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The Journal of Neuroscience, November 24, 2004, 24(47):10750-10762; doi:10.1523/JNEUROSCI.3300-04.2004

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Cellular/Molecular
Regulation of HCN Channel Surface Expression by a Novel C-Terminal Protein-Protein Interaction

Bina Santoro,¹ Brian J. Wainger,¹ and Steven A. Siegelbaum^1,2,3

¹Center for Neurobiology and Behavior, ²Department of Pharmacology, Columbia University, and ³Howard Hughes Medical Institute, New York, New York 10032

Hyperpolarization-activated cation currents (I_h) are carried by channels encoded by a family of four genes (HCN1-4) that are differentially expressed within the brain in specific cellular and subcellular compartments. HCN1 shows a high level of expression in apical dendrites of cortical pyramidal neurons and in presynaptic terminals of cerebellar basket cells, structures with a high density of I_h. Expression of I_h is also regulated by neuronal activity. To isolate proteins that may control HCN channel expression or function, we performed yeast two-hybrid screens using the C-terminal cytoplasmic tails of the HCN proteins as bait. We identified a brain-specific protein, which has been previously termed TRIP8b (for TPR-containing Rab8b interacting protein) and PEX5Rp (for Pex5p-related protein), that specifically interacts with all four HCN channels through a conserved sequence in their C-terminal tails. In situ hybridization and immunohistochemistry show that TRIP8b and HCN1 are colocalized, particularly within dendritic arbors of hippocampal CA1 and neocortical layer V pyramidal neurons. The dendritic expression of TRIP8b in layer V pyramidal neurons is disrupted after deletion of HCN1 through homologous recombination, demonstrating a key in vivo interaction between HCN1 and TRIP8b. TRIP8b dramatically alters the trafficking of HCN channels heterologously expressed in Xenopus oocytes and human embryonic kidney 293 cells, causing a specific decrease in surface expression of HCN protein and I_h density, with a pronounced intracellular accumulation of HCN protein that is colocalized in discrete cytoplasmic clusters with TRIP8b. Finally, TRIP8b expression in cultured pyramidal neurons markedly decreases native I_h density. These data suggest a possible role for TRIP8b in regulating HCN channel density in the plasma membrane.

Key words: hyperpolarization-activated channel; I_h; dendrite; hippocampus; endosome; trafficking

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Received Jan 8, 2004; revised October 13, 2004; accepted October 18, 2004.

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