ArticleThe Journal of neuroscience : the official journal of the Society for Neuroscience2009
Alternatively spliced isoforms of TRIP8b differentially control h channel trafficking and function.
Article in The Journal of neuroscience : the official journal of the Society for Neuroscience, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 102 papers, 1 of them a synthesis that pooled it.
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Who cites it
102 citing papers in PubMed, 1 synthesis or guideline pooled it, 153 citations in OpenAlex.
- The Contribution of HCN Channelopathies in Different Epileptic Syndromes, Mechanisms, Modulators, and Potential Treatment Targets: A Systematic Review.Frontiers in molecular neuroscience · 2022Pooled it
- A tissue-specific atlas of protein-protein associations enables prioritization of candidate disease genes.Nature biotechnology · 2026Article
- HCN channels reveal conserved and divergent physiology in supragranular pyramidal neurons in primate species.Communications biology · 2026Article
- Reward-associated cues reduce H-current amplitude in midbrain dopamine neurons.Neuropharmacology · 2025Article
- 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
- Areal specializations in the morpho-electric and transcriptomic properties of primate layer 5 extratelencephalic projection neurons.Cell reports · 2024Article
- Characterization of hyperpolarization-activated cyclic nucleotide-gated channels in oligodendrocytes.Frontiers in cellular neuroscience · 2024Article
- cAMP-mediated upregulation of HCN channels in VTA dopamine neurons promotes cocaine reinforcement.Molecular psychiatry · 2023Article
- Activation of metabotropic glutamate receptor 1 regulates hippocampal CA1 region excitability in rats with status epilepticus by suppressing the HCN1 channel.Neural regeneration research · 2023Article
- The Impact of Altered HCN1 Expression on Brain Function and Its Relationship with Epileptogenesis.Current neuropharmacology · 2023Review
- Behavioral pattern separation and cognitive flexibility are enhanced in a mouse model of increased lateral entorhinal cortex-dentate gyrus circuit activity.Frontiers in behavioral neuroscience · 2023Article
- Glucocorticoid-glucocorticoid receptor-HCN1 channels reduce neuronal excitability in dorsal hippocampal CA1 neurons.Molecular psychiatry · 2022Article
- Seizures, behavioral deficits, and adverse drug responses in two new genetic mouse models ofeLife · 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
- Identification of HCN1 as a 14-3-3 client.PloS one · 2022Article
- Hippocampal cAMP regulates HCN channel function on two time scales with differential effects on animal behavior.Science translational medicine · 2021Article
- IProgress in biophysics and molecular biology · 2021Review
- Article
42 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 5 institutions in 2 countries.
Funding
Abstract
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels (h channels) are the molecular basis for the current, I(h), which contributes crucially to intrinsic neuronal excitability. The subcellular localization and biophysical properties of h channels govern their function, but the mechanisms controlling these characteristics, and especially the potential role of auxiliary subunits or other binding proteins, remain unclear. We focused on TRIP8b, an h channel-interacting protein that colocalizes with HCN1 in cortical and hippocampal pyramidal neuron dendrites, and found that it exists in multiple alternative splice variants with distinct effects on h channel trafficking and function. The developmentally regulated splice variants of TRIP8b all shared dual, C terminus-located interaction sites with HCN1. When coexpressed with HCN1 in heterologous cells individual TRIP8b isoforms similarly modulated gating of I(h), causing a hyperpolarizing shift in voltage dependence of channel activation, but differentially upregulated or downregulated I(h) current density and HCN1 surface expression. In hippocampal neurons, coexpression of TRIP8b isoforms with HCN1 produced isoform-specific changes of HCN1 localization. Interestingly, the TRIP8b isoforms most abundant in the brain are those predicted to enhance h channel surface expression. Indeed, shRNA knockdown of TRIP8b in hippocampal neurons significantly reduced native I(h). Thus, although TRIP8b exists in multiple splice isoforms, our data suggest that the predominant role of this protein in brain is to promote h channel surface expression and enhance I(h). Because I(h) expression is altered in models of several diseases, including temporal lobe epilepsy, TRIP8b may play a role in both normal neuronal function and in aberrant neuronal excitability associated with neurological disease.
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Registered trials
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