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TRIP8b splice forms act in concert to regulate the localization and expression of HCN1 channels in CA1 pyramidal neurons.

HCN1 channel subunits, which contribute to the hyperpolarization-activated cation current (Ih), are selectively targeted to distal apical dendrites of hippocampal CA1 pyramidal neurons. Here, we addressed the importance of the brain-specific auxiliary subunit of HCN1, TRIP8b, in regulating HCN1 expression and localization. More than ten N-terminal splice variants of TRIP8b exist in brain and exert distinct effects on HCN1 trafficking when overexpressed. We found that isoform-wide disruption of the TRIP8b/HCN1 interaction caused HCN1 to be mistargeted throughout CA1 somatodendritic compartments. In contrast, HCN1 was targeted normally to CA1 distal dendrites in a TRIP8b knockout mouse that selectively lacked exons 1b and 2. Of the two remaining hippocampal TRIP8b isoforms, TRIP8b(1a-4) promoted HCN1 surface expression in dendrites, whereas TRIP8b(1a) suppressed HCN1 misexpression in axons. Thus, proper subcellular localization of HCN1 depends on its differential additive and subtractive sculpting by two isoforms of a single auxiliary subunit.

Pubmed ID: 21555075

Authors

  • Piskorowski R
  • Santoro B
  • Siegelbaum SA

Journal

Neuron

Publication Data

May 12, 2011

Associated Grants

  • Agency: NINDS NIH HHS, Id: F32NS064732
  • Agency: NIMH NIH HHS, Id: MH80745
  • Agency: NINDS NIH HHS, Id: NS36658
  • Agency: NIMH NIH HHS, Id: R01 MH080745
  • Agency: NIMH NIH HHS, Id: R01 MH080745-05
  • Agency: NINDS NIH HHS, Id: R01 NS036658
  • Agency: NINDS NIH HHS, Id: R01 NS036658-13
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Howard Hughes Medical Institute, Id:

Mesh Terms

  • Animals
  • Biophysics
  • CA1 Region, Hippocampal
  • Calcium-Calmodulin-Dependent Protein Kinase Type 2
  • Cyclic Nucleotide-Gated Cation Channels
  • Dendrites
  • Electric Stimulation
  • Excitatory Postsynaptic Potentials
  • Exons
  • Gene Expression Regulation
  • Green Fluorescent Proteins
  • Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
  • In Vitro Techniques
  • Lentivirus
  • Luminescent Proteins
  • Membrane Potentials
  • Membrane Proteins
  • Mice
  • Mice, Knockout
  • Mutation
  • Neurons
  • Patch-Clamp Techniques
  • Potassium Channels
  • Protein Binding
  • Protein Isoforms
  • Protein Transport
  • Pyrimidines
  • RNA, Small Interfering
  • Transduction, Genetic