Trafficking and surface expression of hyperpolarization-activated cyclic nucleotide-gated channels in hippocampal neurons.

Noam Y, Zha Q, Phan L, Wu RL, Chetkovich DM, Wadman WJ, Baram TZ
J Biol Chem. 2010 285 (19): 14724-36

PMID: 20215108 · PMCID: PMC2863223 · DOI:10.1074/jbc.M109.070391

Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels mediate the hyperpolarization-activated current I(h) and thus play important roles in the regulation of brain excitability. The subcellular distribution pattern of the HCN channels influences the effects that they exert on the properties and activity of neurons. However, little is known about the mechanisms that control HCN channel trafficking to subcellular compartments or that regulate their surface expression. Here we studied the dynamics of HCN channel trafficking in hippocampal neurons using dissociated cultures coupled with time lapse imaging of fluorophore-fused HCN channels. HCN1-green fluorescence protein (HCN1-GFP) channels resided in vesicle-like organelles that moved in distinct patterns along neuronal dendrites, and these properties were isoform-specific. HCN1 trafficking required intact actin and tubulin and was rapidly inhibited by activation of either NMDA or AMPA-type ionotropic glutamate receptors in a calcium-dependent manner. Glutamate-induced inhibition of the movement of HCN1-GFP-expressing puncta was associated with increased surface expression of both native and transfected HCN1 channels, and this surface expression was accompanied by augmented I(h). Taken together, the results reveal the highly dynamic nature of HCN1 channel trafficking in hippocampal neurons and provide a novel potential mechanism for rapid regulation of I(h), and hence of neuronal properties, via alterations of HCN1 trafficking and surface expression.

MeSH Terms (19)

Actins Animals Animals, Newborn Biotinylation Cells, Cultured Cyclic Nucleotide-Gated Cation Channels Dendrites Electrophysiology Green Fluorescent Proteins Hippocampus Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels Immunoenzyme Techniques Ion Channel Gating Microtubules Neurons Potassium Channels Rats Rats, Sprague-Dawley Recombinant Fusion Proteins

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