initial segments and for normal action potential firing. J. Cell Biol. 143, 1295–1304 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Komada, M. & Soriano, P. βIV-spectrin regulates sodium channel clustering through ankyrin-G at axon initial segments and nodes of Ranvier. J. Cell Biol. 156, 337–348 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Lemaillet, G., Walker, B. & Lambert, S. Identification of a conserved ankyrin-binding motif in the family of sodium channel α subunits. J. Biol. Chem. 278, 27333–27339 (2003).

    Article  CAS  PubMed  Google Scholar 

  66. Garrido, J. J. et al. A targeting motif involved in sodium channel clustering at the axonal initial segment. Science 300, 2091–2094 (2003). Reports the identification of a motif in the II–III loop of Nav1.2 channels that is necessary and sufficient to target these channels to the AIS.

    Article  CAS  PubMed  Google Scholar 

  67. Srinivasan, Y., Elmer, L., Davis, J., Bennett, V. & Angelides, K. Ankyrin and spectrin associate with voltage-dependent sodium channels in brain. Nature 333, 177–180 (1988).

    Article  CAS  PubMed  Google Scholar 

  68. Fache, M. P. et al. Endocytotic elimination and domain-selective tethering constitute a potential mechanism of protein segregation at the axonal initial segment. J. Cell Biol. 166, 571–578 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Garrido, J. J. et al. Identification of an axonal determinant in the C-terminus of the sodium channel Nav1.2. EMBO J. 20, 5950–5961 (2001). First suggestion that Nav1.2 axonal targeting is by selective elimination in the dendrites through a di-leucine motif in the C-terminus that is associated with the clathrin endocytic pathway.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Monaghan, M. M., Trimmer, J. S. & Rhodes, K. J. Experimental localization of Kv1 family voltage-gated K+ channel α and β subunits in rat hippocampal formation. J. Neurosci. 21, 5973–5983 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Wang, H., Kunkel, D. D., Martin, T. M., Schwartzkroin, P. A. & Tempel, B. L. Heteromultimeric K+ channels in terminal and juxtaparanodal regions of neurons. Nature 365, 75–79 (1993).

    Article  CAS  PubMed  Google Scholar 

  72. Sheng, M., Liao, Y. J., Jan, Y. N. & Jan, L. Y. Presynaptic A-current based on heteromultimeric K+ channels detected in vivo. Nature 365, 72–75 (1993).

    Article  CAS  PubMed  Google Scholar 

  73. Debanne, D., Guerineau, N. C., Gahwiler, B. H. & Thompson, S. M. Action-potential propagation gated by an axonal IA-like K+ conductance in hippocampus. Nature 389, 286–289 (1997).

    Article  CAS  PubMed  Google Scholar 

  74. Lambe, E. K. & Aghajanian, G. K. The role of Kv1.2-containing potassium channels in serotonin-induced glutamate release from thalamocortical terminals in rat frontal cortex. J. Neurosci. 21, 9955–9963 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Wang, H., Kunkel, D. D., Schwartzkroin, P. A. & Tempel, B. L. Localization of Kv1.1 and Kv1.2, two K channel proteins, to synaptic terminals, somata, and dendrites in the mouse brain. J. Neurosci. 14, 4588–4599 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Smart, S. L. et al. Deletion of the KV1.1 potassium channel causes epilepsy in mice. Neuron 20, 809–819 (1998).

    Article  CAS  PubMed  Google Scholar 

  77. Fili, O. et al. Direct interaction of a brain voltage-gated K+ channel with syntaxin 1A: functional impact on channel gating. J. Neurosci. 21, 1964–1974 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Michaelevski, I. et al. Modulation of a brain voltage-gated K+ channel by syntaxin 1A requires the physical interaction of Gβγ with the channel. J. Biol. Chem. 277, 34909–34917 (2002).

    Article  CAS  PubMed  Google Scholar 

  79. Poliak, S. et al. Juxtaparanodal clustering of Shaker-like K+ channels in myelinated axons depends on Caspr2 and TAG-1. J. Cell Biol. 162, 1149–1160 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Gu, C., Jan, Y. N. & Jan, L. Y. A conserved domain in axonal targeting of Kv1 (Shaker) voltage-gated potassium channels. Science 301, 646–649 (2003). Reports that the T1 domain of Kv1 channels is necessary and sufficient to target to the axons that depend on proper association with Kvβ.

    Article  CAS  PubMed  Google Scholar 

  81. Rivera, J. F., Chu, P. J. & Arnold, D. B. The T1 domain of Kv1.3 mediates intracellular targeting to axons. Eur. J. Neurosci. 22, 1853–1862 (2005).

    Article  PubMed  Google Scholar 

  82. Pongs, O. et al. Functional and molecular aspects of voltage-gated K+ channel β subunits. Ann. NY Acad. Sci. 868, 344–355 (1999).

    Article  CAS  PubMed  Google Scholar 

  83. Rhodes, K. J. et al. Association and colocalization of the Kvβ1 and Kvβ2 β-subunits with Kv1 α-subunits in mammalian brain K+ channel complexes. J. Neurosci. 17, 8246–8258 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Gulbis, J. M., Mann, S. & MacKinnon, R. Structure of a voltage-dependent K+ channel β subunit. Cell 97, 943–952 (1999).

    Article  CAS  PubMed  Google Scholar 

  85. Campomanes, C. R. et al. Kv β subunit oxidoreductase activity and Kv1 potassium channel trafficking. J. Biol. Chem. 277, 8298–8305 (2002).

    Article  CAS  PubMed  Google Scholar 

  86. Shi, G. et al. β subunits promote K+ channel surface expression through effects early in biosynthesis. Neuron 16, 843–852 (1996).

    Article  CAS  PubMed  Google Scholar 

  87. Li, D., Takimoto, K. & Levitan, E. S. Surface expression of Kv1 channels is governed by a C-terminal motif. J. Biol. Chem. 275, 11597–11602 (2000).

    Article  CAS  PubMed  Google Scholar 

  88. Manganas, L. N. & Trimmer, J. S. Subunit composition determines Kv1 potassium channel surface expression. J. Biol. Chem. 275, 29685–29693 (2000).

    Article  CAS  PubMed  Google Scholar 

  89. Manganas, L. N. et al. Identification of a trafficking determinant localized to the Kv1 potassium channel pore. Proc. Natl Acad. Sci. USA 98, 14055–14059 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Manganas, L. N. et al. Episodic ataxia type-1 mutations in the Kv1.1 potassium channel display distinct folding and intracellular trafficking properties. J. Biol. Chem. 276, 49427–49434 (2001).

    Article  CAS  PubMed  Google Scholar 

  91. Hattan, D., Nesti, E., Cachero, T. G. & Morielli, A. D. Tyrosine phosphorylation of Kv1.2 modulates its interaction with the actin-binding protein cortactin. J. Biol. Chem. 277, 38596–38606 (2002).

    Article  CAS  PubMed  Google Scholar 

  92. Manganas, L. N. & Trimmer, J. S. Calnexin regulates mammalian Kv1 channel trafficking. Biochem. Biophys. Res. Commun. 322, 577–584 (2004).

    Article  CAS  PubMed  Google Scholar 

  93. Tiffany, A. M. et al. PSD-95 and SAP97 exhibit distinct mechanisms for regulating K+ channel surface expression and clustering. J. Cell Biol. 148, 147–158 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Kim, E., Niethammer, M., Rothschild, A., Jan, Y. N. & Sheng, M. Clustering of Shaker-type K+ channels by interaction with a family of membrane-associated guanylate kinases. Nature 378, 85–88 (1995).

    Article  CAS  PubMed  Google Scholar 

  95. Jugloff, D. G., Khanna, R., Schlichter, L. C. & Jones, O. T. Internalization of the Kv1.4 potassium channel is suppressed by clustering interactions with PSD-95. J. Biol. Chem. 275, 1357–1364 (2000).

    Article  CAS  PubMed  Google Scholar 

  96. Hsueh, Y. P., Kim, E. & Sheng, M. Disulfide-linked head-to-head multimerization in the mechanism of ion channel clustering by PSD-95. Neuron 18, 803–814 (1997).

    Article  CAS  PubMed  Google Scholar 

  97. Hsueh, Y. P. & Sheng, M. Requirement of N-terminal cysteines of PSD-95 for PSD-95 multimerization and ternary complex formation, but not for binding to potassium channel Kv1.4. J. Biol. Chem. 274, 532–536 (1999).

    Article  CAS  PubMed  Google Scholar 

  98. Topinka, J. R. & Bredt, D. S. N-terminal palmitoylation of PSD-95 regulates association with cell membranes and interaction with K+ channel Kv1.4. Neuron 20, 125–134 (1998).

    Article  CAS  PubMed  Google Scholar 

  99. Kim, E. & Sheng, M. Differential K+ channel clustering activity of PSD-95 and SAP97, two related membrane-associated putative guanylate kinases. Neuropharmacology 35, 993–1000 (1996).

    Article  CAS  PubMed  Google Scholar 

  100. 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  PubMed  Google Scholar 

  101. Kim, E. & Sheng, M. PDZ domain proteins of synapses. Nature Rev. Neurosci. 5, 771–781 (2004).

    Article  CAS  Google Scholar 

  102. Rasband, M. N. et al. Clustering of neuronal potassium channels is independent of their interaction with PSD-95. J. Cell Biol. 159, 663–672 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Wang, H. S. et al. KCNQ2 and KCNQ3 potassium channel subunits: molecular correlates of the M-channel. Science 282, 1890–1893 (1998).

    Article  CAS  PubMed  Google Scholar 

  104. Castaldo, P. et al. Benign familial neonatal convulsions caused by altered gating of KCNQ2/KCNQ3 potassium channels. J. Neurosci. 22, RC199 (2002).

    Article  PubMed  PubMed Central  Google Scholar 

  105. Dedek, K. et al. Myokymia and neonatal epilepsy caused by a mutation in the voltage sensor of the KCNQ2 K+ channel. Proc. Natl Acad. Sci. USA 98, 12272–12277 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Arroyo, E. J. et al. Genetic dysmyelination alters the molecular architecture of the nodal region. J. Neurosci. 22, 1726–1737 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Pan, Z. et al. A common ankyrin-G-based mechanism retains KCNQ and Nav channels at electrically active domains of the axon. J. Neurosci. 26, 2599–2603 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Chung, H. J., Jan, Y. N. & Jan, L. Y. Polarized axonal surface expression of neuronal KCNQ channels is mediated by multiple signals in the KCNQ2 and KCNQ3 C-terminal domains. Proc. Natl Acad. Sci. USA 30 May 2006 (doi: 10.1073/pnas.0603376103).

  109. Devaux, J. et al. Kv3.1b is a novel component of CNS nodes. J. Neurosci. 23, 4509–4518 (2003). First report that Kv3.1b is at the nodes of Ranvier.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Goldberg, E. M. et al. Specific functions of synaptically localized potassium channels in synaptic transmission at the neocortical GABAergic fast-spiking cell synapse. J. Neurosci. 25, 5230–5235 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Matsukawa, H., Wolf, A. M., Matsushita, S., Joho, R. H. & Knopfel, T. Motor dysfunction and altered synaptic transmission at the parallel fiber–Purkinje cell synapse in mice lacking potassium channels Kv3.1 and Kv3.3. J. Neurosci. 23, 7677–7684 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Magee, J. C. & Johnston, D. Characterization of single voltage-gated Na+ and Ca2+ channels in apical dendrites of rat CA1 pyramidal neurons. J. Physiol. 487, 67–90 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Johnston, D., Magee, J. C., Colbert, C. M. & Cristie, B. R. Active properties of neuronal dendrites. Annu. Rev. Neurosci. 19, 165–186 (1996).

    Article  CAS  PubMed  Google Scholar 

  114. Magee, J., Hoffman, D., Colbert, C. & Johnston, D. Electrical and calcium signaling in dendrites of hippocampal pyramidal neurons. Annu. Rev. Physiol. 60, 327–346 (1998).

    Article  CAS  PubMed  Google Scholar 

  115. 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  PubMed  Google Scholar 

  116. Johnston, D. et al. Dendritic potassium channels in hippocampal pyramidal neurons. J. Physiol. 525, 75–81 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Jinno, S., Jeromin, A. & Kosaka, T. Postsynaptic and extrasynaptic localization of Kv4.2 channels in the mouse hippocampal region, with special reference to targeted clustering at gabaergic synapses. Neuroscience 134, 483–494 (2005).

    Article  CAS  PubMed  Google Scholar 

  118. Strassle, B. W., Menegola, M., Rhodes, K. J. & Trimmer, J. S. Light and electron microscopic analysis of KChIP and Kv4 localization in rat cerebellar granule cells. J. Comp. Neurol. 484, 144–155 (2005).

    Article  PubMed  Google Scholar 

  119. Chen, X. & Johnston, D. Properties of single voltage-dependent K+ channels in dendrites of CA1 pyramidal neurones of rat hippocampus. J. Physiol. 559, 187–203 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Notomi, T. & Shigemoto, R. Immunohistochemical localization of Ih channel subunits, HCN1–4, in the rat brain. J. Comp. Neurol. 471, 241–276 (2004).

    Article  CAS  PubMed  Google Scholar 

  121. Lorincz, A., Notomi, T., Tamas, G., Shigemoto, R. & Nusser, Z. Polarized and compartment-dependent distribution of HCN1 in pyramidal cell dendrites. Nature Neurosci. 5, 1185–1193 (2002).

    Article  CAS  PubMed  Google Scholar 

  122. Kole, M. H., Hallermann, S. & Stuart, G. J. Single Ih channels in pyramidal neuron dendrites: properties, distribution, and impact on action potential output. J. Neurosci. 26, 1677–1687 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Wang, Z., Xu, N. L., Wu, C. P., Duan, S. & Poo, M. M. Bidirectional changes in spatial dendritic integration accompanying long-term synaptic modifications. Neuron 37, 463–472 (2003).

    Article  CAS  PubMed  Google Scholar 

  124. Fan, Y. et al. Activity-dependent decrease of excitability in rat hippocampal neurons through increases in Ih . Nature Neurosci. 8, 1542–1551 (2005).

    Article  CAS  PubMed  Google Scholar 

  125. Pape, H. C. Queer current and pacemaker: the hyperpolarization-activated cation current in neurons. Annu. Rev. Physiol. 58, 299–327 (1996).

    Article  CAS  PubMed  Google Scholar 

  126. Poolos, N. P., Migliore, M. & Johnston, D. Pharmacological upregulation of h-channels reduces the excitability of pyramidal neuron dendrites. Nature Neurosci. 5, 767–774 (2002).

    Article  CAS  PubMed  Google Scholar 

  127. Berger, T., Senn, W. & Luscher, H. R. Hyperpolarization-activated current Ih disconnects somatic and dendritic spike initiation zones in layer V pyramidal neurons. J. Neurophysiol. 90, 2428–2437 (2003).

    Article  PubMed  Google Scholar 

  128. Williams, S. R. & Stuart, G. J. Role of dendritic synapse location in the control of action potential output. Trends Neurosci. 26, 147–154 (2003).

    Article  CAS  PubMed  Google Scholar 

  129. Williams, S. R. & Stuart, G. J. Voltage- and site-dependent control of the somatic impact of dendritic IPSPs. J. Neurosci. 23, 7358–7367 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Williams, S. R. & Stuart, G. J. Site independence of EPSP time course is mediated by dendritic Ih in neocortical pyramidal neurons. J. Neurophysiol. 83, 3177–3182 (2000).

    Article  CAS  PubMed  Google Scholar 

  131. Magee, J. C. Dendritic Ih normalizes temporal summation in hippocampal CA1 neurons. Nature Neurosci. 2, 848 (1999). Reports that the HCN current density gradient maintains temporal resolution of synaptic potentials.

    Article  CAS  PubMed  Google Scholar 

  132. Migliore, M. & Shepherd, G. M. Emerging rules for the distributions of active dendritic conductances. Nature Rev. Neurosci. 3, 362–370 (2002).

    Article  CAS  Google Scholar 

  133. Zhang, W. & Linden, D. J. The other side of the engram: experience-driven changes in neuronal intrinsic excitability. Nature Rev. Neurosci. 4, 885–900 (2003).

    Article  CAS  Google Scholar 

  134. Frick, A. & Johnston, D. Plasticity of dendritic excitability. J. Neurobiol. 64, 100–115 (2005).

    Article  CAS  PubMed  Google Scholar 

  135. Bernard, C. et al. Acquired dendritic channelopathy in temporal lobe epilepsy. Science 305, 532–535 (2004).

    Article  CAS  PubMed  Google Scholar 

  136. Ludwig, A. et al. Absence epilepsy and sinus dysrhythmia in mice lacking the pacemaker channel HCN2. EMBO J. 22, 216–224 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Shah, M. M., Anderson, A. E., Leung, V., Lin, X. & Johnston, D. Seizure-induced plasticity of h channels in entorhinal cortical layer III pyramidal neurons. Neuron 44, 495–508 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Chen, K., Aradi, I., Santhakumar, V. & Soltesz, I. H-channels in epilepsy: new targets for seizure control? Trends Pharmacol. Sci. 23, 552–557 (2002).

    Article  PubMed  Google Scholar 

  139. Brewster, A. L., Bernard, J. A., Gall, C. M. & Baram, T. Z. Formation of heteromeric hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in the hippocampus is regulated by developmental seizures. Neurobiol. Dis. 19, 200–207 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Chen, S., Wang, J. & Siegelbaum, S. A. Properties of hyperpolarization-activated pacemaker current defined by coassembly of HCN1 and HCN2 subunits and basal modulation by cyclic nucleotide. J. Gen. Physiol. 117, 491–504 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Proenza, C. et al. Different roles for the cyclic nucleotide binding domain and amino terminus in assembly and expression of hyperpolarization-activated, cyclic nucleotide-gated channels. J. Biol. Chem. 277, 29634–29642 (2002).

    Article  CAS  PubMed  Google Scholar 

  142. Tran, N. et al. A conserved domain in the NH2 terminus important for assembly and functional expression of pacemaker channels. J. Biol. Chem. 277, 43588–43592 (2002).

    Article  CAS  PubMed  Google Scholar 

  143. Zagotta, W. N. et al. Structural basis for modulation and agonist specificity of HCN pacemaker channels. Nature 425, 200–205 (2003).

    Article  CAS  PubMed  Google Scholar 

  144. Akhavan, A. et al. Identification of the cyclic-nucleotide-binding domain as a conserved determinant of ion-channel cell-surface localization. J. Cell Sci. 118, 2803–2812 (2005).

    Article  CAS  PubMed  Google Scholar 

  145. Magee, J. C. Dendritic hyperpolarization-activated currents modify the integrative properties of hippocampal CA1 pyramidal neurons. J. Neurosci. 18, 7613–7624 (1998). Reports an increase in current density of I h using cell-attached patch from the soma to the dendrites in hippocampal CA1 pyramidal neurons.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Nolan, M. F. et al. A behavioral role for dendritic integration: HCN1 channels constrain spatial memory and plasticity at inputs to distal dendrites of CA1 pyramidal neurons. Cell 119, 719–732 (2004).

    CAS  PubMed  Google Scholar 

  147. Nolan, M. F. et al. The hyperpolarization-activated HCN1 channel is important for motor learning and neuronal integration by cerebellar Purkinje cells. Cell 115, 551–564 (2003).

    Article  CAS  PubMed  Google Scholar 

  148. Qu, J. et al. MiRP1 modulates HCN2 channel expression and gating in cardiac myocytes. J. Biol. Chem. 279, 43497–43502 (2004).

    Article  CAS  PubMed  Google Scholar 

  149. Santoro, B., Wainger, B. J. & Siegelbaum, S. A. Regulation of HCN channel surface expression by a novel C-terminal protein–protein interaction. J. Neurosci. 24, 10750–10762 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Gravante, B. et al. Interaction of the pacemaker channel HCN1 with filamin A. J. Biol. Chem. 279, 43847–43853 (2004).

    Article  CAS  PubMed  Google Scholar 

  151. Kimura, K., Kitano, J., Nakajima, Y. & Nakanishi, S. Hyperpolarization-activated, cyclic nucleotide-gated HCN2 cation channel forms a protein assembly with multiple neuronal scaffold proteins in distinct modes of protein–protein interaction. Genes Cells 9, 631–640 (2004).

    Article  CAS  PubMed  Google Scholar 

  152. Murakoshi, H. & Trimmer, J. S. Identification of the Kv2.1 K+ channel as a major component of the delayed rectifier K+ current in rat hippocampal neurons. J. Neurosci. 19, 1728–1735 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Malin, S. A. & Nerbonne, J. M. Delayed rectifier K+ currents, IK, are encoded by Kv2 α-subunits and regulate tonic firing in mammalian sympathetic neurons. J. Neurosci. 22, 10094–10105 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Misonou, H. et al. Regulation of ion channel localization and phosphorylation by neuronal activity. Nature Neurosci. 7, 711–718 (2004). Seminal paper describing the activity-dependent phosphorylation of Kv2.1 leading to clustering of these channels at somatodendritic membranes, which thereby changes the current properties of the neuron.

    Article  CAS  PubMed  Google Scholar 

  155. Misonou, H., Mohapatra, D. P., Menegola, M. & Trimmer, J. S. Calcium- and metabolic state-dependent modulation of the voltage-dependent Kv2.1 channel regulates neuronal excitability in response to ischemia. J. Neurosci. 25, 11184–11193 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  156. Misonou, H., Mohapatra, D. P. & Trimmer, J. S. Kv2.1: a voltage-gated K+ channel critical to dynamic control of neuronal excitability. Neurotoxicology 26, 743–752 (2005).

    Article  CAS  PubMed  Google Scholar 

  157. 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  PubMed  Google Scholar 

  158. Du, J., Haak, L. L., Phillips-Tansey, E., Russell, J. T. & McBain, C. J. Frequency-dependent regulation of rat hippocampal somato-dendritic excitability by the K+ channel subunit Kv2.1. J. Physiol. 522, 19–31 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Rhodes, K. J. et al. KChIPs and Kv4 α subunits as integral components of A-type potassium channels in mammalian brain. J. Neurosci. 24, 7903–7915 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. An, W. F. et al. Modulation of A-type potassium channels by a family of calcium sensors. Nature 403, 553–556 (2000).

    Article  CAS  PubMed  Google Scholar 

  161. Johnston, D. et al. Active dendrites, potassium channels and synaptic plasticity. Phil. Trans. R. Soc. Lond. B 358, 667–674 (2003).

    Article  CAS  Google Scholar 

  162. Cai, X. et al. Unique roles of SK and Kv4.2 potassium channels in dendritic integration. Neuron 44, 351–364 (2004).

    Article  CAS  PubMed  Google Scholar 

  163. Yuan, W., Burkhalter, A. & Nerbonne, J. M. Functional role of the fast transient outward K+ current IA in pyramidal neurons in (rat) primary visual cortex. J. Neurosci. 25, 9185–9194 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Alonso, G. & Widmer, H. Clustering of KV4.2 potassium channels in postsynaptic membrane of rat supraoptic neurons: an ultrastructural study. Neuroscience 77, 617–621 (1997).

    Article  CAS  PubMed  Google Scholar 

  165. Shibasaki, K. et al. Mossy fibre contact triggers the targeting of Kv4.2 potassium channels to dendrites and synapses in developing cerebellar granule neurons. J. Neurochem. 89, 897–907 (2004).

    Article  CAS  PubMed  Google Scholar 

  166. Frick, A., Magee, J. & Johnston, D. LTP is accompanied by an enhanced local excitability of pyramidal neuron dendrites. Nature Neurosci. 7, 126–135 (2004).

    Article  CAS  PubMed  Google Scholar 

  167. Petrecca, K., Miller, D. M. & Shrier, A. Localization and enhanced current density of the Kv4.2 potassium channel by interaction with the actin-binding protein filamin. J. Neurosci. 20, 8736–8744 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Rivera, J. F., Ahmad, S., Quick, M. W., Liman, E. R. & Arnold, D. B. An evolutionarily conserved dileucine motif in Shal K+ channels mediates dendritic targeting. Nature Neurosci. 6, 243–250 (2003). Reports a C-terminal di-leucine motif that is necessary and sufficient for dendritic targeting of Kv4.2.

    Article  CAS  PubMed  Google Scholar 

  169. Chu, P. J., Rivera, J. F. & Arnold, D. B. A role for Kif17 in transport of Kv4.2. J. Biol. Chem. 281, 365–373 (2006).

    Article  CAS  PubMed  Google Scholar 

  170. Ren, X., Hayashi, Y., Yoshimura, N. & Takimoto, K. Transmembrane interaction mediates complex formation between peptidase homologues and Kv4 channels. Mol. Cell. Neurosci. 29, 320–332 (2005).

    Article  CAS  PubMed  Google Scholar 

  171. Jerng, H. H., Kunjilwar, K. & Pfaffinger, P. J. Multiprotein assembly of Kv4.2, KChIP3 and DPP10 produces ternary channel complexes with ISA-like properties. J. Physiol. 568, 767–788 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Zagha, E. et al. DPP10 modulates Kv4-mediated A-type potassium channels. J. Biol. Chem. 280, 18853–18861 (2005).

    Article  CAS  PubMed  Google Scholar 

  173. Strop, P., Bankovich, A. J., Hansen, K. C., Garcia, K. C. & Brunger, A. T. Structure of a human A-type potassium channel interacting protein DPPX, a member of the dipeptidyl aminopeptidase family. J. Mol. Biol. 343, 1055–1065 (2004).

    Article  CAS  PubMed  Google Scholar 

  174. Jerng, H. H., Qian, Y. & Pfaffinger, P. J. Modulation of Kv4.2 channel expression and gating by dipeptidyl peptidase 10 (DPP10). Biophys. J. 87, 2380–2396 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Shibata, R. et al. A fundamental role for KChIPs in determining the molecular properties and trafficking of Kv4.2 potassium channels. J. Biol. Chem. 278, 36445–36454 (2003).

    Article  CAS  PubMed  Google Scholar 

  176. Hasdemir, B., Fitzgerald, D. J., Prior, I. A., Tepikin, A. V. & Burgoyne, R. D. Traffic of Kv4 K+ channels mediated by KChIP1 is via a novel post-ER vesicular pathway. J. Cell Biol. 171, 459–469 (2005). Describes that KChIP1 can increase surface expression of Kv4.2 by a pathway that is COPII independent.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Deng, Q. et al. A C-terminal domain directs Kv3.3 channels to dendrites. J. Neurosci. 25, 11531–11541 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Martina, M., Yao, G. L. & Bean, B. P. Properties and functional role of voltage-dependent potassium channels in dendrites of rat cerebellar Purkinje neurons. J. Neurosci. 23, 5698–5707 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Ozaita, A. et al. A unique role for Kv3 voltage-gated potassium channels in starburst amacrine cell signaling in mouse retina. J. Neurosci. 24, 7335–7343 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Euler, T., Detwiler, P. B. & Denk, W. Directionally selective calcium signals in dendrites of starburst amacrine cells. Nature 418, 845–852 (2002).

    Article  CAS  PubMed  Google Scholar 

  181. Parameshwaran-Iyer, S., Carr, C. E. & Perney, T. M. Localization of KCNC1 (Kv3.1) potassium channel subunits in the avian auditory nucleus magnocellularis and nucleus laminaris during development. J. Neurobiol. 55, 165–178 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Hell, J. W. et al. Identification and differential subcellular localization of the neuronal class C and class D L-type calcium channel α1 subunits. J. Cell Biol. 123, 949–962 (1993).

    Article  CAS  PubMed  Google Scholar 

  183. Westenbroek, R. E. et al. Biochemical properties and subcellular distribution of an N-type calcium channel α1 subunit. Neuron 9, 1099–1115 (1992).

    Article  CAS  PubMed  Google Scholar 

  184. Castillo, P. E., Weisskopf, M. G. & Nicoll, R. A. The role of Ca2+ channels in hippocampal mossy fiber synaptic transmission and long-term potentiation. Neuron 12, 261–269 (1994).

    Article  CAS  PubMed  Google Scholar 

  185. Dietrich, D. et al. Functional specialization of presynaptic Cav2.3 Ca2+ channels. Neuron 39, 483–496 (2003).

    Article  CAS  PubMed  Google Scholar 

  186. Yasuda, R., Sabatini, B. L. & Svoboda, K. Plasticity of calcium channels in dendritic spines. Nature Neurosci. 6, 948–955 (2003).

    Article  CAS  PubMed  Google Scholar 

  187. Magee, J. C., Avery, R. B., Christie, B. R. & Johnston, D. Dihydropyridine-sensitive, voltage-gated Ca2+ channels contribute to the resting intracellular Ca2+ concentration of hippocampal CA1 pyramidal neurons. J. Neurophysiol. 76, 3460–3470 (1996).

    Article  CAS  PubMed  Google Scholar 

  188. Bichet, D. et al. The I–II loop of the Ca2+ channel α1 subunit contains an endoplasmic reticulum retention signal antagonized by the β subunit. Neuron 25, 177–190 (2000).

    Article  CAS  PubMed  Google Scholar 

  189. Leroy, J. et al. Interaction via a key tryptophan in the I–II linker of N-type calcium channels is required for β1 but not for palmitoylated β2, implicating an additional binding site in the regulation of channel voltage-dependent properties. J. Neurosci. 25, 6984–6996 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Takahashi, S. X., Miriyala, J., Tay, L. H., Yue, D. T. & Colecraft, H. M. A CaVβ SH3/guanylate kinase domain interaction regulates multiple properties of voltage-gated Ca2+ channels. J. Gen. Physiol. 126, 365–377 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Viard, P. et al. PI3K promotes voltage-dependent calcium channel trafficking to the plasma membrane. Nature Neurosci. 7, 939–946 (2004).

    Article  CAS  PubMed  Google Scholar 

  192. Cornet, V. et al. Multiple determinants in voltage-dependent P/Q calcium channels control their retention in the endoplasmic reticulum. Eur. J. Neurosci. 16, 883–895 (2002).

    Article  PubMed  Google Scholar 

  193. Altier, C. et al. Trafficking of L-type calcium channels mediated by the postsynaptic scaffolding protein AKAP79. J. Biol. Chem. 277, 33598–33603 (2002).

    Article  CAS  PubMed  Google Scholar 

  194. Canti, C. et al. The metal-ion-dependent adhesion site in the Von Willebrand factor-A-domain of α2δ subunits is key to trafficking voltage-gated Ca2+ channels. Proc. Natl Acad. Sci. USA 102, 11230–11235 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Carr, C. E., Soares, D., Parameshwaran, S. & Perney, T. Evolution and development of time coding systems. Curr. Opin. Neurobiol. 11, 727–733 (2001).

    Article  CAS  PubMed  Google Scholar 

  196. Jentsch, T. J., Neagoe, I. & Scheel, O. CLC chloride channels and transporters. Curr. Opin. Neurobiol. 15, 319–325 (2005).

    Article  CAS  PubMed  Google Scholar 

  197. Scheel, O., Zdebik, A. A., Lourdel, S. & Jentsch, T. J. Voltage-dependent electrogenic chloride/proton exchange by endosomal CLC proteins. Nature 436, 424–427 (2005).

    Article  CAS  PubMed  Google Scholar 

  198. Boiko, T. et al. Functional specialization of the axon initial segment by isoform-specific sodium channel targeting. J. Neurosci. 23, 2306–2313 (2003). Reports the differential expression of Nav1.2 and Nav1.6 during development at the axon initial segment and that the appearance of Nav1.6 coincides with repetitive firing in retinal ganglion cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Boiko, T. et al. Compact myelin dictates the differential targeting of two sodium channel isoforms in the same axon. Neuron 30, 91–104 (2001). Describes the differential expression of Nav1.2 and Nav1.6 during development at the nodes of Ranvier.

    Article  CAS  PubMed  Google Scholar 

  200. Wang, G. Y., Ratto, G., Bisti, S. & Chalupa, L. M. Functional development of intrinsic properties in ganglion cells of the mammalian retina. J. Neurophysiol. 78, 2895–2903 (1997).

    Article  CAS  PubMed  Google Scholar 

  201. Grinspan, J. B., Coulalaglou, M., Beesley, J. S., Carpio, D. F. & Scherer, S. S. Maturation-dependent apoptotic cell death of oligodendrocytes in myelin-deficient rats. J. Neurosci. Res. 54, 623–634 (1998).

    Article  CAS  PubMed  Google Scholar 

  202. Kaplan, M. R. et al. Induction of sodium channel clustering by oligodendrocytes. Nature 386, 724–728 (1997).

    Article  CAS  PubMed  Google Scholar 

  203. Henry, E. W. & Sidman, R. L. Long lives for homozygous trembler mutant mice despite virtual absence of peripheral nerve myelin. Science 241, 344–346 (1988).

    Article  CAS  PubMed  Google Scholar 

  204. Baba, H. et al. Completion of myelin compaction, but not the attachment of oligodendroglial processes triggers K+ channel clustering. J. Neurosci. Res. 58, 752–764 (1999).

    Article  CAS  PubMed  Google Scholar 

  205. Kaplan, M. R. et al. Differential control of clustering of the sodium channels Nav1.2 and Nav1.6 at developing CNS nodes of Ranvier. Neuron 30, 105–119 (2001). Reports the changing distribution of Nav1.2 and Nav1.6 channels in a myelinating culture system.

    Article  CAS  PubMed  Google Scholar 

  206. Rasband, M. N., Trimmer, J. S., Peles, E., Levinson, S. R. & Shrager, P. K+ channel distribution and clustering in developing and hypomyelinated axons of the optic nerve. J. Neurocytol. 28, 319–331 (1999).

    Article  CAS  PubMed  Google Scholar 

  207. Rasband, M. N. & Shrager, P. Ion channel sequestration in central nervous system axons. J. Physiol. 525, 63–73 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We would like to thank F. Haass for critical reading of the manuscript. We thank K. Raab-Graham and members of the Jan laboratory for helpful discussions. H.C.L. was supported by an American Heart Association pre-doctoral fellowship, Western States Affiliate. L.Y.J. is a Howard Hughes Medical Institute investigator.

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Authors and Affiliations

  1. Center for Basic Neuroscience, University of Texas Southwestern Medical Center, Dallas, 75390, Texas, USA

    Helen C. Lai

  2. Howard Hughes Medical Institute, University of California, San Francisco, 1550 4th Street, the Rock Hall, San Francisco, 94158, California, USA

    Lily Y. Jan

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Glossary

Axon initial segment

(AIS). The area of the axon near the soma that contains a high density of voltage-gated sodium channels, which are responsible for the initial depolarization that leads to the initiation of the action potential.

Saltatory conduction

The way an action potential 'jumps' between nodes of a myelinated axon, for fast conduction.

Back-propagation

The propagation of action potentials 'backward' up the dendrites.

Long-term potentiation

(LTP).The prolonged strengthening of synaptic communication, which is induced by patterned input and is thought to be involved in learning and memory formation.

Long-term depression

(LTD). An enduring weakening of synaptic strength that is thought to interact with long-term potentiation (LTP) in the cellular mechanisms of learning and memory in structures such as the hippocampus and cerebellum. Unlike LTP, which is produced by brief high-frequency stimulation, LTD can be produced by long-term, low-frequency stimulation.

Juxtaparanode

A region of the axon that is adjacent to the paranodes, which are adjacent to the nodes of Ranvier and are located underneath the myelin sheath.

L1 CAM

A cell adhesion molecule in the nervous system that is important for cell–cell interactions that occur through 6 immunoglobulin G-like protein domains and 3–5 fibronectin type II domains.

KChIPs

β-subunits of Kv4 channels, which have four calcium-binding EF hands with homology to the recoverin/neuronal calcium sensor -1 (NCS1) family.

CD26

A dipeptidyl aminopeptidase and cell adhesion protein.

Directed targeting

The specific transport of proteins to their proper location (axons or dendrites) after their exit from the ER.

Transcytosis

The targeting of membrane proteins first to one compartment and then, after their endocytosis, to another subcellular compartment.

Selective retention

Interaction with anchor proteins at specific sites causes membrane proteins that are transported to the neuronal membrane uniformly to remain only at those sites (sequestration/retention/stabilizing/anchoring), while being internalized elsewhere.

Contactin

A glycosylphosphatidylinositol (GPI) anchored glycoprotein with structural homology to the L1 CAM extracellular domain. It has six IgG-like protein domains followed by four fibronectin type III domains.

Ankyrin G

One of three types of ankyrin adaptor proteins that link integral membrane proteins to the spectrin/actin membrane cytoskeleton. Known as “G” for giant or general, it has two main alternative splice forms that generate proteins of 270 kDa and 480 kDa.

βIV spectrin

A splice form of the β-subunit of spectrin, which is a tetramer with two α- and two β-subunits that form two antiparallel heterodimers.

Chimeric fusion protein

A polypeptide that is created by fusing an amino acid sequence of interest to a reporter protein.

CD4

A single-span transmembrane protein that tends to yield a uniform distribution in axons and dendrites when it is expressed in neurons.

ER export or retention motifs

Amino acid sequences that have been identified in a number of proteins to be responsible for either exit from, or retention in, the ER (for example, RXR).

Endocytic motif

A common amino acid sequence (for example, YXXφ) that signals clathrin-mediated endocytosis.

ER chaperone

A protein that is located in the ER and that helps other proteins to fold.

PDZ binding motif

A PDZ domain binding motif of approximately five amino acids, which is typically located at the extreme C-terminus of a protein.

M current

(IM). A slow, sub-threshold non-inactivating potassium current that is carried by KCNQ2/3 heteromeric channels and is named for its inhibition by muscarinic agonists.

A-type currents

A rapidly inactivating voltage-dependent potassium current.

4-AP

4-Aminopyridine, a blocker of certain voltage-gated potassium channels.

I h

A hyperpolarization-activated cation current that has been identified in cardiac pacemaker and Purkinje fibres for rhythmic and burst firing.

Filamin A

A dimeric scaffold-like protein that connects membrane proteins to the actin cytoskeleton.

Delayed rectifier current

(IK). Current that is mediated by voltage-gated potassium channels, which activate with a delay after the onset of depolarization.

Calcineurin

A calcium–calmodulin-dependent protein phosphatase.

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Lai, H., Jan, L. The distribution and targeting of neuronal voltage-gated ion channels. Nat Rev Neurosci 7, 548–562 (2006). https://doi.org/10.1038/nrn1938

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