Trafficking and gating of hyperpolarization-activated cyclic nucleotide-gated channels are regulated by interaction with Tetratricopeptide Repeat-containing Rab8b-interacting Protein (TRIP8b) and cyclic AMP at distinct sites

Ye Han, Yoav Noam, Alan S. Lewis, Johnie J. Gallagher, Wytse J. Wadman, Tallie Z. Baram, Dane M. Chetkovich

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

Ion channel trafficking and gating are often influenced by interactions with auxiliary subunits. Tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) is an auxiliary subunit for neuronal hyperpolarization- activated cyclic nucleotide-gated (HCN) channels. TRIP8b interacts directly with two distinct sites of HCN channel pore-forming subunits to control channel trafficking and gating. Here we use mutagenesis combined with electrophysiological studies to define and distinguish the functional importance of the HCN/TRIP8b interaction sites. Interaction with the last three amino acids of the HCN1 C terminus governed the effect of TRIP8b on channel trafficking, whereas TRIP8b interaction with the HCN1 cyclic nucleotide binding domain (CNBD) affected trafficking and gating. Biochemical studies revealed that direct interaction between TRIP8b and the HCN1 CNBD was disrupted by cAMP and that TRIP8b binding to the CNBD required an arginine residue also necessary for cAMP binding. In accord, increasing cAMP levels in cells antagonized the up-regulation of HCN1 channels mediated by a TRIP8b construct binding the CNBD exclusively. These data illustrate the distinct roles of the two TRIP8b-HCN interaction domains and suggest that TRIP8b and cAMP may directly compete for binding the HCNC NBD to control HCN channel gating, kinetics, and trafficking.

Original languageEnglish (US)
Pages (from-to)20823-20834
Number of pages12
JournalJournal of Biological Chemistry
Volume286
Issue number23
DOIs
StatePublished - Jun 10 2011

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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