{"gene":"DPP10","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2005,"finding":"DPP10 physically associates with native Kv4.2 channels in rat brain (confirmed by co-immunoprecipitation from brain membranes), facilitates Kv4.2 protein trafficking to the cell membrane, increases A-type current magnitude, and modifies voltage dependence and kinetic properties of the current to resemble neuronal A-type currents. Chimera experiments showed that the intracellular and transmembrane domains (not the extracellular domain) are required for Kv4.2 channel modulation.","method":"Co-immunoprecipitation from rat brain membranes, heterologous expression with voltage-clamp electrophysiology, domain-swap chimera analysis, in situ hybridization","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP from native tissue, electrophysiology in heterologous system, domain dissection by chimeras; multiple orthogonal methods in one study","pmids":["15671030"],"is_preprint":false},{"year":2004,"finding":"DPP10 co-immunoprecipitates with Kv4.2 from oocyte extracts, enhances Kv4.2 surface current ~5-fold without increasing total protein level, accelerates inactivation and recovery from inactivation, and introduces hyperpolarizing shifts in conductance-voltage and steady-state inactivation relationships. The cytoplasmic N-terminal domain of DPP10 was identified as the determinant for acceleration of inactivation.","method":"Co-immunoprecipitation, two-electrode voltage-clamp in Xenopus oocytes, N-terminal domain deletion/truncation experiments","journal":"Biophysical journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus electrophysiology plus domain mapping; independently replicates findings of PMID:15671030","pmids":["15454437"],"is_preprint":false},{"year":2005,"finding":"Kv4.2, KChIP3, and DPP10 form a ternary macromolecular complex in rat brain and in heterologous expression systems (Xenopus oocytes and CHO cells), demonstrated by immunoprecipitation. The ternary complex produces current waveforms distinct from any binary combination, and recovery from inactivation in the ternary complex (~18–26 ms) closely matches native neuronal ISA.","method":"Co-immunoprecipitation from rat brain and heterologous cells, two-electrode voltage-clamp and patch-clamp electrophysiology in oocytes and CHO cells","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP from native tissue plus heterologous reconstitution with functional readout; replicated across two expression systems","pmids":["16123112"],"is_preprint":false},{"year":2007,"finding":"DPP10 splice variants (DPP10a, DPP10c, DPP10d) differentially regulate Kv4.2+KChIP3+DPP10 channel complex gating. DPP10a produces uniquely fast inactivation kinetics that accelerate with increasing depolarization and dominate when co-expressed with KChIP4a or other DPP10 isoforms. DPP10a transcripts are prominently expressed in cortex while DPP10c and DPP10d show more diffuse distributions.","method":"Electrophysiology (two-electrode voltage-clamp in Xenopus oocytes, patch-clamp in CHO cells), real-time qRT-PCR, in situ hybridization","journal":"Molecular and cellular neurosciences","confidence":"High","confidence_rationale":"Tier 2 / Moderate — electrophysiology with multiple splice variants plus expression mapping; single lab but two orthogonal functional and expression methods","pmids":["17475505"],"is_preprint":false},{"year":2006,"finding":"DPP10 modulates Kv4.3 gating (accelerates inactivation, shifts steady-state activation and inactivation) and also modulates Kv1.4 (faster time-to-peak, negative shift in half-inactivation), demonstrating that DPP10 is not restricted to Kv4 channels. DPP10 and KChIP2b act on different inactivation states of Kv4.3: KChIP2b nearly abolishes closed-state inactivation, whereas DPP10 permits its development. A DPP10 truncation mutant containing only the transmembrane and 58 cytoplasmic amino acids reproduced wild-type DPP10 effects on Kv4.3 gating.","method":"Heterologous co-expression with patch-clamp electrophysiology, truncation mutant analysis","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean electrophysiology with domain truncation, single lab, single expression system","pmids":["16738002"],"is_preprint":false},{"year":2006,"finding":"Multiple DPP10 (DPPY) splicing variants with alternative first exons exist in brain, adrenal gland, and pancreas with species- and tissue-specific expression patterns. Splicing variants and an N-terminal peptide-deleted DPPY produce similar changes in Kv4.3 gating, indicating the N-terminal cytoplasmic region is not required for Kv4.3 modulation.","method":"RT-PCR/cloning of splice variants, electrophysiology (Kv4.3 gating assay in heterologous system)","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — electrophysiology with multiple variants, single lab, single expression system","pmids":["16899223"],"is_preprint":false},{"year":2005,"finding":"DPP10 (DPL2-s, 789-aa isoform) lacks dipeptidyl peptidase activity; substitutions to reconstitute the catalytic serine (Gly644→Ser, Lys643Gly644→TrpSer, Asp561Lys643Gly644→TyrTrpSer) failed to confer enzymatic activity. DPP10 is glycosylated, expressed primarily on the cell surface of transfected cells, and produces multiple forms (96 kDa soluble, 100 kDa transmembrane, ~250 kDa multimeric).","method":"Site-directed mutagenesis of catalytic motif, enzymatic activity assay, PNGase F deglycosylation, cell-surface expression analysis","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1 / Moderate — active-site mutagenesis with enzyme activity assay directly demonstrating lack of catalytic activity; multiple mutagenesis variants tested","pmids":["16290253"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of human DPP10 (DPPY) was solved, revealing two domains: a β-propeller and an α/β-hydrolase fold (S9B serine protease subfamily). The catalytic serine is replaced by a glycine, explaining lack of enzymatic activity. The entrance channels to the active site differ from DPP4, and the DPP10 dimer interface was characterized.","method":"X-ray crystallography","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure with structural comparison to DPP4 and DPP6; directly validates prior biochemical findings on enzymatic inactivity","pmids":["25740212"],"is_preprint":false},{"year":2010,"finding":"N-linked glycosylation of DPP10 is required for its cell surface expression and for its accelerating effects on Kv4.3 current kinetics. Pharmacological inhibition of glycosylation by tunicamycin completely blocked DPP10 glycosylation, reduced cell surface expression, and abolished the accelerating effects of DPP10 on Kv4.3 inactivation and recovery from inactivation. Similar effects were observed in native human atrial myocytes.","method":"Pharmacological inhibition of glycosylation (tunicamycin, neuraminidase) in CHO cells and human atrial myocytes, flow cytometry for surface expression, patch-clamp electrophysiology","journal":"Pflugers Archiv : European journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological disruption plus native cell validation; two orthogonal approaches but single lab","pmids":["20354865"],"is_preprint":false},{"year":2012,"finding":"N-glycosylation of DPP10 occurs at six specific asparagine residues; glycosylation at N90, N119, N257, and N342 is required for DPP10 trafficking to the plasma membrane. N257 is critical: N257Q completely blocked DPP10 surface sorting and prevented DPP10 dimerization, and disrupted functional interaction with the Kv4.3/KChIP2a complex.","method":"Site-directed mutagenesis (N→Q substitutions), flow cytometry, co-immunoprecipitation, electrophysiology","journal":"The international journal of biochemistry & cell biology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — site-directed mutagenesis of specific glycosylation sites with multiple orthogonal readouts (surface expression, dimerization, functional modulation); single lab","pmids":["22387313"],"is_preprint":false},{"year":2015,"finding":"DPP10 preferentially forms a 4:2 (Kv4.2:DPP10) stoichiometric complex. In the absence of Kv4.2, approximately 70% of DPP10 forms dimers in the plasma membrane. The Kv4.2 current amplitude and recovery from inactivation changed depending on the co-expression level of DPP10, indicating stoichiometry-dependent modulation. The preference for 4:2 stoichiometry is attributed to the bulky dimeric structure of the extracellular domain of DPP10.","method":"Single-molecule imaging/subunit counting (fluorescent protein fusion), two-electrode voltage-clamp in Xenopus oocytes at variable expression ratios","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — single-molecule stoichiometry counting plus functional electrophysiology; rigorous quantitative approach in single study","pmids":["26209633"],"is_preprint":false},{"year":2014,"finding":"DPP10 protein (DPP10789 isoform) localizes to neuronal cell bodies predominantly at the plasma membrane and cytoplasm in normal rat brain, with strong reactivity in distal dendrites of CA1 pyramidal cells. In Alzheimer's disease brains, DPP10789 is redistributed to neurofibrillary tangles and plaque-associated dystrophic neurites, colocalizing with doubly phosphorylated tau (Ser-202/Thr-205). Truncated DPP10789 fragments increase significantly in AD brains by Western blot.","method":"Immunohistochemistry, immunofluorescence co-localization, Western blot on human brain tissue","journal":"BioMed research international","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization by IHC/immunofluorescence on human tissue with colocalization analysis; multiple brain regions and disease conditions","pmids":["25025038"],"is_preprint":false},{"year":2014,"finding":"DPP10 protein co-localizes with Kv4.3, KChIP1 in inhibitory interneurons (parvalbumin+ or somatostatin+) in hippocampus and neocortex, and with Kv4.2/Kv4.3/KChIP3 in neocortical layer 5 pyramidal neurons and olfactory bulb mitral cells in adult rat brain, supporting the existence of a Kv4/KChIP/DPP10 ternary complex in vivo. DPP10 is absent from glia.","method":"Immunohistochemistry with DPP10-specific antibody, triple immunofluorescence co-localization in rat brain sections","journal":"The Journal of comparative neurology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct protein localization by immunohistochemistry with co-localization; corroborates biochemical co-IP evidence from PMID:16123112","pmids":["25355692"],"is_preprint":false},{"year":2019,"finding":"DPP10 interacts physically with Nav1.5 channels in human ventricles (co-immunoprecipitation confirmed). In rat cardiomyocytes expressing DPP10 by adenoviral gene transfer, DPP10 reduced Na+ current density, shifted voltage-dependent activation and inactivation to more positive potentials, increased window Na+ current, reduced time-to-peak Na+ current, and accelerated recovery from inactivation.","method":"Co-immunoprecipitation from human ventricular tissue, adenoviral overexpression in rat cardiomyocytes, patch-clamp electrophysiology, action potential recording","journal":"International journal of cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP from native human tissue plus functional electrophysiology in native cardiomyocytes; single lab, two orthogonal methods","pmids":["30638748"],"is_preprint":false},{"year":2016,"finding":"The Drosophila DPP10 ortholog acts as an ancillary subunit of Kv4 channels (binds rat Kv4.3 and causes negative shifts in voltage dependence of activation and inactivation, faster inactivation and recovery) AND retains dipeptidyl peptidase enzymatic activity (hydrolyzes Gly-Pro-MCA with Km similar to human DPP4 but ~6-fold lower kcat/immunoreactivity), demonstrating that the ancestral protein had dual function and that enzymatic activity was lost in mammalian DPP10.","method":"Co-immunoprecipitation, electrophysiology (two-electrode voltage-clamp), enzymatic activity assay with fluorescent substrate","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1-2 / Weak — ortholog study with reconstituted enzymatic assay and electrophysiology; single lab but two orthogonal methods","pmids":["27198182"],"is_preprint":false}],"current_model":"DPP10 is an enzymatically inactive (catalytic Ser replaced by Gly), N-glycosylated type II transmembrane protein that functions as an auxiliary subunit of voltage-gated K+ channels: it physically associates with Kv4.2/Kv4.3 (preferentially in a 4:2 Kv4:DPP10 stoichiometry), promotes their trafficking to the plasma membrane, and modifies their gating kinetics (accelerating inactivation and recovery, shifting voltage dependence) in a manner dependent on its transmembrane/intracellular domains and N-glycosylation state; together with KChIPs, DPP10 forms ternary complexes that reconstitute native neuronal ISA currents, and DPP10 also interacts with and modulates cardiac Nav1.5 channels."},"narrative":{"mechanistic_narrative":"DPP10 is an N-glycosylated type II transmembrane protein that functions as an auxiliary subunit of voltage-gated potassium channels, controlling the trafficking and gating of Kv4 channels that generate neuronal A-type currents [PMID:15671030, PMID:15454437]. Although it adopts the β-propeller plus α/β-hydrolase architecture of the S9B dipeptidyl peptidase family, its catalytic serine is replaced by glycine, and mutagenesis aimed at restoring the active site fails to confer enzymatic activity, establishing DPP10 as a catalytically dead pseudo-peptidase [PMID:16290253, PMID:25740212]. DPP10 physically associates with Kv4.2 and Kv4.3, promotes their surface expression, and accelerates inactivation and recovery from inactivation while introducing hyperpolarizing shifts in voltage dependence; these gating effects are conferred by its transmembrane and intracellular regions rather than its extracellular ectodomain [PMID:15671030, PMID:15454437, PMID:16738002]. Together with KChIP subunits, DPP10 assembles into ternary Kv4/KChIP/DPP10 complexes that reconstitute current waveforms and recovery kinetics matching native neuronal ISA, and such complexes are co-localized in defined neuronal populations in vivo [PMID:16123112, PMID:25355692]. Channel modulation is stoichiometry-dependent, with DPP10 preferentially forming a 4:2 (Kv4:DPP10) complex, and depends critically on N-linked glycosylation, where site-specific glycans (notably N257) drive DPP10 surface sorting, dimerization, and functional interaction with the channel [PMID:22387313, PMID:26209633]. Beyond Kv4, DPP10 physically interacts with cardiac Nav1.5 channels in human ventricle and modifies sodium current density and gating [PMID:30638748]. DPP10 protein is also redistributed to neurofibrillary tangles and dystrophic neurites in Alzheimer's disease brain [PMID:25025038].","teleology":[{"year":2004,"claim":"Established that DPP10 is a functional Kv4 channel partner, not merely a co-expressed protein, by showing it binds Kv4.2 and remodels its surface current and gating.","evidence":"Co-immunoprecipitation and two-electrode voltage-clamp in Xenopus oocytes with N-terminal truncation mapping","pmids":["15454437"],"confidence":"High","gaps":["Performed in heterologous oocytes only","Did not address whether native brain complexes exist","Stoichiometry of the complex unresolved"]},{"year":2005,"claim":"Confirmed the Kv4.2-DPP10 interaction occurs natively in brain and localized the modulatory determinant to the transmembrane/intracellular domains, defining how DPP10 sculpts A-type currents.","evidence":"Co-immunoprecipitation from rat brain membranes, heterologous electrophysiology, domain-swap chimeras, in situ hybridization","pmids":["15671030"],"confidence":"High","gaps":["Did not establish three-way complex with KChIPs","Mechanism of gating modulation at structural level unknown"]},{"year":2005,"claim":"Demonstrated that DPP10 is enzymatically dead despite its peptidase fold, reframing it as a non-catalytic accessory subunit rather than an active dipeptidyl peptidase.","evidence":"Site-directed mutagenesis of the catalytic motif with enzyme activity assays, PNGase F deglycosylation, cell-surface analysis","pmids":["16290253"],"confidence":"High","gaps":["Why active-site reconstitution failed to restore activity not structurally explained at the time","Soluble vs transmembrane form roles unclear"]},{"year":2005,"claim":"Showed that Kv4/KChIP/DPP10 form a ternary macromolecular complex whose gating reconstitutes native neuronal ISA, defining the physiological channel assembly.","evidence":"Co-immunoprecipitation from rat brain and heterologous cells with electrophysiology in oocytes and CHO cells","pmids":["16123112"],"confidence":"High","gaps":["Subunit stoichiometry not quantified","Spatial distribution in defined neuron types not yet shown"]},{"year":2006,"claim":"Extended DPP10 modulation beyond Kv4 to Kv1.4 and mapped the minimal modulatory unit to the transmembrane plus a short cytoplasmic segment, distinguishing DPP10's action from KChIP on channel inactivation states.","evidence":"Heterologous patch-clamp co-expression with truncation mutant analysis","pmids":["16738002","16899223"],"confidence":"Medium","gaps":["Conflicting conclusions on N-terminal requirement across studies","Single expression system"]},{"year":2007,"claim":"Showed splice variants tune the gating phenotype of the ternary complex, providing a mechanism for regional diversity of A-type currents.","evidence":"Electrophysiology of DPP10 isoforms in oocytes and CHO cells with qRT-PCR and in situ hybridization","pmids":["17475505"],"confidence":"High","gaps":["Functional consequence of isoform distribution in vivo untested","Structural basis of isoform-specific kinetics unknown"]},{"year":2012,"claim":"Defined N-linked glycosylation, particularly at N257, as required for DPP10 trafficking, dimerization, and functional channel modulation, linking post-translational modification to assembly.","evidence":"Site-directed N→Q mutagenesis with flow cytometry, co-IP, and electrophysiology; complemented by tunicamycin/neuraminidase disruption in CHO cells and human atrial myocytes","pmids":["22387313","20354865"],"confidence":"High","gaps":["How glycosylation mechanistically enables dimerization not resolved","In vivo relevance of individual glycosites untested"]},{"year":2014,"claim":"Localized DPP10 to specific neuronal populations alongside Kv4 and KChIP subunits, and documented its aberrant redistribution to tau pathology in Alzheimer's disease.","evidence":"Immunohistochemistry and triple immunofluorescence co-localization in rat and human brain, Western blot","pmids":["25355692","25025038"],"confidence":"Medium","gaps":["Causal role of DPP10 in AD pathology not established","Functional consequence of fragment accumulation unknown"]},{"year":2015,"claim":"Provided the structural basis for enzymatic inactivity and quantified the preferred 4:2 Kv4:DPP10 stoichiometry, explaining how the extracellular dimer constrains complex assembly and modulation.","evidence":"X-ray crystallography of human DPP10; single-molecule subunit counting plus variable-ratio electrophysiology in oocytes","pmids":["25740212","26209633"],"confidence":"High","gaps":["No structure of the assembled Kv4/DPP10 complex","How transmembrane/intracellular domains transmit gating effects not captured by ectodomain structure"]},{"year":2016,"claim":"Showed the Drosophila ortholog is both a Kv4 ancillary subunit and an active dipeptidyl peptidase, establishing that the ancestral protein was bifunctional and enzymatic activity was lost in mammalian DPP10.","evidence":"Co-IP, electrophysiology, and fluorescent-substrate enzymatic assay on the ortholog","pmids":["27198182"],"confidence":"Medium","gaps":["Ortholog assay does not address human DPP10 physiology","Single lab, two methods"]},{"year":2019,"claim":"Identified cardiac Nav1.5 as a DPP10 partner, broadening its role beyond potassium channels into sodium current regulation in the heart.","evidence":"Co-immunoprecipitation from human ventricular tissue and adenoviral overexpression with patch-clamp in rat cardiomyocytes","pmids":["30638748"],"confidence":"Medium","gaps":["Single lab","Physiological/arrhythmic consequence in vivo not established","Domain requirements for Nav1.5 modulation unmapped"]},{"year":null,"claim":"How DPP10's transmembrane and intracellular domains physically couple to and reshape channel gating, and whether its multiple channel partnerships (Kv4, Kv1.4, Nav1.5) operate through a shared mechanism, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of an assembled channel-DPP10 complex","Shared vs distinct modulatory mechanism across channel families unknown","Physiological consequences of loss in mammals uncharacterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,4,10]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,6,9,11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,11]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,2,12]},{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[13]}],"complexes":["Kv4/KChIP/DPP10 ternary channel complex"],"partners":["KCND2","KCND3","KCNA4","KCNIP3","KCNIP2","SCN5A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8N608","full_name":"Inactive dipeptidyl peptidase 10","aliases":["Dipeptidyl peptidase IV-related protein 3","DPRP-3","Dipeptidyl peptidase X","DPP X","Dipeptidyl peptidase-like protein 2","DPL2"],"length_aa":796,"mass_kda":90.9,"function":"Promotes cell surface expression of the potassium channel KCND2 (PubMed:15454437). Modulates the activity and gating characteristics of the potassium channel KCND2 (PubMed:15454437). Has no dipeptidyl aminopeptidase activity (PubMed:12662155)","subcellular_location":"Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q8N608/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DPP10","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DPP10","total_profiled":1310},"omim":[{"mim_id":"608258","title":"DIPEPTIDYL PEPTIDASE IX; DPP9","url":"https://www.omim.org/entry/608258"},{"mim_id":"608209","title":"DIPEPTIDYL PEPTIDASE X; DPP10","url":"https://www.omim.org/entry/608209"},{"mim_id":"209850","title":"AUTISM","url":"https://www.omim.org/entry/209850"},{"mim_id":"126141","title":"DIPEPTIDYL PEPTIDASE VI; DPP6","url":"https://www.omim.org/entry/126141"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"adrenal gland","ntpm":10.1},{"tissue":"brain","ntpm":20.3},{"tissue":"pancreas","ntpm":16.3}],"url":"https://www.proteinatlas.org/search/DPP10"},"hgnc":{"alias_symbol":["DPRP3","DPL2","DPPY"],"prev_symbol":[]},"alphafold":{"accession":"Q8N608","domains":[{"cath_id":"3.40.50.1820","chopping":"530-782","consensus_level":"medium","plddt":94.2804,"start":530,"end":782}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N608","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N608-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8N608-F1-predicted_aligned_error_v6.png","plddt_mean":90.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DPP10","jax_strain_url":"https://www.jax.org/strain/search?query=DPP10"},"sequence":{"accession":"Q8N608","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8N608.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8N608/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8N608"}},"corpus_meta":[{"pmid":"15671030","id":"PMC_15671030","title":"DPP10 modulates Kv4-mediated A-type potassium channels.","date":"2005","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15671030","citation_count":118,"is_preprint":false},{"pmid":"15454437","id":"PMC_15454437","title":"Modulation of Kv4.2 channel expression and gating by dipeptidyl peptidase 10 (DPP10).","date":"2004","source":"Biophysical journal","url":"https://pubmed.ncbi.nlm.nih.gov/15454437","citation_count":117,"is_preprint":false},{"pmid":"16123112","id":"PMC_16123112","title":"Multiprotein assembly of Kv4.2, KChIP3 and DPP10 produces ternary channel complexes with ISA-like properties.","date":"2005","source":"The Journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/16123112","citation_count":116,"is_preprint":false},{"pmid":"17475505","id":"PMC_17475505","title":"DPP10 splice variants are localized in distinct neuronal populations and act to differentially regulate the inactivation properties of Kv4-based ion channels.","date":"2007","source":"Molecular and cellular neurosciences","url":"https://pubmed.ncbi.nlm.nih.gov/17475505","citation_count":42,"is_preprint":false},{"pmid":"16738002","id":"PMC_16738002","title":"DPP10 is an inactivation modulatory protein of Kv4.3 and Kv1.4.","date":"2006","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/16738002","citation_count":31,"is_preprint":false},{"pmid":"16899223","id":"PMC_16899223","title":"Species and tissue differences in the expression of DPPY splicing variants.","date":"2006","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/16899223","citation_count":29,"is_preprint":false},{"pmid":"25740212","id":"PMC_25740212","title":"Structure of human dipeptidyl peptidase 10 (DPPY): a modulator of neuronal Kv4 channels.","date":"2015","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/25740212","citation_count":29,"is_preprint":false},{"pmid":"19672052","id":"PMC_19672052","title":"Polymorphisms of PHF11 and DPP10 are associated with asthma and related traits in a Chinese population.","date":"2009","source":"Respiration; international review of thoracic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/19672052","citation_count":25,"is_preprint":false},{"pmid":"8233814","id":"PMC_8233814","title":"Conserved sequence motif DPPY in region IV of the phage T4 Dam DNA-[N6-adenine]-methyltransferase is important for S-adenosyl-L-methionine binding.","date":"1993","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/8233814","citation_count":25,"is_preprint":false},{"pmid":"25025038","id":"PMC_25025038","title":"Dipeptidyl peptidase 10 (DPP10(789)): a voltage gated potassium channel associated protein is abnormally expressed in Alzheimer's and other neurodegenerative diseases.","date":"2014","source":"BioMed research international","url":"https://pubmed.ncbi.nlm.nih.gov/25025038","citation_count":24,"is_preprint":false},{"pmid":"16290253","id":"PMC_16290253","title":"Molecular characterization of a novel dipeptidyl peptidase like 2-short form (DPL2-s) that is highly expressed in the brain and lacks dipeptidyl peptidase activity.","date":"2005","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/16290253","citation_count":20,"is_preprint":false},{"pmid":"20354865","id":"PMC_20354865","title":"Impaired glycosylation blocks DPP10 cell surface expression and alters the electrophysiology of Ito channel complex.","date":"2010","source":"Pflugers Archiv : European journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/20354865","citation_count":16,"is_preprint":false},{"pmid":"25355692","id":"PMC_25355692","title":"Immunohistochemical localization of DPP10 in rat brain supports the existence of a Kv4/KChIP/DPPL ternary complex in neurons.","date":"2014","source":"The Journal of comparative neurology","url":"https://pubmed.ncbi.nlm.nih.gov/25355692","citation_count":14,"is_preprint":false},{"pmid":"16617501","id":"PMC_16617501","title":"Conserved sequence motif DPPY in region IV of the phage T4 Dam DNA-[N-adenine]-methyltransferase is important for S-adenosyl-L-methionine binding.","date":"1993","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/16617501","citation_count":14,"is_preprint":false},{"pmid":"32319592","id":"PMC_32319592","title":"Tetramethylpyrazine reduces prostate cancer malignancy through inactivation of the DPP10‑AS1/CBP/FOXM1 signaling pathway.","date":"2020","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/32319592","citation_count":13,"is_preprint":false},{"pmid":"33744851","id":"PMC_33744851","title":"Long non-coding RNA DPP10-AS1 exerts anti-tumor effects on colon cancer via the upregulation of ADCY1 by regulating microRNA-127-3p.","date":"2021","source":"Aging","url":"https://pubmed.ncbi.nlm.nih.gov/33744851","citation_count":13,"is_preprint":false},{"pmid":"28670437","id":"PMC_28670437","title":"Use of clinical chromosomal microarray in Chinese patients with autism spectrum disorder-implications of a copy number variation involving DPP10.","date":"2017","source":"Molecular autism","url":"https://pubmed.ncbi.nlm.nih.gov/28670437","citation_count":13,"is_preprint":false},{"pmid":"26209633","id":"PMC_26209633","title":"Kv4.2 and accessory dipeptidyl peptidase-like protein 10 (DPP10) subunit preferentially form a 4:2 (Kv4.2:DPP10) channel complex.","date":"2015","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26209633","citation_count":11,"is_preprint":false},{"pmid":"30638748","id":"PMC_30638748","title":"DPP10 is a new regulator of Nav1.5 channels in human heart.","date":"2019","source":"International journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/30638748","citation_count":8,"is_preprint":false},{"pmid":"22387313","id":"PMC_22387313","title":"N-glycosylation of the mammalian dipeptidyl aminopeptidase-like protein 10 (DPP10) regulates trafficking and interaction with Kv4 channels.","date":"2012","source":"The international journal of biochemistry & cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/22387313","citation_count":8,"is_preprint":false},{"pmid":"37078946","id":"PMC_37078946","title":"DPP10-AS1-Mediated Downregulation of MicroRNA-324-3p Is Conducive to the Malignancy of Pancreatic Cancer by Enhancing CLDN3 Expression.","date":"2022","source":"Pancreas","url":"https://pubmed.ncbi.nlm.nih.gov/37078946","citation_count":5,"is_preprint":false},{"pmid":"27198182","id":"PMC_27198182","title":"Fly DPP10 acts as a channel ancillary subunit and possesses peptidase activity.","date":"2016","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/27198182","citation_count":5,"is_preprint":false},{"pmid":"22298003","id":"PMC_22298003","title":"Crystallization and preliminary X-ray diffraction analysis of human dipeptidyl peptidase 10 (DPPY), a component of voltage-gated potassium channels.","date":"2012","source":"Acta crystallographica. Section F, Structural biology and crystallization communications","url":"https://pubmed.ncbi.nlm.nih.gov/22298003","citation_count":2,"is_preprint":false},{"pmid":"37242299","id":"PMC_37242299","title":"Omega-3 Fatty Acids Interact with DPP10 Region Genotype in Association with Childhood Atopy.","date":"2023","source":"Nutrients","url":"https://pubmed.ncbi.nlm.nih.gov/37242299","citation_count":1,"is_preprint":false},{"pmid":"41739708","id":"PMC_41739708","title":"Clinical Significance of DPP10-AS1 and Its Potential Mechanism in Chronic Obstructive Pulmonary Disease through miR-34c-5p.","date":"2025","source":"Folia biologica","url":"https://pubmed.ncbi.nlm.nih.gov/41739708","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15406,"output_tokens":4289,"usd":0.055276,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":12106,"output_tokens":3644,"usd":0.075815,"stage2_stop_reason":"end_turn"},"total_usd":0.131091,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2005,\n      \"finding\": \"DPP10 physically associates with native Kv4.2 channels in rat brain (confirmed by co-immunoprecipitation from brain membranes), facilitates Kv4.2 protein trafficking to the cell membrane, increases A-type current magnitude, and modifies voltage dependence and kinetic properties of the current to resemble neuronal A-type currents. Chimera experiments showed that the intracellular and transmembrane domains (not the extracellular domain) are required for Kv4.2 channel modulation.\",\n      \"method\": \"Co-immunoprecipitation from rat brain membranes, heterologous expression with voltage-clamp electrophysiology, domain-swap chimera analysis, in situ hybridization\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP from native tissue, electrophysiology in heterologous system, domain dissection by chimeras; multiple orthogonal methods in one study\",\n      \"pmids\": [\"15671030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"DPP10 co-immunoprecipitates with Kv4.2 from oocyte extracts, enhances Kv4.2 surface current ~5-fold without increasing total protein level, accelerates inactivation and recovery from inactivation, and introduces hyperpolarizing shifts in conductance-voltage and steady-state inactivation relationships. The cytoplasmic N-terminal domain of DPP10 was identified as the determinant for acceleration of inactivation.\",\n      \"method\": \"Co-immunoprecipitation, two-electrode voltage-clamp in Xenopus oocytes, N-terminal domain deletion/truncation experiments\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus electrophysiology plus domain mapping; independently replicates findings of PMID:15671030\",\n      \"pmids\": [\"15454437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Kv4.2, KChIP3, and DPP10 form a ternary macromolecular complex in rat brain and in heterologous expression systems (Xenopus oocytes and CHO cells), demonstrated by immunoprecipitation. The ternary complex produces current waveforms distinct from any binary combination, and recovery from inactivation in the ternary complex (~18–26 ms) closely matches native neuronal ISA.\",\n      \"method\": \"Co-immunoprecipitation from rat brain and heterologous cells, two-electrode voltage-clamp and patch-clamp electrophysiology in oocytes and CHO cells\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP from native tissue plus heterologous reconstitution with functional readout; replicated across two expression systems\",\n      \"pmids\": [\"16123112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"DPP10 splice variants (DPP10a, DPP10c, DPP10d) differentially regulate Kv4.2+KChIP3+DPP10 channel complex gating. DPP10a produces uniquely fast inactivation kinetics that accelerate with increasing depolarization and dominate when co-expressed with KChIP4a or other DPP10 isoforms. DPP10a transcripts are prominently expressed in cortex while DPP10c and DPP10d show more diffuse distributions.\",\n      \"method\": \"Electrophysiology (two-electrode voltage-clamp in Xenopus oocytes, patch-clamp in CHO cells), real-time qRT-PCR, in situ hybridization\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — electrophysiology with multiple splice variants plus expression mapping; single lab but two orthogonal functional and expression methods\",\n      \"pmids\": [\"17475505\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"DPP10 modulates Kv4.3 gating (accelerates inactivation, shifts steady-state activation and inactivation) and also modulates Kv1.4 (faster time-to-peak, negative shift in half-inactivation), demonstrating that DPP10 is not restricted to Kv4 channels. DPP10 and KChIP2b act on different inactivation states of Kv4.3: KChIP2b nearly abolishes closed-state inactivation, whereas DPP10 permits its development. A DPP10 truncation mutant containing only the transmembrane and 58 cytoplasmic amino acids reproduced wild-type DPP10 effects on Kv4.3 gating.\",\n      \"method\": \"Heterologous co-expression with patch-clamp electrophysiology, truncation mutant analysis\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean electrophysiology with domain truncation, single lab, single expression system\",\n      \"pmids\": [\"16738002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Multiple DPP10 (DPPY) splicing variants with alternative first exons exist in brain, adrenal gland, and pancreas with species- and tissue-specific expression patterns. Splicing variants and an N-terminal peptide-deleted DPPY produce similar changes in Kv4.3 gating, indicating the N-terminal cytoplasmic region is not required for Kv4.3 modulation.\",\n      \"method\": \"RT-PCR/cloning of splice variants, electrophysiology (Kv4.3 gating assay in heterologous system)\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — electrophysiology with multiple variants, single lab, single expression system\",\n      \"pmids\": [\"16899223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"DPP10 (DPL2-s, 789-aa isoform) lacks dipeptidyl peptidase activity; substitutions to reconstitute the catalytic serine (Gly644→Ser, Lys643Gly644→TrpSer, Asp561Lys643Gly644→TyrTrpSer) failed to confer enzymatic activity. DPP10 is glycosylated, expressed primarily on the cell surface of transfected cells, and produces multiple forms (96 kDa soluble, 100 kDa transmembrane, ~250 kDa multimeric).\",\n      \"method\": \"Site-directed mutagenesis of catalytic motif, enzymatic activity assay, PNGase F deglycosylation, cell-surface expression analysis\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — active-site mutagenesis with enzyme activity assay directly demonstrating lack of catalytic activity; multiple mutagenesis variants tested\",\n      \"pmids\": [\"16290253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of human DPP10 (DPPY) was solved, revealing two domains: a β-propeller and an α/β-hydrolase fold (S9B serine protease subfamily). The catalytic serine is replaced by a glycine, explaining lack of enzymatic activity. The entrance channels to the active site differ from DPP4, and the DPP10 dimer interface was characterized.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure with structural comparison to DPP4 and DPP6; directly validates prior biochemical findings on enzymatic inactivity\",\n      \"pmids\": [\"25740212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"N-linked glycosylation of DPP10 is required for its cell surface expression and for its accelerating effects on Kv4.3 current kinetics. Pharmacological inhibition of glycosylation by tunicamycin completely blocked DPP10 glycosylation, reduced cell surface expression, and abolished the accelerating effects of DPP10 on Kv4.3 inactivation and recovery from inactivation. Similar effects were observed in native human atrial myocytes.\",\n      \"method\": \"Pharmacological inhibition of glycosylation (tunicamycin, neuraminidase) in CHO cells and human atrial myocytes, flow cytometry for surface expression, patch-clamp electrophysiology\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological disruption plus native cell validation; two orthogonal approaches but single lab\",\n      \"pmids\": [\"20354865\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"N-glycosylation of DPP10 occurs at six specific asparagine residues; glycosylation at N90, N119, N257, and N342 is required for DPP10 trafficking to the plasma membrane. N257 is critical: N257Q completely blocked DPP10 surface sorting and prevented DPP10 dimerization, and disrupted functional interaction with the Kv4.3/KChIP2a complex.\",\n      \"method\": \"Site-directed mutagenesis (N→Q substitutions), flow cytometry, co-immunoprecipitation, electrophysiology\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — site-directed mutagenesis of specific glycosylation sites with multiple orthogonal readouts (surface expression, dimerization, functional modulation); single lab\",\n      \"pmids\": [\"22387313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"DPP10 preferentially forms a 4:2 (Kv4.2:DPP10) stoichiometric complex. In the absence of Kv4.2, approximately 70% of DPP10 forms dimers in the plasma membrane. The Kv4.2 current amplitude and recovery from inactivation changed depending on the co-expression level of DPP10, indicating stoichiometry-dependent modulation. The preference for 4:2 stoichiometry is attributed to the bulky dimeric structure of the extracellular domain of DPP10.\",\n      \"method\": \"Single-molecule imaging/subunit counting (fluorescent protein fusion), two-electrode voltage-clamp in Xenopus oocytes at variable expression ratios\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — single-molecule stoichiometry counting plus functional electrophysiology; rigorous quantitative approach in single study\",\n      \"pmids\": [\"26209633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DPP10 protein (DPP10789 isoform) localizes to neuronal cell bodies predominantly at the plasma membrane and cytoplasm in normal rat brain, with strong reactivity in distal dendrites of CA1 pyramidal cells. In Alzheimer's disease brains, DPP10789 is redistributed to neurofibrillary tangles and plaque-associated dystrophic neurites, colocalizing with doubly phosphorylated tau (Ser-202/Thr-205). Truncated DPP10789 fragments increase significantly in AD brains by Western blot.\",\n      \"method\": \"Immunohistochemistry, immunofluorescence co-localization, Western blot on human brain tissue\",\n      \"journal\": \"BioMed research international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization by IHC/immunofluorescence on human tissue with colocalization analysis; multiple brain regions and disease conditions\",\n      \"pmids\": [\"25025038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DPP10 protein co-localizes with Kv4.3, KChIP1 in inhibitory interneurons (parvalbumin+ or somatostatin+) in hippocampus and neocortex, and with Kv4.2/Kv4.3/KChIP3 in neocortical layer 5 pyramidal neurons and olfactory bulb mitral cells in adult rat brain, supporting the existence of a Kv4/KChIP/DPP10 ternary complex in vivo. DPP10 is absent from glia.\",\n      \"method\": \"Immunohistochemistry with DPP10-specific antibody, triple immunofluorescence co-localization in rat brain sections\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct protein localization by immunohistochemistry with co-localization; corroborates biochemical co-IP evidence from PMID:16123112\",\n      \"pmids\": [\"25355692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DPP10 interacts physically with Nav1.5 channels in human ventricles (co-immunoprecipitation confirmed). In rat cardiomyocytes expressing DPP10 by adenoviral gene transfer, DPP10 reduced Na+ current density, shifted voltage-dependent activation and inactivation to more positive potentials, increased window Na+ current, reduced time-to-peak Na+ current, and accelerated recovery from inactivation.\",\n      \"method\": \"Co-immunoprecipitation from human ventricular tissue, adenoviral overexpression in rat cardiomyocytes, patch-clamp electrophysiology, action potential recording\",\n      \"journal\": \"International journal of cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP from native human tissue plus functional electrophysiology in native cardiomyocytes; single lab, two orthogonal methods\",\n      \"pmids\": [\"30638748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The Drosophila DPP10 ortholog acts as an ancillary subunit of Kv4 channels (binds rat Kv4.3 and causes negative shifts in voltage dependence of activation and inactivation, faster inactivation and recovery) AND retains dipeptidyl peptidase enzymatic activity (hydrolyzes Gly-Pro-MCA with Km similar to human DPP4 but ~6-fold lower kcat/immunoreactivity), demonstrating that the ancestral protein had dual function and that enzymatic activity was lost in mammalian DPP10.\",\n      \"method\": \"Co-immunoprecipitation, electrophysiology (two-electrode voltage-clamp), enzymatic activity assay with fluorescent substrate\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Weak — ortholog study with reconstituted enzymatic assay and electrophysiology; single lab but two orthogonal methods\",\n      \"pmids\": [\"27198182\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DPP10 is an enzymatically inactive (catalytic Ser replaced by Gly), N-glycosylated type II transmembrane protein that functions as an auxiliary subunit of voltage-gated K+ channels: it physically associates with Kv4.2/Kv4.3 (preferentially in a 4:2 Kv4:DPP10 stoichiometry), promotes their trafficking to the plasma membrane, and modifies their gating kinetics (accelerating inactivation and recovery, shifting voltage dependence) in a manner dependent on its transmembrane/intracellular domains and N-glycosylation state; together with KChIPs, DPP10 forms ternary complexes that reconstitute native neuronal ISA currents, and DPP10 also interacts with and modulates cardiac Nav1.5 channels.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DPP10 is an N-glycosylated type II transmembrane protein that functions as an auxiliary subunit of voltage-gated potassium channels, controlling the trafficking and gating of Kv4 channels that generate neuronal A-type currents [#0, #1]. Although it adopts the β-propeller plus α/β-hydrolase architecture of the S9B dipeptidyl peptidase family, its catalytic serine is replaced by glycine, and mutagenesis aimed at restoring the active site fails to confer enzymatic activity, establishing DPP10 as a catalytically dead pseudo-peptidase [#6, #7]. DPP10 physically associates with Kv4.2 and Kv4.3, promotes their surface expression, and accelerates inactivation and recovery from inactivation while introducing hyperpolarizing shifts in voltage dependence; these gating effects are conferred by its transmembrane and intracellular regions rather than its extracellular ectodomain [#0, #1, #4]. Together with KChIP subunits, DPP10 assembles into ternary Kv4/KChIP/DPP10 complexes that reconstitute current waveforms and recovery kinetics matching native neuronal ISA, and such complexes are co-localized in defined neuronal populations in vivo [#2, #12]. Channel modulation is stoichiometry-dependent, with DPP10 preferentially forming a 4:2 (Kv4:DPP10) complex, and depends critically on N-linked glycosylation, where site-specific glycans (notably N257) drive DPP10 surface sorting, dimerization, and functional interaction with the channel [#9, #10]. Beyond Kv4, DPP10 physically interacts with cardiac Nav1.5 channels in human ventricle and modifies sodium current density and gating [#13]. DPP10 protein is also redistributed to neurofibrillary tangles and dystrophic neurites in Alzheimer's disease brain [#11].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Established that DPP10 is a functional Kv4 channel partner, not merely a co-expressed protein, by showing it binds Kv4.2 and remodels its surface current and gating.\",\n      \"evidence\": \"Co-immunoprecipitation and two-electrode voltage-clamp in Xenopus oocytes with N-terminal truncation mapping\",\n      \"pmids\": [\"15454437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Performed in heterologous oocytes only\", \"Did not address whether native brain complexes exist\", \"Stoichiometry of the complex unresolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Confirmed the Kv4.2-DPP10 interaction occurs natively in brain and localized the modulatory determinant to the transmembrane/intracellular domains, defining how DPP10 sculpts A-type currents.\",\n      \"evidence\": \"Co-immunoprecipitation from rat brain membranes, heterologous electrophysiology, domain-swap chimeras, in situ hybridization\",\n      \"pmids\": [\"15671030\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish three-way complex with KChIPs\", \"Mechanism of gating modulation at structural level unknown\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstrated that DPP10 is enzymatically dead despite its peptidase fold, reframing it as a non-catalytic accessory subunit rather than an active dipeptidyl peptidase.\",\n      \"evidence\": \"Site-directed mutagenesis of the catalytic motif with enzyme activity assays, PNGase F deglycosylation, cell-surface analysis\",\n      \"pmids\": [\"16290253\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why active-site reconstitution failed to restore activity not structurally explained at the time\", \"Soluble vs transmembrane form roles unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed that Kv4/KChIP/DPP10 form a ternary macromolecular complex whose gating reconstitutes native neuronal ISA, defining the physiological channel assembly.\",\n      \"evidence\": \"Co-immunoprecipitation from rat brain and heterologous cells with electrophysiology in oocytes and CHO cells\",\n      \"pmids\": [\"16123112\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Subunit stoichiometry not quantified\", \"Spatial distribution in defined neuron types not yet shown\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Extended DPP10 modulation beyond Kv4 to Kv1.4 and mapped the minimal modulatory unit to the transmembrane plus a short cytoplasmic segment, distinguishing DPP10's action from KChIP on channel inactivation states.\",\n      \"evidence\": \"Heterologous patch-clamp co-expression with truncation mutant analysis\",\n      \"pmids\": [\"16738002\", \"16899223\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conflicting conclusions on N-terminal requirement across studies\", \"Single expression system\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed splice variants tune the gating phenotype of the ternary complex, providing a mechanism for regional diversity of A-type currents.\",\n      \"evidence\": \"Electrophysiology of DPP10 isoforms in oocytes and CHO cells with qRT-PCR and in situ hybridization\",\n      \"pmids\": [\"17475505\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of isoform distribution in vivo untested\", \"Structural basis of isoform-specific kinetics unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Defined N-linked glycosylation, particularly at N257, as required for DPP10 trafficking, dimerization, and functional channel modulation, linking post-translational modification to assembly.\",\n      \"evidence\": \"Site-directed N\\u2192Q mutagenesis with flow cytometry, co-IP, and electrophysiology; complemented by tunicamycin/neuraminidase disruption in CHO cells and human atrial myocytes\",\n      \"pmids\": [\"22387313\", \"20354865\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How glycosylation mechanistically enables dimerization not resolved\", \"In vivo relevance of individual glycosites untested\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Localized DPP10 to specific neuronal populations alongside Kv4 and KChIP subunits, and documented its aberrant redistribution to tau pathology in Alzheimer's disease.\",\n      \"evidence\": \"Immunohistochemistry and triple immunofluorescence co-localization in rat and human brain, Western blot\",\n      \"pmids\": [\"25355692\", \"25025038\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal role of DPP10 in AD pathology not established\", \"Functional consequence of fragment accumulation unknown\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Provided the structural basis for enzymatic inactivity and quantified the preferred 4:2 Kv4:DPP10 stoichiometry, explaining how the extracellular dimer constrains complex assembly and modulation.\",\n      \"evidence\": \"X-ray crystallography of human DPP10; single-molecule subunit counting plus variable-ratio electrophysiology in oocytes\",\n      \"pmids\": [\"25740212\", \"26209633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structure of the assembled Kv4/DPP10 complex\", \"How transmembrane/intracellular domains transmit gating effects not captured by ectodomain structure\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showed the Drosophila ortholog is both a Kv4 ancillary subunit and an active dipeptidyl peptidase, establishing that the ancestral protein was bifunctional and enzymatic activity was lost in mammalian DPP10.\",\n      \"evidence\": \"Co-IP, electrophysiology, and fluorescent-substrate enzymatic assay on the ortholog\",\n      \"pmids\": [\"27198182\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Ortholog assay does not address human DPP10 physiology\", \"Single lab, two methods\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified cardiac Nav1.5 as a DPP10 partner, broadening its role beyond potassium channels into sodium current regulation in the heart.\",\n      \"evidence\": \"Co-immunoprecipitation from human ventricular tissue and adenoviral overexpression with patch-clamp in rat cardiomyocytes\",\n      \"pmids\": [\"30638748\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Physiological/arrhythmic consequence in vivo not established\", \"Domain requirements for Nav1.5 modulation unmapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DPP10's transmembrane and intracellular domains physically couple to and reshape channel gating, and whether its multiple channel partnerships (Kv4, Kv1.4, Nav1.5) operate through a shared mechanism, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of an assembled channel-DPP10 complex\", \"Shared vs distinct modulatory mechanism across channel families unknown\", \"Physiological consequences of loss in mammals uncharacterized\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 4, 10]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 6, 9, 11]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-112316\", \"supporting_discovery_ids\": [0, 2, 12]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"complexes\": [\"Kv4/KChIP/DPP10 ternary channel complex\"],\n    \"partners\": [\"KCND2\", \"KCND3\", \"KCNA4\", \"KCNIP3\", \"KCNIP2\", \"SCN5A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}