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Showing PEX5L — TRIP8B is a alias.

PEX5L

PEX5-related protein · UniProt Q8IYB4

Length
626 aa
Mass
69.7 kDa
Annotated
2026-06-10
35 papers in source corpus 25 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PEX5L/TRIP8b is a brain-enriched auxiliary (beta) subunit of hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels that controls both HCN gating and subcellular trafficking (PMID:19555649, PMID:19439603, PMID:19555650). It binds the pore-forming HCN subunits at two distinct C-terminal sites: an upstream interaction between the TRIP8b conserved core and the HCN C-linker/cyclic nucleotide-binding domain (CNBD), which is necessary and sufficient to inhibit channel opening, and a downstream interaction between the TRIP8b tetratricopeptide-repeat (TPR) domain and the HCN C-terminal SNL tripeptide, which stabilizes the complex and drives upregulatory trafficking; binding at the two sites is allosterically coupled, conferring HCN binding specificity (PMID:21411649, PMID:22550182, PMID:28887304). The structure of the TPR–SNL interface was solved crystallographically, and the assembled channel adopts an obligate 4:4 (one TRIP8b per HCN subunit) stoichiometry (PMID:22550182, PMID:36225302). At the CNBD, TRIP8b binds the apo (cAMP-free) state and reduces cyclic-nucleotide sensitivity, acting predominantly as a partial competitive antagonist of cAMP, thereby suppressing cAMP/beta-adrenergic potentiation of HCN currents (PMID:19555650, PMID:28864772). Through nine alternative N-terminal splice isoforms carrying distinct trafficking motifs and clathrin-binding sequences, TRIP8b sculpts HCN1 surface expression and somatodendritic-versus-axonal distribution, and routes HCN channels through clathrin-coated vesicles toward endosomes and lysosomes; loss of TRIP8b reduces dendritic Ih, mistargets HCN, and accelerates its lysosomal degradation (PMID:19555649, PMID:19439603, PMID:21555075, PMID:21749376, PMID:21593326). TRIP8b-dependent HCN dendritic trafficking bidirectionally controls antidepressant-like behavior in mice, and Ser237 phosphorylation that enhances HCN binding is lost in a model of temporal lobe epilepsy, linking TRIP8b regulation to neuronal excitability disorders (PMID:27400855, PMID:31492750). Independently of its channel role, PEX5L functions as a co-receptor for PTS2-mediated peroxisomal import, forming a trimeric cargo–PEX7–PEX5L complex in which cargo binding strengthens the PEX7 interaction (PMID:25538232).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 2001 Medium

    Before any channel role was known, the question was what cellular pathway TRIP8b participates in; identifying it as a Rab8b partner in the regulated secretory pathway gave the first functional foothold.

    Evidence Yeast two-hybrid from rat brain, in vitro binding, co-IP, and ACTH secretion assay in AtT20 cells

    PMID:11278749

    Open questions at the time
    • Did not connect TRIP8b to HCN channels
    • Physiological relevance of Rab8b binding to endogenous trafficking unresolved
  2. 2008 Medium

    It was unclear how the TRIP8b TPR domain achieves binding specificity; comparison with Pex5p showed overlapping, context-dependent recognition of Rab8b and PTS1-like C-terminal peptides.

    Evidence Biochemical binding, peptide competition, and mutagenesis of TPR domains

    PMID:18346465

    Open questions at the time
    • No HCN substrate tested here
    • Did not establish in-cell consequences of binding promiscuity
  3. 2009 High

    The defining advance was establishing TRIP8b as the HCN auxiliary beta subunit and showing it dually controls gating (inhibiting opening, suppressing cAMP/cyclic-nucleotide responsiveness) and isoform-dependent surface expression.

    Evidence Affinity purification + mass spectrometry, heterologous expression of multiple splice isoforms, electrophysiology, surface assays, and cardiomyocyte expression

    PMID:19439603 PMID:19555649 PMID:19555650

    Open questions at the time
    • Molecular basis of the two binding sites not yet mapped
    • Stoichiometry of the complex unknown
    • Mechanism of cAMP antagonism unresolved
  4. 2011 High

    To explain how one protein both gates and traffics HCN, the two C-terminal interaction sites were dissected: the conserved-core/CNBD site mediates gating inhibition and downregulation, while the TPR/SNL site stabilizes the complex and drives upregulation, with cAMP directly disrupting CNBD binding.

    Evidence Systematic mutagenesis, co-IP, biochemical competition, and electrophysiology in heterologous cells and neurons

    PMID:21411649 PMID:21504900

    Open questions at the time
    • Atomic structure of CNBD interface not yet solved
    • Quantitative stoichiometry still inferred
  5. 2011 Medium

    It was unknown how TRIP8b removes HCN from the surface; identification of two N-terminal clathrin-binding motifs and recruitment of HCN to clathrin/endosome/lysosome puncta defined the endocytic mechanism.

    Evidence In vitro binding, mutagenesis, co-IP, cell imaging, and purification of brain clathrin-coated vesicles

    PMID:21749376

    Open questions at the time
    • Adaptor requirements (e.g., AP2) only partially defined
    • In vivo contribution of clathrin route to HCN turnover not quantified
  6. 2011 High

    To test physiological function, TRIP8b knockout and isoform-specific genetic models showed that proper distal dendritic HCN localization requires additive and subtractive sculpting by distinct isoforms, and that loss of TRIP8b reduces dendritic Ih and routes HCN to lysosomal degradation.

    Evidence Constitutive and isoform-specific knockout mice, viral isoform rescue, electrophysiology, immunohistochemistry, lysosome trafficking assays

    PMID:21555075 PMID:21593326

    Open questions at the time
    • Trafficking machinery linking isoform motifs to compartments incompletely defined
    • Cell-type specificity beyond hippocampus not addressed
  7. 2012 High

    The stoichiometry and TPR-site structure were resolved, establishing an obligate 4:4 complex and the atomic basis of the TPR–SNL interaction.

    Evidence Single-molecule fluorescence bleaching, FSEC, fluorescence anisotropy, and X-ray crystallography of the TPR–HCN2 peptide complex

    PMID:22550182

    Open questions at the time
    • CNBD-site structure not captured here
    • Conformational basis of cAMP antagonism still open
  8. 2012 High

    To determine whether TRIP8b acts uniformly across neuronal compartments, knockout and isoform-overexpression studies revealed compartment-selective roles, with dendritic HCN1 requiring TRIP8b while axonal/presynaptic HCN1 was largely TRIP8b-independent and shaped by specific isoforms.

    Evidence Isoform-specific knockout mice, viral overexpression, electrophysiology, electron microscopy, immunohistochemistry

    PMID:22363812 PMID:23077068

    Open questions at the time
    • Mechanistic basis of axonal vs dendritic targeting differences unresolved
    • Isoform-specific binding partners not identified
  9. 2014 High

    The structural mechanism of cAMP desensitization was probed: NMR of the apo HCN2 CNBD mapped the TRIP8b site and indicated an allosteric mechanism preventing cAMP-induced conformational change rather than direct competition.

    Evidence NMR structure determination and interaction-site mapping with conformational analysis

    PMID:25197093

    Open questions at the time
    • Allosteric vs competitive mechanism not definitively distinguished
    • Dynamics of the apo-state interaction unresolved
  10. 2014 Medium

    Two distinct roles outside the canonical model were established: TRIP8b controls HCN1 abundance (not surface trafficking) in retina, and PEX5L acts as a PTS2 import co-receptor via a cargo-dependent trimeric PEX7 complex.

    Evidence Knockout mouse with Western/immunohistochemistry (retina); mammalian two-hybrid, co-IP, and peroxisomal transfer assays (PTS2 import)

    PMID:24409334 PMID:25538232

    Open questions at the time
    • Tissue basis for abundance-vs-localization role difference unknown
    • Structural basis of cargo–PEX7–PEX5L assembly not determined
    • Relationship between channel and peroxisomal functions of the same gene unresolved
  11. 2015 High

    Refining the CNBD mechanism, spectroscopic studies confirmed TRIP8b binds the apo CNBD without altering domain structure, providing a structural framework for reduced cyclic-nucleotide dependence.

    Evidence EPR and NMR spectroscopy with interface identification

    PMID:25800552

    Open questions at the time
    • Did not resolve competitive component of antagonism
    • Kinetics of cAMP/TRIP8b exchange not measured
  12. 2016 High

    To connect molecular trafficking to behavior, viral rescue in TRIP8b KO mice demonstrated that TRIP8b-mediated HCN dendritic trafficking bidirectionally controls antidepressant-like behavior.

    Evidence Viral rescue with wild-type and trafficking-impairing mutants in KO mice, immunohistochemistry, behavioral assays

    PMID:27400855

    Open questions at the time
    • Circuit-level mechanism linking Ih to behavior not defined
    • Whether other ion channels contribute unresolved
  13. 2017 High

    The cAMP-antagonism mechanism was quantitatively refined to a predominantly partial competitive model, and allosteric coupling between TPR and CNBD-binding domains was shown to set HCN binding specificity over PTS1-type substrates.

    Evidence Fluorescence anisotropy, biolayer interferometry, DEER spectroscopy, kinetic modeling (mechanism); fluorescence polarization, co-IP, mutagenesis (allostery)

    PMID:28864772 PMID:28887304

    Open questions at the time
    • Partial contradiction with the purely allosteric model from earlier NMR work
    • Physiological switch between channel and peroxisomal binding not defined
  14. 2019 Medium

    Post-translational regulation was identified: Ser237 phosphorylation enhances HCN binding and influences gating, is enriched in distal dendrites, and is lost with HCN mislocalization in an epilepsy model.

    Evidence Phosphospecific antibody, co-IP, electrophysiology, immunohistochemistry, kainic acid TLE model

    PMID:31492750

    Open questions at the time
    • Kinase/phosphatase regulating Ser237 not identified
    • Causal role of dephosphorylation in epileptogenesis not established
  15. 2020 Medium

    Gating and trafficking functions were genetically separated using HCN N-bundle-loop mutations that abolish TRIP8b CNBD binding without altering cAMP affinity.

    Evidence Structure-guided HCN mutagenesis, binding assays, electrophysiology in cortical neurons

    PMID:32633755

    Open questions at the time
    • Mutations validated in a single neuronal context
    • In vivo consequences of selective uncoupling not tested
  16. 2022 Medium

    An independent biophysical method confirmed the one-TRIP8b-per-HCN-subunit (4:4) stoichiometry on purified HCN4 complexes.

    Evidence Single-molecule mass photometry of purified HCN4–TRIP8b complexes

    PMID:36225302

    Open questions at the time
    • Single method confirmation
    • Whether partial occupancy occurs in vivo not addressed
  17. 2026 Medium

    The CNBD-antagonism mechanism was exploited therapeutically: a minimal TRIP8b-derived peptide that blocks cAMP-mediated HCN2 potentiation reduced pain hypersensitivity, establishing the TRIP8b–CNBD interface as a drug target.

    Evidence In vitro electrophysiology, viral DRG expression of TRIP8bnano, rat neuropathic pain behavioral assays

    PMID:42010827

    Open questions at the time
    • Selectivity across HCN isoforms in vivo not fully characterized
    • Long-term efficacy and off-target effects unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unknown how a single protein partitions between its HCN channel auxiliary-subunit role and its peroxisomal PTS2 co-receptor role, and what governs this functional switch in vivo.
  • No study integrates the channel and peroxisomal functions
  • Regulatory determinants of partner selection (allostery, isoform, phosphorylation) not jointly tested
  • Structure of the CNBD-bound complex and of the cargo–PEX7–PEX5L assembly not determined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0098772 molecular function regulator activity 4 GO:0060090 molecular adaptor activity 3 GO:0038024 cargo receptor activity 1
Localization
GO:0005886 plasma membrane 3 GO:0005764 lysosome 2 GO:0005777 peroxisome 1 GO:0005829 cytosol 1 GO:0031410 cytoplasmic vesicle 1
Pathway
R-HSA-112316 Neuronal System 4 R-HSA-162582 Signal Transduction 2 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-9609507 Protein localization 1
Partners
AP2CIRLCLATHRINHCN1HCN2HCN4PEX7RAB8B
Complex memberships
HCN channel auxiliary complex (4:4 HCN:TRIP8b)cargo–PEX7–PEX5L PTS2 import complex

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2009 TRIP8b (PEX5L) exists as at least nine alternative N-terminal splice isoforms in brain and functions as an auxiliary subunit of HCN1 channels: all isoforms inhibit channel opening by shifting activation to more negative potentials, while individual isoforms differentially downregulate or upregulate HCN1 surface expression. Heterologous expression of splice isoforms, electrophysiology, surface expression assays Neuron High 19439603 19555649
2009 PEX5R/TRIP8b was identified as the beta (auxiliary) subunit of HCN channels in mammalian brain by affinity purification and high-resolution mass spectrometry; coassembly with PEX5R/TRIP8b largely impairs cAMP-dependent activation of HCN2 and HCN4, while gating by phosphoinositides and basal voltage-dependence remain unaffected; de novo expression of PEX5R/TRIP8b in cardiomyocytes abolishes beta-adrenergic stimulation of HCN channels. Affinity purification, high-resolution mass spectrometry, electrophysiology in heterologous cells and cardiomyocytes Neuron High 19555650
2001 TRIP8b was identified as a Rab8b-interacting protein via yeast two-hybrid screen from rat brain cDNA; interaction was verified by in vitro binding and co-immunoprecipitation; TRIP8b is present in both cytosolic and membrane fractions of AtT20 cells; overexpression of TRIP8b stimulates cAMP-induced ACTH secretion, implicating it in the regulated secretory pathway. Yeast two-hybrid, in vitro binding, co-immunoprecipitation, subcellular fractionation, ACTH secretion assay in stable cell lines The Journal of biological chemistry Medium 11278749
2011 TRIP8b knockout mice show dramatically reduced Ih in hippocampal pyramidal neurons due to reduction of HCN channels on the neuronal surface and disrupted dendritic localization of HCN channels; absence of TRIP8b increases HCN subunit targeting to and degradation by lysosomes. Knockout mouse, electrophysiology, immunohistochemistry, subcellular fractionation, lysosome trafficking assay The Journal of neuroscience High 21593326
2011 TRIP8b interacts with HCN1 at two distinct C-terminal sites: (1) an upstream site where the HCN1 C-linker/cyclic nucleotide-binding domain (CNBD) interacts with an 80 aa domain in the conserved core of TRIP8b — necessary and sufficient for inhibition of channel opening and sufficient for downregulatory trafficking effects; (2) a downstream site where the HCN1 C-terminal SNL tripeptide interacts with the TRIP8b tetratricopeptide repeat (TPR) domain — stabilizes the complex and is required for upregulatory trafficking effects. Mutagenesis, co-immunoprecipitation, electrophysiology in heterologous cells and neurons The Journal of neuroscience High 21411649
2011 Isoform-wide disruption of TRIP8b/HCN1 interaction causes HCN1 mistargeting throughout CA1 somatodendritic compartments; selective removal of exons 1b and 2 leaves two hippocampal isoforms — TRIP8b(1a-4) promotes HCN1 surface expression in dendrites while TRIP8b(1a) suppresses HCN1 misexpression in axons — demonstrating that proper distal dendritic localization requires additive and subtractive sculpting by two distinct isoforms. Knockout mouse (isoform-specific), isoform-wide interaction mutant, viral overexpression in neurons, immunohistochemistry Neuron High 21555075
2011 Interaction of TRIP8b with the HCN1 C-terminal SNL tripeptide (via TPR domain) governs channel trafficking effects, whereas TRIP8b interaction with the HCN1 CNBD affects both trafficking and gating; cAMP directly disrupts TRIP8b binding to the CNBD (requiring an arginine residue also required for cAMP binding), and elevated cAMP antagonizes TRIP8b-mediated upregulation of HCN1. Site-directed mutagenesis, electrophysiology, co-immunoprecipitation, biochemical competition assays The Journal of biological chemistry High 21504900
2012 TRIP8b and HCN2 form an obligate 4:4 (tetrameric) complex; the TRIP8b TPR region binds the HCN C-terminal SNL tripeptide and the TRIP8b conserved region binds the HCN CNBD; X-ray crystal structure of the TRIP8b TPR domain in complex with the HCN2 C-terminal peptide was determined. Single-molecule fluorescence bleaching, fluorescence-detection size-exclusion chromatography, fluorescence anisotropy, X-ray crystallography Proceedings of the National Academy of Sciences of the United States of America High 22550182
2014 NMR solution structure of the HCN2 CNBD (apo form) was determined and TRIP8b interaction site mapped; TRIP8b does not compete with cAMP for the same binding region on the CNBD but instead acts via an allosteric mechanism that prevents cAMP-induced conformational changes in the CNBD. NMR spectroscopy, structural mapping, conformational change analysis Proceedings of the National Academy of Sciences of the United States of America High 25197093
2015 EPR and NMR studies show that TRIP8b binds to the apo (cAMP-free) state of the HCN2 CNBD without changing the overall domain structure, and the binding interface on the CNBD was identified, providing a structural framework for TRIP8b's reduction of cyclic nucleotide dependence. Electron paramagnetic resonance (EPR), NMR spectroscopy Structure High 25800552
2012 TRIP8b is required for HCN1 trafficking to dendrites but presynaptic (axonal terminal) cortical HCN1 expression and function is comparable between TRIP8b-null and wild-type mice, demonstrating compartment-selective roles of TRIP8b in HCN channel trafficking. TRIP8b knockout mouse, electrophysiology, electron microscopy The Journal of neuroscience High 23077068
2012 Specific TRIP8b isoforms regulate axonal HCN1 trafficking in perforant path; TRIP8b(1a) isoform promotes somatodendritic and reduces axonal HCN1 expression when overexpressed in entorhinal neurons, whereas TRIP8b(1a-4) does not alter axonal distribution. Knockout mouse (isoform-specific), viral overexpression in cultured neurons, immunohistochemistry PloS one Medium 22363812
2008 The TPR domains of Pex5Rp/TRIP8b and Pex5p have distinct but overlapping substrate specificities for Rab8b and PTS1-like C-terminal peptides; changes in surrounding residues or conformational state of binding partners alter binding activities, showing the binding specificity of the TRIP8b TPR domain is context-dependent. Biochemical binding assays, peptide competition, mutagenesis Biochimica et biophysica acta Medium 18346465
2014 PEX5L acts as a co-receptor for PTS2-mediated peroxisomal import: in the presence of PEX5L, the interaction strength between PTS2 cargo and PEX7 is drastically increased; cargo binding is a prerequisite for PEX7–PEX5L interaction; overexpression of PTS2 cargo stimulates PEX7 transfer to peroxisomes, suggesting sequential formation of a trimeric cargo–PEX7–PEX5L complex is required for PTS2 import. Mammalian two-hybrid assay, overexpression, co-immunoprecipitation, peroxisomal transfer assay The Journal of biological chemistry Medium 25538232
2008 TRIP8b interacts with the calcium-independent receptor of alpha-latrotoxin (CIRL); affinity chromatography of brain extracts on immobilized TRIP8b identified clathrin and AP2 complex subunits as major TRIP8b-interacting proteins, suggesting a role in receptor-mediated endocytosis. Yeast two-hybrid, affinity chromatography, mass spectrometry Biochemistry. Biokhimiia Low 18620529
2011 TRIP8b directly interacts with clathrin through two short clathrin-binding motifs in its N-terminal (non-TPR) region; co-expression of HCN1 with TRIP8b in HEK293 cells translocates channels from cell surface to large intracellular puncta co-localizing with clathrin, early endosome, and lysosome markers; a clathrin-non-binding TRIP8b mutant fails to recruit clathrin to these puncta; TRIP8b is present in purified clathrin-coated vesicles from brain. In vitro binding assay, mutagenesis, co-immunoprecipitation, live/fixed cell imaging, purification of clathrin-coated vesicles Journal of neurochemistry Medium 21749376
2017 TRIP8b reduces cAMP affinity for the HCN2 CNBD; using fluorescence anisotropy, biolayer interferometry, and DEER spectroscopy, TRIP8b was found to act predominantly as a partial competitive antagonist of cAMP at the CNBD binding site, largely competing with a portion of the cAMP-binding pocket rather than exclusively acting noncompetitively. Fluorescence anisotropy, biolayer interferometry, double electron-electron resonance (DEER) spectroscopy, kinetic modeling The Journal of biological chemistry High 28864772
2017 Allosteric coupling between TRIP8b's TPR domains and its CNBD-binding domain confers binding specificity for HCN channels: binding at either the HCN CNBD site or the HCN C-terminal (SNL) site increases affinity at the other site, and this allostery also limits TRIP8b binding to PTS1-type substrates. Fluorescence polarization, co-immunoprecipitation, mutagenesis The Journal of biological chemistry Medium 28887304
2016 Restoration of TRIP8b expression to the hippocampus of TRIP8b KO mice (viral rescue) was sufficient to reverse both impaired HCN channel dendritic trafficking and antidepressant-like behavioral effects; a TRIP8b mutant further impairing HCN channel trafficking increased the antidepressant-like phenotype, demonstrating that TRIP8b-mediated HCN channel trafficking bidirectionally controls antidepressant-like behavior. Viral rescue in KO mice, mutagenesis, immunohistochemistry, behavioral assays Molecular psychiatry High 27400855
2019 Phosphorylation of TRIP8b at Ser237 enhances its binding to HCN channels and influences channel gating by altering affinity for the HCN cytoplasmic domain; phospho-Ser237 TRIP8b is enriched in CA1 distal dendrites in vivo; this phosphorylation is reduced in the kainic acid model of TLE, correlating with HCN channel mislocalization. Phosphospecific antibody, co-immunoprecipitation, electrophysiology, immunohistochemistry, kainic acid TLE model The Journal of biological chemistry Medium 31492750
2020 Two point mutations (N/A and C/D) in the N-bundle loop of HCN connecting the CNBD to the C-linker strongly reduce TRIP8b binding to the CNBD without altering cAMP affinity, dissociating TRIP8b's gating effects from its trafficking effects in cortical neurons. Structure-guided mutagenesis, binding assays, electrophysiology in cortical neurons The Journal of general physiology Medium 32633755
2022 Single-molecule mass photometry of purified HCN4-TRIP8b complexes confirmed a 1:1 stoichiometry (four TRIP8b subunits per tetrameric HCN4 channel), independently validating the 4:4 stoichiometry reported by fluorescence bleaching. Single-molecule mass photometry Frontiers in physiology Medium 36225302
2014 TRIP8b is required for maximal HCN1 expression in the retina: in TRIP8b KO mice, HCN1 total protein is greatly reduced in retinal neurons but HCN1 surface trafficking is unaffected, indicating that in photoreceptors TRIP8b controls HCN1 abundance rather than localization. Knockout mouse, immunohistochemistry, Western blot, confocal microscopy PloS one Medium 24409334
2026 A minimal peptide derivative of TRIP8b (TRIP8bnano) selectively prevents cAMP binding to the HCN2 CNBD and abolishes cAMP-mediated potentiation of HCN2 currents in dorsal root ganglion neurons; DRG-targeted expression of TRIP8bnano significantly reduced mechanical and thermal hypersensitivity in a rat neuropathic pain model. In vitro electrophysiology (HEK293T and DRG neurons), viral DRG expression, rat neuropathic pain behavioral assays The Journal of physiology Medium 42010827

Source papers

Stage 0 corpus · 35 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 TRIP8b splice variants form a family of auxiliary subunits that regulate gating and trafficking of HCN channels in the brain. Neuron 134 19555649
2009 Alternatively spliced isoforms of TRIP8b differentially control h channel trafficking and function. The Journal of neuroscience : the official journal of the Society for Neuroscience 122 19439603
2011 Deletion of the hyperpolarization-activated cyclic nucleotide-gated channel auxiliary subunit TRIP8b impairs hippocampal Ih localization and function and promotes antidepressant behavior in mice. The Journal of neuroscience : the official journal of the Society for Neuroscience 108 21593326
2009 Association with the auxiliary subunit PEX5R/Trip8b controls responsiveness of HCN channels to cAMP and adrenergic stimulation. Neuron 105 19555650
2014 Structural basis for the mutual antagonism of cAMP and TRIP8b in regulating HCN channel function. Proceedings of the National Academy of Sciences of the United States of America 70 25197093
2011 TRIP8b regulates HCN1 channel trafficking and gating through two distinct C-terminal interaction sites. The Journal of neuroscience : the official journal of the Society for Neuroscience 70 21411649
2011 TRIP8b splice forms act in concert to regulate the localization and expression of HCN1 channels in CA1 pyramidal neurons. Neuron 63 21555075
2011 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. The Journal of biological chemistry 54 21504900
2001 Rab8b and its interacting partner TRIP8b are involved in regulated secretion in AtT20 cells. The Journal of biological chemistry 53 11278749
2016 HCN-channel dendritic targeting requires bipartite interaction with TRIP8b and regulates antidepressant-like behavioral effects. Molecular psychiatry 44 27400855
2012 Structure and stoichiometry of an accessory subunit TRIP8b interaction with hyperpolarization-activated cyclic nucleotide-gated channels. Proceedings of the National Academy of Sciences of the United States of America 42 22550182
2015 Structural mechanism for the regulation of HCN ion channels by the accessory protein TRIP8b. Structure (London, England : 1993) 37 25800552
2015 Reduction of thalamic and cortical Ih by deletion of TRIP8b produces a mouse model of human absence epilepsy. Neurobiology of disease 33 26459112
2014 Mechanistic insights into PTS2-mediated peroxisomal protein import: the co-receptor PEX5L drastically increases the interaction strength between the cargo protein and the receptor PEX7. The Journal of biological chemistry 33 25538232
2017 Modulation of thalamocortical oscillations by TRIP8b, an auxiliary subunit for HCN channels. Brain structure & function 32 29168010
2012 TRIP8b-independent trafficking and plasticity of adult cortical presynaptic HCN1 channels. The Journal of neuroscience : the official journal of the Society for Neuroscience 31 23077068
2017 Mechanism for the inhibition of the cAMP dependence of HCN ion channels by the auxiliary subunit TRIP8b. The Journal of biological chemistry 24 28864772
2012 Regulation of axonal HCN1 trafficking in perforant path involves expression of specific TRIP8b isoforms. PloS one 24 22363812
2020 The structure and function of TRIP8b, an auxiliary subunit of hyperpolarization-activated cyclic-nucleotide gated channels. Channels (Austin, Tex.) 22 32189562
2019 Phosphorylation of the HCN channel auxiliary subunit TRIP8b is altered in an animal model of temporal lobe epilepsy and modulates channel function. The Journal of biological chemistry 20 31492750
2008 Comparison of the PTS1- and Rab8b-binding properties of Pex5p and Pex5Rp/TRIP8b. Biochimica et biophysica acta 19 18346465
2022 PEX5R/Trip8b-HCN2 channel regulating neuroinflammation involved in perioperative neurocognitive disorders. Cell & bioscience 16 36104739
2013 Short- and long-term plasticity in CA1 neurons from mice lacking h-channel auxiliary subunit TRIP8b. Journal of neurophysiology 14 23966674
2008 Analysis of proteins interacting with TRIP8b adapter. Biochemistry. Biokhimiia 14 18620529
2017 Allostery between two binding sites in the ion channel subunit TRIP8b confers binding specificity to HCN channels. The Journal of biological chemistry 10 28887304
2022 Genetic variants in DDO and PEX5L in peroxisome-related pathways predict non-small cell lung cancer survival. Molecular carcinogenesis 9 35502931
2020 Rational design of a mutation to investigate the role of the brain protein TRIP8b in limiting the cAMP response of HCN channels in neurons. The Journal of general physiology 9 32633755
2014 TRIP8b is required for maximal expression of HCN1 in the mouse retina. PloS one 9 24409334
2022 Discovery of a small-molecule inhibitor of the TRIP8b-HCN interaction with efficacy in neurons. The Journal of biological chemistry 6 35623388
2021 Characterization of the HCN Interaction Partner TRIP8b/PEX5R in the Intracardiac Nervous System of TRIP8b-Deficient and Wild-Type Mice. International journal of molecular sciences 6 33946275
2016 Method for Identifying Small Molecule Inhibitors of the Protein-protein Interaction Between HCN1 and TRIP8b. Journal of visualized experiments : JoVE 6 27911380
2023 Characterization of Kv1.2-mediated outward current in TRIP8b-deficient mice. Biological chemistry 3 36852869
2011 Association of adaptor protein TRIP8b with clathrin. Journal of neurochemistry 2 21749376
2026 TRIP8bnano peptide prevents cAMP binding to HCN2 channels alleviating pain-like behaviors in rats with neuropathic pain. The Journal of physiology 0 42010827
2022 Validation of the binding stoichiometry between HCN channels and their neuronal regulator TRIP8b by single molecule measurements. Frontiers in physiology 0 36225302

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