ArticleMolecular psychiatry2017
HCN-channel dendritic targeting requires bipartite interaction with TRIP8b and regulates antidepressant-like behavioral effects.
Article in Molecular psychiatry, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 38 papers.
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Who cites it
38 citing papers in PubMed, 51 citations in OpenAlex.
- Channel Dysfunction as the Basis for Comorbidities in Multiple Sclerosis and Depression.Archiv der Pharmazie · 2026Review
- Dorsal CA1 projections to nucleus accumbens and lateral septum differentially regulate social and locomotor behavior.Cerebral cortex (New York, N.Y. : 1991) · 2026Article
- Design and validation of novel brain-penetrant HCN channel inhibitors to ameliorate social stress-induced susceptible phenotype.Molecular psychiatry · 2025Article
- Hippocampal dorsal CA1: Functional connectivity and role in HCN channelopathies in affective diseases and epilepsy.IBRO neuroscience reports · 2025Article
- HCN channels in the lateral habenula regulate pain and comorbid depressive-like behaviors in mice.CNS neuroscience & therapeutics · 2024Article
- A Molecular Framework for Delirium.The Neurohospitalist · 2024Review
- Effect of Acute Ketamine Treatment on Sympathetic Regulation Indexed by Electrodermal Activity in Adolescent Major Depression.Pharmaceuticals (Basel, Switzerland) · 2024Article
- Protein kinase Cγ negatively regulates the intrinsic excitability in zebrin-negative cerebellar Purkinje cells.Frontiers in cellular neuroscience · 2024Article
- Characterization of hyperpolarization-activated cyclic nucleotide-gated channels in oligodendrocytes.Frontiers in cellular neuroscience · 2024Article
- Spatiotemporal features of neurovascular (un)coupling with stimulus-induced activity and hypercapnia challenge in cerebral cortex and olfactory bulb.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2023Article
- GluN2A mediates ketamine-induced rapid antidepressant-like responses.Nature neuroscience · 2023Article
- Antidepressant-like activity of a brain penetrant HCN channel inhibitor in mice.Frontiers in pharmacology · 2023Article
- Target deconvolution studies of (2R,6R)-hydroxynorketamine: an elusive search.Molecular psychiatry · 2022Article
- PEX5R/Trip8b-HCN2 channel regulating neuroinflammation involved in perioperative neurocognitive disorders.Cell & bioscience · 2022Article
- Discovery of a small-molecule inhibitor of the TRIP8b-HCN interaction with efficacy in neurons.The Journal of biological chemistry · 2022Article
- Regulation of HCN Channels by Protein Interactions.Frontiers in physiology · 2022Review
- Chronic Cerebral Hypoperfusion-induced Dysregulations of Hyperpolarization- activated Cyclic Nucleotide-gated, KCNQ and G Protein-coupled Inwardly Rectifying Potassium Channels Correlated with Susceptibility and Unsusceptibility to Anxiety Behaviors.Current neurovascular research · 2022Article
- Hippocampal cAMP regulates HCN channel function on two time scales with differential effects on animal behavior.Science translational medicine · 2021Article
- Physiology and Therapeutic Potential of SK, H, and M Medium AfterHyperPolarization Ion Channels.Frontiers in molecular neuroscience · 2021Review
- The structure and function of TRIP8b, an auxiliary subunit of hyperpolarization-activated cyclic-nucleotide gated channels.Channels (Austin, Tex.) · 2020Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
Abstract
Major depressive disorder (MDD) is a prevalent psychiatric condition with limited therapeutic options beyond monoaminergic therapies. Although effective in some individuals, many patients fail to respond adequately to existing treatments, and new pharmacologic targets are needed. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate excitability in neurons, and blocking HCN channel function has been proposed as a novel antidepressant strategy. However, systemic blockade of HCN channels produces cardiac effects that limit this approach. Knockout (KO) of the brain-specific HCN-channel auxiliary subunit tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b) also produces antidepressant-like behavioral effects and suggests that inhibiting TRIP8b function could produce antidepressant-like effects without affecting the heart. We examined the structural basis of TRIP8b-mediated HCN-channel trafficking and its relationship with antidepressant-like behavior using a viral rescue approach in TRIP8b KO mice. We found that restoring TRIP8b to the hippocampus was sufficient to reverse the impaired HCN-channel trafficking and antidepressant-like behavioral effects caused by TRIP8b KO. Moreover, we found that hippocampal expression of a mutated version of TRIP8b further impaired HCN-channel trafficking and increased the antidepressant-like behavioral phenotype of TRIP8b KO mice. Thus, modulating the TRIP8b-HCN interaction bidirectionally influences channel trafficking and antidepressant-like behavior. Overall, our work suggests that small-molecule inhibitors of the interaction between TRIP8b and HCN should produce antidepressant-like behaviors and could represent a new paradigm for the treatment of MDD.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.