{"gene":"DPP10","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2004,"finding":"DPP10 physically associates with Kv4.2 channels (co-immunoprecipitation from oocyte extracts) and, upon coexpression, enhances Kv4.2 surface current ~5-fold, accelerates inactivation and recovery from inactivation, and shifts conductance-voltage and steady-state inactivation curves in the hyperpolarizing direction; the cytoplasmic N-terminal domain of DPP10 determines the acceleration of inactivation.","method":"Two-electrode voltage-clamp in Xenopus oocytes, co-immunoprecipitation, N-terminal domain truncation experiments","journal":"Biophysical journal","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus detailed electrophysiology with domain mapping; replicated by independent lab","pmids":["15454437"],"is_preprint":false},{"year":2005,"finding":"DPP10 facilitates Kv4.2 protein trafficking to the cell membrane, increases A-type current magnitude, and modifies voltage dependence and kinetics to resemble native neuronal A-type currents; DPP10 co-immunoprecipitates with Kv4.2 from native rat brain membranes, confirming it is a component of native channel complexes; chimera experiments show the intracellular and transmembrane domains (not the extracellular domain) are critical for Kv4.2 modulation.","method":"Heterologous expression (oocytes/HEK cells), co-immunoprecipitation from rat brain, in situ hybridization, DPPX/DPP10/DPPIV chimera analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP from native tissue plus chimera domain mapping, independent replication of core findings","pmids":["15671030"],"is_preprint":false},{"year":2005,"finding":"KChIP3 and DPP10 associate simultaneously with Kv4.2 in rat brain and in Xenopus oocytes, forming a ternary Kv4.2/KChIP3/DPP10 complex; the ternary complex produces uniquely rapid recovery from inactivation (τrec ~18–26 ms) matching native ISA, faster than either binary complex, establishing DPP10 as an essential component of the native somatodendritic A-type channel macromolecular complex.","method":"Immunoprecipitation from rat brain and Xenopus oocytes, two-electrode voltage-clamp, CHO cell expression","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP from native tissue, confirmed in two heterologous systems, multiple orthogonal readouts","pmids":["16123112"],"is_preprint":false},{"year":2005,"finding":"DPP10 lacks dipeptidyl peptidase enzymatic activity; substitution of Gly644→Ser or restoration of the full catalytic triad (Asp561, Lys643, Gly644 → Tyr, Trp, Ser) did not confer dipeptidyl peptidase activity, indicating the absence of activity is due to missing critical catalytic residues beyond the catalytic serine replacement.","method":"Site-directed mutagenesis of catalytic residues, enzymatic activity assay in transfected 293T cells","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 1 — direct mutagenesis with enzymatic activity readout","pmids":["16290253"],"is_preprint":false},{"year":2006,"finding":"DPP10 modulates Kv4.3 inactivation including closed-state inactivation, and also modulates Kv1.4 by accelerating time-to-peak and shifting steady-state inactivation; the transmembrane plus cytoplasmic 58-amino-acid domain of DPP10 alone is sufficient to reproduce wild-type DPP10 effects on Kv4.3 gating, indicating this minimal domain mediates channel interaction.","method":"Heterologous expression in Xenopus oocytes, truncation mutant (TM+58 aa cytoplasmic domain) electrophysiology","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 — truncation/domain mapping with electrophysiological readout, single lab","pmids":["16738002"],"is_preprint":false},{"year":2006,"finding":"Multiple DPP10 (DPPY) splice variants with alternative first exons are expressed in a species- and tissue-specific manner; all splice variants as well as an N-terminal-deleted DPP10 produce similar changes in Kv4.3 gating, indicating the N-terminal cytoplasmic domain variability does not critically alter gating modulation per se.","method":"RT-PCR, heterologous expression electrophysiology in Xenopus oocytes","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — functional electrophysiology with multiple isoforms, single lab","pmids":["16899223"],"is_preprint":false},{"year":2007,"finding":"DPP10 splice variant DPP10a produces uniquely fast inactivation kinetics that accelerates with increasing depolarization in the Kv4.2/KChIP3/DPP10 ternary complex, and DPP10a-specific inactivation dominates when co-expressed with KChIP4a or other DPP10 isoforms; DPP10a is prominently expressed in cortex while DPP10c/d show more diffuse distributions.","method":"Two-electrode voltage clamp in Xenopus oocytes, qRT-PCR, in situ hybridization","journal":"Molecular and cellular neurosciences","confidence":"Medium","confidence_rationale":"Tier 2 — functional isoform comparison with multiple electrophysiology readouts and expression mapping, single lab","pmids":["17475505"],"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 inactivation and recovery; pharmacological inhibition of glycosylation (tunicamycin) blocks DPP10 surface trafficking and abolishes DPP10-mediated modulation of Kv4.3 current kinetics in CHO cells and native human atrial myocytes.","method":"Tunicamycin and neuraminidase treatment, flow cytometry, whole-cell patch clamp in CHO cells and human atrial myocytes","journal":"Pflugers Archiv : European journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 — pharmacological disruption with functional electrophysiological readout in heterologous and native cells, single lab","pmids":["20354865"],"is_preprint":false},{"year":2012,"finding":"N-glycosylation of DPP10 occurs at six specific asparagine residues in the extracellular domain; glycosylation at N90, N119, N257, and N342 is necessary for plasma membrane trafficking; N257 glycosylation is additionally required for DPP10 dimerization and interaction with the Kv4.3/KChIP2a complex.","method":"Site-directed mutagenesis (N→Q), flow cytometry surface expression, co-immunoprecipitation, electrophysiology in CHO cells","journal":"The international journal of biochemistry & cell biology","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis at defined sites with multiple orthogonal readouts (trafficking, dimerization, channel interaction, electrophysiology)","pmids":["22387313"],"is_preprint":false},{"year":2014,"finding":"DPP10 protein is localized predominantly in neuronal cell bodies (not glia) in rat brain, present at both plasma membrane and cytoplasm; immunohistochemistry with co-localization analysis confirms Kv4.3/KChIP1/DPP10 and Kv4.2/Kv4.3/KChIP3/DPP10 ternary complexes exist in specific neuronal populations (parvalbumin/somatostatin interneurons, layer 5 pyramidal neurons, olfactory bulb mitral cells) in vivo.","method":"Immunohistochemistry with custom DPP10 antibody, co-localization analysis in rat brain sections","journal":"The Journal of comparative neurology","confidence":"Medium","confidence_rationale":"Tier 3 — direct localization experiment with in vivo co-localization evidence, single lab","pmids":["25355692"],"is_preprint":false},{"year":2015,"finding":"Crystal structure of human DPP10 reveals two-domain architecture (β-propeller and α/β-hydrolase fold) belonging to the S9B serine protease subfamily; the catalytic serine is replaced by glycine, explaining enzymatic inactivity; differences in the entrance channel to the active site compared to DPP4 provide a structural basis for lack of activity; the dimer interface is structurally characterized.","method":"X-ray crystallography (crystal structure solved by molecular replacement using DPP6 as search model)","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with structural validation of inactive catalytic site and dimer interface","pmids":["25740212"],"is_preprint":false},{"year":2015,"finding":"The Kv4.2/DPP10 complex preferentially adopts a 4:2 stoichiometry (four Kv4.2 subunits per two DPP10 subunits); DPP10 forms dimers (~70%) in the plasma membrane even in the absence of Kv4.2; the stoichiometry is variable depending on relative expression levels and influences biophysical properties of Kv4.2 current.","method":"Single-molecule imaging/subunit counting in Xenopus oocytes, two-electrode voltage clamp at different Kv4.2:DPP10 ratios","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — single-molecule stoichiometry determination with functional correlation, rigorous quantitative approach","pmids":["26209633"],"is_preprint":false},{"year":2016,"finding":"The Drosophila DPP10 ortholog retains channel ancillary subunit function (binds rat Kv4.3, causes negative shifts in activation and inactivation, accelerates inactivation and recovery) but also possesses dipeptidyl peptidase enzymatic activity, suggesting the loss of enzymatic activity in mammalian DPP10 is a derived feature.","method":"Co-immunoprecipitation, two-electrode voltage clamp, fluorometric enzymatic activity assay with Gly-Pro-MCA substrate","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 1/2 — in vitro enzymatic assay plus electrophysiology for fly ortholog; relevant as comparative mechanistic insight, single lab","pmids":["27198182"],"is_preprint":false},{"year":2019,"finding":"DPP10 physically interacts with cardiac Nav1.5 channels (co-immunoprecipitation from human ventricle); adenoviral DPP10 expression in rat cardiomyocytes shifts Nav1.5 activation and inactivation to more positive potentials, reduces upstroke velocity, accelerates time-to-peak Na+ current and recovery from inactivation, and increases window Na+ current.","method":"Co-immunoprecipitation from human ventricular tissue, adenoviral gene transfer in rat cardiomyocytes, patch-clamp electrophysiology, action potential recordings","journal":"International journal of cardiology","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP from native tissue plus functional electrophysiology in primary cardiomyocytes, single lab","pmids":["30638748"],"is_preprint":false}],"current_model":"DPP10 is an enzymatically inactive, N-glycosylated type II transmembrane protein of the S9B serine protease family that functions as an auxiliary subunit of voltage-gated K+ (Kv4.1/4.2/4.3) and Na+ (Nav1.5) channels: it dimerizes via its extracellular domain, traffics to the plasma membrane in a glycosylation-dependent manner, and — through its transmembrane and cytoplasmic domains — accelerates channel inactivation and recovery, shifts voltage dependence of activation and inactivation, and increases surface current density; together with KChIP proteins it forms native ternary Kv4/KChIP/DPP10 macromolecular complexes responsible for somatodendritic subthreshold A-type currents (ISA) in neurons, with splice-variant-specific N-termini further tuning inactivation kinetics in a brain-region-specific manner."},"narrative":{"teleology":[{"year":2004,"claim":"Establishing DPP10 as a Kv4.2 auxiliary subunit resolved how a catalytically dead dipeptidyl peptidase-family protein could have a physiological role — it directly binds and modulates Kv4 channel gating, with the cytoplasmic N-terminus controlling inactivation acceleration.","evidence":"Co-immunoprecipitation and two-electrode voltage clamp with N-terminal truncation in Xenopus oocytes","pmids":["15454437"],"confidence":"High","gaps":["Mechanism by which DPP10 promotes channel surface expression was unknown","Whether DPP10 participates in native neuronal channel complexes was unresolved","How DPP10 cooperates with KChIP co-subunits was not addressed"]},{"year":2005,"claim":"Demonstration that DPP10 co-immunoprecipitates with Kv4.2 from native rat brain and forms ternary complexes with KChIP3 that uniquely reconstitute the rapid recovery kinetics of native ISA established DPP10 as an essential component of neuronal A-type channel macromolecular complexes.","evidence":"Co-IP from rat brain membranes, chimera domain mapping, ternary reconstitution electrophysiology in oocytes and CHO cells","pmids":["15671030","16123112"],"confidence":"High","gaps":["Stoichiometry of the ternary complex was unknown","Structural basis for interaction was not resolved","Identity of specific neuronal populations expressing the complex was not mapped"]},{"year":2005,"claim":"Mutagenesis of the catalytic triad residues confirmed that DPP10 is enzymatically inactive even when key catalytic residues are restored, establishing that its physiological function is non-enzymatic.","evidence":"Site-directed mutagenesis with enzymatic activity assay in 293T cells","pmids":["16290253"],"confidence":"High","gaps":["Structural basis for lack of activity was not yet determined","Whether ancestral DPP10 orthologs possessed enzymatic activity was unknown"]},{"year":2006,"claim":"Identification that the transmembrane plus 58-amino-acid cytoplasmic domain of DPP10 is the minimal unit sufficient for Kv4 gating modulation, and that multiple splice variants with alternative N-termini similarly modulate Kv4.3, refined understanding of which protein regions are functionally essential versus modulatory.","evidence":"Truncation mutant electrophysiology and splice variant RT-PCR/expression in Xenopus oocytes","pmids":["16738002","16899223"],"confidence":"Medium","gaps":["Whether splice-variant-specific N-termini confer distinct kinetics in ternary complexes was untested","In vivo relevance of splice variant expression patterns was not demonstrated"]},{"year":2007,"claim":"Discovery that the DPP10a splice variant produces uniquely fast, voltage-dependent inactivation that dominates in ternary complexes revealed that N-terminal splice variation does tune channel kinetics in an isoform-specific manner, with DPP10a enriched in cortex suggesting region-specific ISA tuning.","evidence":"Two-electrode voltage clamp in oocytes with isoform combinations, qRT-PCR and in situ hybridization","pmids":["17475505"],"confidence":"Medium","gaps":["Mechanism by which the DPP10a N-terminus produces faster inactivation was not resolved","Functional impact in cortical neurons in vivo was not tested"]},{"year":2010,"claim":"Pharmacological disruption of N-glycosylation abolished DPP10 surface expression and its functional effects on Kv4.3 in both heterologous cells and native human atrial myocytes, establishing glycosylation as a prerequisite for DPP10 trafficking and channel modulation.","evidence":"Tunicamycin treatment, flow cytometry, and patch clamp in CHO cells and human atrial myocytes","pmids":["20354865"],"confidence":"Medium","gaps":["Which specific glycosylation sites were essential was not determined","Whether glycosylation affects DPP10 dimerization was unknown"]},{"year":2012,"claim":"Site-directed mutagenesis of six N-glycosylation sites identified four asparagines required for surface trafficking and pinpointed N257 as additionally essential for DPP10 dimerization and interaction with the Kv4.3/KChIP2a complex, linking a specific post-translational modification to complex assembly.","evidence":"N→Q mutagenesis at six sites, flow cytometry, co-IP, and electrophysiology in CHO cells","pmids":["22387313"],"confidence":"High","gaps":["Structural mechanism by which N257 glycosylation enables dimerization was not resolved","Whether glycosylation requirements differ across DPP10 splice variants was untested"]},{"year":2014,"claim":"Immunohistochemical mapping in rat brain localized DPP10 to neuronal somata and confirmed in vivo co-localization with Kv4.2, Kv4.3, KChIP1, and KChIP3 in defined neuronal populations (parvalbumin/somatostatin interneurons, layer 5 pyramidal neurons, olfactory bulb mitral cells), validating the ternary complex model in native circuits.","evidence":"Immunohistochemistry with custom DPP10 antibody and co-localization analysis in rat brain sections","pmids":["25355692"],"confidence":"Medium","gaps":["Functional consequences of DPP10 loss in these specific neuron types were not assessed","Co-localization does not prove physical interaction in every identified neuron type"]},{"year":2015,"claim":"The crystal structure of human DPP10 revealed the β-propeller/α/β-hydrolase two-domain fold with glycine replacing the catalytic serine and a remodeled active-site entrance, providing the structural explanation for enzymatic inactivity; single-molecule imaging separately established that the Kv4.2/DPP10 complex preferentially adopts a 4:2 stoichiometry with DPP10 forming constitutive dimers.","evidence":"X-ray crystallography (molecular replacement from DPP6); single-molecule subunit counting and voltage clamp in Xenopus oocytes","pmids":["25740212","26209633"],"confidence":"High","gaps":["No structure of the Kv4/DPP10 or Kv4/KChIP/DPP10 complex existed","How the transmembrane and cytoplasmic domains engage the channel pore domain was structurally unresolved","Whether 4:4 versus 4:2 stoichiometry exists in native neurons was not determined"]},{"year":2016,"claim":"The Drosophila DPP10 ortholog retained both channel modulatory and dipeptidyl peptidase enzymatic activities, indicating that loss of catalytic function in mammalian DPP10 is a derived evolutionary event rather than an ancestral feature of the family.","evidence":"Co-IP, electrophysiology, and fluorometric enzyme assay for Drosophila ortholog with rat Kv4.3","pmids":["27198182"],"confidence":"Medium","gaps":["Physiological significance of enzymatic activity in Drosophila was not explored","Evolutionary timeline of catalytic loss was not traced"]},{"year":2019,"claim":"Discovery that DPP10 co-immunoprecipitates with Nav1.5 from human ventricle and modulates cardiac sodium current gating extended DPP10's role beyond Kv4 channels to cardiac sodium channels, with implications for cardiac conduction.","evidence":"Co-IP from human ventricular tissue, adenoviral DPP10 expression in rat cardiomyocytes, patch-clamp electrophysiology","pmids":["30638748"],"confidence":"Medium","gaps":["Domain determinants of DPP10-Nav1.5 interaction were not mapped","Whether KChIPs participate in the Nav1.5/DPP10 complex is unknown","In vivo cardiac phenotype of DPP10 loss or gain has not been studied"]},{"year":null,"claim":"No high-resolution structure of the full Kv4/KChIP/DPP10 ternary complex exists, and the in vivo physiological consequences of DPP10 deletion in specific neuronal or cardiac cell types remain uncharacterized.","evidence":"","pmids":[],"confidence":"High","gaps":["No cryo-EM or crystal structure of the full ternary complex has been reported","No DPP10 knockout or conditional knockout phenotyping in neurons or heart has been published in the timeline","Mechanism of DPP10 specificity for Kv4 versus other Kv or Nav channels is structurally unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,2,4,13]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,2,11]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7,8,9,11]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-112316","term_label":"Neuronal System","supporting_discovery_ids":[0,1,2,6,9]},{"term_id":"R-HSA-382551","term_label":"Transport of small molecules","supporting_discovery_ids":[0,1,4,13]}],"complexes":["Kv4/KChIP/DPP10 ternary complex"],"partners":["KCND2","KCND3","KCNIP3","KCNIP2","KCNIP1","SCN5A"],"other_free_text":[]},"mechanistic_narrative":"DPP10 is an enzymatically inactive type II transmembrane glycoprotein of the S9B serine protease family that functions as an auxiliary subunit of voltage-gated potassium (Kv4) and sodium (Nav1.5) channels, shaping neuronal and cardiac excitability. DPP10 physically associates with Kv4.2 and Kv4.3 channels through its transmembrane and short cytoplasmic domains, accelerating channel inactivation and recovery from inactivation, shifting voltage dependence in the hyperpolarizing direction, and increasing surface current density; together with KChIP proteins it forms native ternary Kv4/KChIP/DPP10 complexes that reconstitute somatodendritic subthreshold A-type currents (ISA) in specific neuronal populations [PMID:15454437, PMID:16123112, PMID:25355692]. N-linked glycosylation at specific extracellular asparagine residues is required for DPP10 dimerization, plasma membrane trafficking, and functional modulation of Kv4 channels, while the crystal structure reveals a β-propeller/α/β-hydrolase two-domain architecture with a glycine substitution at the catalytic serine position that accounts for the complete absence of dipeptidyl peptidase activity [PMID:22387313, PMID:25740212, PMID:16290253]. DPP10 also interacts with cardiac Nav1.5 channels, modulating sodium current kinetics and voltage dependence in cardiomyocytes [PMID:30638748]."},"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":"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":"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":116,"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":115,"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":41,"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":19,"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 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cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/30638748","citation_count":7,"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":4,"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":4,"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},{"pmid":null,"id":"bio_10.1101_2025.01.16.633336","title":"A new deep-branching environmental lineage of algae","date":"2025-01-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.01.16.633336","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.11.30.691411","title":"Interrogating the Regulatory Function of HAQERs during Human Cortical Development","date":"2025-12-01","source":"bioRxiv","url":"https://doi.org/10.1101/2025.11.30.691411","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15671,"output_tokens":3642,"usd":0.050821},"stage2":{"model":"claude-opus-4-6","input_tokens":7056,"output_tokens":3317,"usd":0.177308},"total_usd":0.228129,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"DPP10 physically associates with Kv4.2 channels (co-immunoprecipitation from oocyte extracts) and, upon coexpression, enhances Kv4.2 surface current ~5-fold, accelerates inactivation and recovery from inactivation, and shifts conductance-voltage and steady-state inactivation curves in the hyperpolarizing direction; the cytoplasmic N-terminal domain of DPP10 determines the acceleration of inactivation.\",\n      \"method\": \"Two-electrode voltage-clamp in Xenopus oocytes, co-immunoprecipitation, N-terminal domain truncation experiments\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus detailed electrophysiology with domain mapping; replicated by independent lab\",\n      \"pmids\": [\"15454437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"DPP10 facilitates Kv4.2 protein trafficking to the cell membrane, increases A-type current magnitude, and modifies voltage dependence and kinetics to resemble native neuronal A-type currents; DPP10 co-immunoprecipitates with Kv4.2 from native rat brain membranes, confirming it is a component of native channel complexes; chimera experiments show the intracellular and transmembrane domains (not the extracellular domain) are critical for Kv4.2 modulation.\",\n      \"method\": \"Heterologous expression (oocytes/HEK cells), co-immunoprecipitation from rat brain, in situ hybridization, DPPX/DPP10/DPPIV chimera analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP from native tissue plus chimera domain mapping, independent replication of core findings\",\n      \"pmids\": [\"15671030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"KChIP3 and DPP10 associate simultaneously with Kv4.2 in rat brain and in Xenopus oocytes, forming a ternary Kv4.2/KChIP3/DPP10 complex; the ternary complex produces uniquely rapid recovery from inactivation (τrec ~18–26 ms) matching native ISA, faster than either binary complex, establishing DPP10 as an essential component of the native somatodendritic A-type channel macromolecular complex.\",\n      \"method\": \"Immunoprecipitation from rat brain and Xenopus oocytes, two-electrode voltage-clamp, CHO cell expression\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP from native tissue, confirmed in two heterologous systems, multiple orthogonal readouts\",\n      \"pmids\": [\"16123112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"DPP10 lacks dipeptidyl peptidase enzymatic activity; substitution of Gly644→Ser or restoration of the full catalytic triad (Asp561, Lys643, Gly644 → Tyr, Trp, Ser) did not confer dipeptidyl peptidase activity, indicating the absence of activity is due to missing critical catalytic residues beyond the catalytic serine replacement.\",\n      \"method\": \"Site-directed mutagenesis of catalytic residues, enzymatic activity assay in transfected 293T cells\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct mutagenesis with enzymatic activity readout\",\n      \"pmids\": [\"16290253\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"DPP10 modulates Kv4.3 inactivation including closed-state inactivation, and also modulates Kv1.4 by accelerating time-to-peak and shifting steady-state inactivation; the transmembrane plus cytoplasmic 58-amino-acid domain of DPP10 alone is sufficient to reproduce wild-type DPP10 effects on Kv4.3 gating, indicating this minimal domain mediates channel interaction.\",\n      \"method\": \"Heterologous expression in Xenopus oocytes, truncation mutant (TM+58 aa cytoplasmic domain) electrophysiology\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — truncation/domain mapping with electrophysiological readout, single lab\",\n      \"pmids\": [\"16738002\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Multiple DPP10 (DPPY) splice variants with alternative first exons are expressed in a species- and tissue-specific manner; all splice variants as well as an N-terminal-deleted DPP10 produce similar changes in Kv4.3 gating, indicating the N-terminal cytoplasmic domain variability does not critically alter gating modulation per se.\",\n      \"method\": \"RT-PCR, heterologous expression electrophysiology in Xenopus oocytes\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional electrophysiology with multiple isoforms, single lab\",\n      \"pmids\": [\"16899223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"DPP10 splice variant DPP10a produces uniquely fast inactivation kinetics that accelerates with increasing depolarization in the Kv4.2/KChIP3/DPP10 ternary complex, and DPP10a-specific inactivation dominates when co-expressed with KChIP4a or other DPP10 isoforms; DPP10a is prominently expressed in cortex while DPP10c/d show more diffuse distributions.\",\n      \"method\": \"Two-electrode voltage clamp in Xenopus oocytes, qRT-PCR, in situ hybridization\",\n      \"journal\": \"Molecular and cellular neurosciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional isoform comparison with multiple electrophysiology readouts and expression mapping, single lab\",\n      \"pmids\": [\"17475505\"],\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 inactivation and recovery; pharmacological inhibition of glycosylation (tunicamycin) blocks DPP10 surface trafficking and abolishes DPP10-mediated modulation of Kv4.3 current kinetics in CHO cells and native human atrial myocytes.\",\n      \"method\": \"Tunicamycin and neuraminidase treatment, flow cytometry, whole-cell patch clamp in CHO cells and human atrial myocytes\",\n      \"journal\": \"Pflugers Archiv : European journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — pharmacological disruption with functional electrophysiological readout in heterologous and native cells, 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 in the extracellular domain; glycosylation at N90, N119, N257, and N342 is necessary for plasma membrane trafficking; N257 glycosylation is additionally required for DPP10 dimerization and interaction with the Kv4.3/KChIP2a complex.\",\n      \"method\": \"Site-directed mutagenesis (N→Q), flow cytometry surface expression, co-immunoprecipitation, electrophysiology in CHO cells\",\n      \"journal\": \"The international journal of biochemistry & cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis at defined sites with multiple orthogonal readouts (trafficking, dimerization, channel interaction, electrophysiology)\",\n      \"pmids\": [\"22387313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"DPP10 protein is localized predominantly in neuronal cell bodies (not glia) in rat brain, present at both plasma membrane and cytoplasm; immunohistochemistry with co-localization analysis confirms Kv4.3/KChIP1/DPP10 and Kv4.2/Kv4.3/KChIP3/DPP10 ternary complexes exist in specific neuronal populations (parvalbumin/somatostatin interneurons, layer 5 pyramidal neurons, olfactory bulb mitral cells) in vivo.\",\n      \"method\": \"Immunohistochemistry with custom DPP10 antibody, co-localization analysis in rat brain sections\",\n      \"journal\": \"The Journal of comparative neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — direct localization experiment with in vivo co-localization evidence, single lab\",\n      \"pmids\": [\"25355692\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Crystal structure of human DPP10 reveals two-domain architecture (β-propeller and α/β-hydrolase fold) belonging to the S9B serine protease subfamily; the catalytic serine is replaced by glycine, explaining enzymatic inactivity; differences in the entrance channel to the active site compared to DPP4 provide a structural basis for lack of activity; the dimer interface is structurally characterized.\",\n      \"method\": \"X-ray crystallography (crystal structure solved by molecular replacement using DPP6 as search model)\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with structural validation of inactive catalytic site and dimer interface\",\n      \"pmids\": [\"25740212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The Kv4.2/DPP10 complex preferentially adopts a 4:2 stoichiometry (four Kv4.2 subunits per two DPP10 subunits); DPP10 forms dimers (~70%) in the plasma membrane even in the absence of Kv4.2; the stoichiometry is variable depending on relative expression levels and influences biophysical properties of Kv4.2 current.\",\n      \"method\": \"Single-molecule imaging/subunit counting in Xenopus oocytes, two-electrode voltage clamp at different Kv4.2:DPP10 ratios\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — single-molecule stoichiometry determination with functional correlation, rigorous quantitative approach\",\n      \"pmids\": [\"26209633\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The Drosophila DPP10 ortholog retains channel ancillary subunit function (binds rat Kv4.3, causes negative shifts in activation and inactivation, accelerates inactivation and recovery) but also possesses dipeptidyl peptidase enzymatic activity, suggesting the loss of enzymatic activity in mammalian DPP10 is a derived feature.\",\n      \"method\": \"Co-immunoprecipitation, two-electrode voltage clamp, fluorometric enzymatic activity assay with Gly-Pro-MCA substrate\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1/2 — in vitro enzymatic assay plus electrophysiology for fly ortholog; relevant as comparative mechanistic insight, single lab\",\n      \"pmids\": [\"27198182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DPP10 physically interacts with cardiac Nav1.5 channels (co-immunoprecipitation from human ventricle); adenoviral DPP10 expression in rat cardiomyocytes shifts Nav1.5 activation and inactivation to more positive potentials, reduces upstroke velocity, accelerates time-to-peak Na+ current and recovery from inactivation, and increases window Na+ current.\",\n      \"method\": \"Co-immunoprecipitation from human ventricular tissue, adenoviral gene transfer in rat cardiomyocytes, patch-clamp electrophysiology, action potential recordings\",\n      \"journal\": \"International journal of cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP from native tissue plus functional electrophysiology in primary cardiomyocytes, single lab\",\n      \"pmids\": [\"30638748\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DPP10 is an enzymatically inactive, N-glycosylated type II transmembrane protein of the S9B serine protease family that functions as an auxiliary subunit of voltage-gated K+ (Kv4.1/4.2/4.3) and Na+ (Nav1.5) channels: it dimerizes via its extracellular domain, traffics to the plasma membrane in a glycosylation-dependent manner, and — through its transmembrane and cytoplasmic domains — accelerates channel inactivation and recovery, shifts voltage dependence of activation and inactivation, and increases surface current density; together with KChIP proteins it forms native ternary Kv4/KChIP/DPP10 macromolecular complexes responsible for somatodendritic subthreshold A-type currents (ISA) in neurons, with splice-variant-specific N-termini further tuning inactivation kinetics in a brain-region-specific manner.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"DPP10 is an enzymatically inactive type II transmembrane glycoprotein of the S9B serine protease family that functions as an auxiliary subunit of voltage-gated potassium (Kv4) and sodium (Nav1.5) channels, shaping neuronal and cardiac excitability. DPP10 physically associates with Kv4.2 and Kv4.3 channels through its transmembrane and short cytoplasmic domains, accelerating channel inactivation and recovery from inactivation, shifting voltage dependence in the hyperpolarizing direction, and increasing surface current density; together with KChIP proteins it forms native ternary Kv4/KChIP/DPP10 complexes that reconstitute somatodendritic subthreshold A-type currents (ISA) in specific neuronal populations [PMID:15454437, PMID:16123112, PMID:25355692]. N-linked glycosylation at specific extracellular asparagine residues is required for DPP10 dimerization, plasma membrane trafficking, and functional modulation of Kv4 channels, while the crystal structure reveals a β-propeller/α/β-hydrolase two-domain architecture with a glycine substitution at the catalytic serine position that accounts for the complete absence of dipeptidyl peptidase activity [PMID:22387313, PMID:25740212, PMID:16290253]. DPP10 also interacts with cardiac Nav1.5 channels, modulating sodium current kinetics and voltage dependence in cardiomyocytes [PMID:30638748].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing DPP10 as a Kv4.2 auxiliary subunit resolved how a catalytically dead dipeptidyl peptidase-family protein could have a physiological role — it directly binds and modulates Kv4 channel gating, with the cytoplasmic N-terminus controlling inactivation acceleration.\",\n      \"evidence\": \"Co-immunoprecipitation and two-electrode voltage clamp with N-terminal truncation in Xenopus oocytes\",\n      \"pmids\": [\"15454437\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which DPP10 promotes channel surface expression was unknown\",\n        \"Whether DPP10 participates in native neuronal channel complexes was unresolved\",\n        \"How DPP10 cooperates with KChIP co-subunits was not addressed\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstration that DPP10 co-immunoprecipitates with Kv4.2 from native rat brain and forms ternary complexes with KChIP3 that uniquely reconstitute the rapid recovery kinetics of native ISA established DPP10 as an essential component of neuronal A-type channel macromolecular complexes.\",\n      \"evidence\": \"Co-IP from rat brain membranes, chimera domain mapping, ternary reconstitution electrophysiology in oocytes and CHO cells\",\n      \"pmids\": [\"15671030\", \"16123112\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry of the ternary complex was unknown\",\n        \"Structural basis for interaction was not resolved\",\n        \"Identity of specific neuronal populations expressing the complex was not mapped\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Mutagenesis of the catalytic triad residues confirmed that DPP10 is enzymatically inactive even when key catalytic residues are restored, establishing that its physiological function is non-enzymatic.\",\n      \"evidence\": \"Site-directed mutagenesis with enzymatic activity assay in 293T cells\",\n      \"pmids\": [\"16290253\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural basis for lack of activity was not yet determined\",\n        \"Whether ancestral DPP10 orthologs possessed enzymatic activity was unknown\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Identification that the transmembrane plus 58-amino-acid cytoplasmic domain of DPP10 is the minimal unit sufficient for Kv4 gating modulation, and that multiple splice variants with alternative N-termini similarly modulate Kv4.3, refined understanding of which protein regions are functionally essential versus modulatory.\",\n      \"evidence\": \"Truncation mutant electrophysiology and splice variant RT-PCR/expression in Xenopus oocytes\",\n      \"pmids\": [\"16738002\", \"16899223\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether splice-variant-specific N-termini confer distinct kinetics in ternary complexes was untested\",\n        \"In vivo relevance of splice variant expression patterns was not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Discovery that the DPP10a splice variant produces uniquely fast, voltage-dependent inactivation that dominates in ternary complexes revealed that N-terminal splice variation does tune channel kinetics in an isoform-specific manner, with DPP10a enriched in cortex suggesting region-specific ISA tuning.\",\n      \"evidence\": \"Two-electrode voltage clamp in oocytes with isoform combinations, qRT-PCR and in situ hybridization\",\n      \"pmids\": [\"17475505\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Mechanism by which the DPP10a N-terminus produces faster inactivation was not resolved\",\n        \"Functional impact in cortical neurons in vivo was not tested\"\n      ]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Pharmacological disruption of N-glycosylation abolished DPP10 surface expression and its functional effects on Kv4.3 in both heterologous cells and native human atrial myocytes, establishing glycosylation as a prerequisite for DPP10 trafficking and channel modulation.\",\n      \"evidence\": \"Tunicamycin treatment, flow cytometry, and patch clamp in CHO cells and human atrial myocytes\",\n      \"pmids\": [\"20354865\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Which specific glycosylation sites were essential was not determined\",\n        \"Whether glycosylation affects DPP10 dimerization was unknown\"\n      ]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Site-directed mutagenesis of six N-glycosylation sites identified four asparagines required for surface trafficking and pinpointed N257 as additionally essential for DPP10 dimerization and interaction with the Kv4.3/KChIP2a complex, linking a specific post-translational modification to complex assembly.\",\n      \"evidence\": \"N→Q mutagenesis at six sites, flow cytometry, co-IP, and electrophysiology in CHO cells\",\n      \"pmids\": [\"22387313\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Structural mechanism by which N257 glycosylation enables dimerization was not resolved\",\n        \"Whether glycosylation requirements differ across DPP10 splice variants was untested\"\n      ]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Immunohistochemical mapping in rat brain localized DPP10 to neuronal somata and confirmed in vivo co-localization with Kv4.2, Kv4.3, KChIP1, and KChIP3 in defined neuronal populations (parvalbumin/somatostatin interneurons, layer 5 pyramidal neurons, olfactory bulb mitral cells), validating the ternary complex model in native circuits.\",\n      \"evidence\": \"Immunohistochemistry with custom DPP10 antibody and co-localization analysis in rat brain sections\",\n      \"pmids\": [\"25355692\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional consequences of DPP10 loss in these specific neuron types were not assessed\",\n        \"Co-localization does not prove physical interaction in every identified neuron type\"\n      ]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"The crystal structure of human DPP10 revealed the β-propeller/α/β-hydrolase two-domain fold with glycine replacing the catalytic serine and a remodeled active-site entrance, providing the structural explanation for enzymatic inactivity; single-molecule imaging separately established that the Kv4.2/DPP10 complex preferentially adopts a 4:2 stoichiometry with DPP10 forming constitutive dimers.\",\n      \"evidence\": \"X-ray crystallography (molecular replacement from DPP6); single-molecule subunit counting and voltage clamp in Xenopus oocytes\",\n      \"pmids\": [\"25740212\", \"26209633\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No structure of the Kv4/DPP10 or Kv4/KChIP/DPP10 complex existed\",\n        \"How the transmembrane and cytoplasmic domains engage the channel pore domain was structurally unresolved\",\n        \"Whether 4:4 versus 4:2 stoichiometry exists in native neurons was not determined\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The Drosophila DPP10 ortholog retained both channel modulatory and dipeptidyl peptidase enzymatic activities, indicating that loss of catalytic function in mammalian DPP10 is a derived evolutionary event rather than an ancestral feature of the family.\",\n      \"evidence\": \"Co-IP, electrophysiology, and fluorometric enzyme assay for Drosophila ortholog with rat Kv4.3\",\n      \"pmids\": [\"27198182\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Physiological significance of enzymatic activity in Drosophila was not explored\",\n        \"Evolutionary timeline of catalytic loss was not traced\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Discovery that DPP10 co-immunoprecipitates with Nav1.5 from human ventricle and modulates cardiac sodium current gating extended DPP10's role beyond Kv4 channels to cardiac sodium channels, with implications for cardiac conduction.\",\n      \"evidence\": \"Co-IP from human ventricular tissue, adenoviral DPP10 expression in rat cardiomyocytes, patch-clamp electrophysiology\",\n      \"pmids\": [\"30638748\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Domain determinants of DPP10-Nav1.5 interaction were not mapped\",\n        \"Whether KChIPs participate in the Nav1.5/DPP10 complex is unknown\",\n        \"In vivo cardiac phenotype of DPP10 loss or gain has not been studied\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"No high-resolution structure of the full Kv4/KChIP/DPP10 ternary complex exists, and the in vivo physiological consequences of DPP10 deletion in specific neuronal or cardiac cell types remain uncharacterized.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No cryo-EM or crystal structure of the full ternary complex has been reported\",\n        \"No DPP10 knockout or conditional knockout phenotyping in neurons or heart has been published in the timeline\",\n        \"Mechanism of DPP10 specificity for Kv4 versus other Kv or Nav channels is structurally unresolved\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\n        \"term_id\": \"GO:0098772\",\n        \"supporting_discovery_ids\": [0, 1, 2, 4, 13]\n      },\n      {\n        \"term_id\": \"GO:0005198\",\n        \"supporting_discovery_ids\": [0, 1, 2, 11]\n      }\n    ],\n    \"localization\": [\n      {\n        \"term_id\": \"GO:0005886\",\n        \"supporting_discovery_ids\": [7, 8, 9, 11]\n      },\n      {\n        \"term_id\": \"GO:0005829\",\n        \"supporting_discovery_ids\": [9]\n      }\n    ],\n    \"pathway\": [\n      {\n        \"term_id\": \"R-HSA-112316\",\n        \"supporting_discovery_ids\": [0, 1, 2, 6, 9]\n      },\n      {\n        \"term_id\": \"R-HSA-382551\",\n        \"supporting_discovery_ids\": [0, 1, 4, 13]\n      }\n    ],\n    \"complexes\": [\n      \"Kv4/KChIP/DPP10 ternary complex\"\n    ],\n    \"partners\": [\n      \"KCND2\",\n      \"KCND3\",\n      \"KCNIP3\",\n      \"KCNIP2\",\n      \"KCNIP1\",\n      \"SCN5A\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}