Abstract
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.
Copyright © 2011 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Biophysics / methods
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CA1 Region, Hippocampal / cytology*
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Calcium-Calmodulin-Dependent Protein Kinase Type 2 / genetics
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Cyclic Nucleotide-Gated Cation Channels / antagonists & inhibitors
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Cyclic Nucleotide-Gated Cation Channels / deficiency
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Cyclic Nucleotide-Gated Cation Channels / metabolism*
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Dendrites / metabolism
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Electric Stimulation / methods
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Excitatory Postsynaptic Potentials / drug effects
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Excitatory Postsynaptic Potentials / genetics
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Exons / physiology
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / genetics
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Green Fluorescent Proteins / genetics
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Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
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In Vitro Techniques
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Lentivirus / genetics
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Luminescent Proteins / genetics
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Membrane Potentials / drug effects
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Membrane Potentials / genetics
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Membrane Proteins / deficiency
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Membrane Proteins / metabolism*
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Mice
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Mice, Knockout
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Mutation / genetics
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Neurons / cytology
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Neurons / physiology*
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Patch-Clamp Techniques
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Peroxins
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Potassium Channels / deficiency
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Potassium Channels / metabolism*
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Protein Binding / drug effects
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Protein Binding / genetics
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Protein Isoforms / genetics
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Protein Isoforms / metabolism*
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Protein Transport / drug effects
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Protein Transport / genetics
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Pyrimidines / pharmacology
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RNA, Small Interfering / metabolism
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RNA, Small Interfering / pharmacology
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Transduction, Genetic / methods
Substances
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Cyclic Nucleotide-Gated Cation Channels
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Hcn1 protein, mouse
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Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels
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Luminescent Proteins
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Membrane Proteins
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Peroxins
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Pex5l protein, mouse
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Potassium Channels
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Protein Isoforms
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Pyrimidines
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RNA, Small Interfering
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enhanced green fluorescent protein
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fluorescent protein 583
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ICI D2788
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Green Fluorescent Proteins
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Calcium-Calmodulin-Dependent Protein Kinase Type 2