Clustering and activity tuning of Kv1 channels in myelinated hippocampal axons

J Biol Chem. 2011 Jul 22;286(29):25835-47. doi: 10.1074/jbc.M111.219113. Epub 2011 May 20.


Precise localization of axonal ion channels is crucial for proper electrical and chemical functions of axons. In myelinated axons, Kv1 (Shaker) voltage-gated potassium (Kv) channels are clustered in the juxtaparanodal regions flanking the node of Ranvier. The clustering can be disrupted by deletion of various proteins in mice, including contactin-associated protein-like 2 (Caspr2) and transient axonal glycoprotein-1 (TAG-1), a glycosylphosphatidylinositol-anchored cell adhesion molecule. However, the mechanism and function of Kv1 juxtaparanodal clustering remain unclear. Here, using a new myelin coculture of hippocampal neurons and oligodendrocytes, we report that tyrosine phosphorylation plays a critical role in TAG-1-mediated clustering of axonal Kv1.2 channels. In the coculture, myelin specifically ensheathed axons but not dendrites of hippocampal neurons and clustered endogenous axonal Kv1.2 into internodes. The trans-homophilic interaction of TAG-1 was sufficient to position Kv1.2 clusters on axonal membranes in a neuron/HEK293 coculture. Mutating a tyrosine residue (Tyr⁴⁵⁸) in the Kv1.2 C terminus or blocking tyrosine phosphorylation disrupted myelin- and TAG-1-mediated clustering of axonal Kv1.2. Furthermore, Kv1.2 voltage dependence and activation threshold were reduced by TAG-1 coexpression. This effect was eliminated by the Tyr⁴⁵⁸ mutation or by cholesterol depletion. Taken together, our studies suggest that myelin regulates both trafficking and activity of Kv1 channels along hippocampal axons through TAG-1.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Axons / metabolism*
  • Cell Membrane / metabolism
  • Coculture Techniques
  • Contactin 2 / metabolism
  • HEK293 Cells
  • Hippocampus / cytology*
  • Humans
  • Kv1.2 Potassium Channel / chemistry
  • Kv1.2 Potassium Channel / metabolism*
  • Myelin Sheath / physiology*
  • Neurons / cytology
  • Phosphorylation
  • Rats
  • Signal Transduction
  • Sodium Channels / metabolism
  • Tyrosine / metabolism


  • Contactin 2
  • Kv1.2 Potassium Channel
  • Sodium Channels
  • Tyrosine