{"gene":"CRCP","run_date":"2026-06-09T22:57:19","timeline":{"discoveries":[{"year":2000,"finding":"CGRP-RCP (CRCP) is required for CGRP- and adrenomedullin-mediated signal transduction but not for CGRP binding or receptor density: antisense suppression of RCP greatly reduced cAMP signaling without affecting ligand binding, demonstrating RCP acts as a coupling protein that links the CGRP receptor to downstream effectors rather than as a chaperone. RCP co-immunoprecipitated with calcitonin receptor-like receptor (CRLR), indicating direct physical interaction. A functional CGRP or adrenomedullin receptor complex thus requires at least three proteins: CRLR (receptor), RAMP (chaperone), and RCP (signal coupling).","method":"Stable antisense cell lines, cAMP signaling assays, radioligand binding assays, co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP plus functional antisense knockdown with specific phenotypic readout (loss of signaling without loss of binding), multiple orthogonal methods in a single focused study","pmids":["10903324"],"is_preprint":false},{"year":2003,"finding":"Human CGRP-RCP (CRCP) is the genuine orthologue of yeast RNA polymerase III subunit C17 (RPC17): CGRP-RCP functionally rescued a Δrpc17 yeast strain, and the purified mutant Pol III contained CGRP-RCP with decreased but faithful transcription initiation activity. CGRP-RCP was also identified by mass spectrometry in a highly purified human RNA Pol III preparation, indicating it is a bona fide subunit of human Pol III.","method":"Yeast complementation assay, in vitro transcription of reconstituted Pol III, mass spectrometry of purified human Pol III","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — functional reconstitution in yeast complementation, in vitro transcription activity, and mass spectrometry identification, multiple orthogonal methods","pmids":["12482973"],"is_preprint":false},{"year":2003,"finding":"In yeast, C17 (the CRCP orthologue) forms a heterodimer with C25 (RPC25) analogous to the Rpb4/Rpb7 subcomplex of RNA Pol II: genetic suppression screens and co-immunopurification/two-hybrid experiments established the C17–C25 interaction, and sequence/molecular modeling indicated structural similarity to the archaeal RpoE/RpoF heterodimer.","method":"Genetic suppression screens, co-immunopurification, two-hybrid assay, sequence analysis and molecular modeling","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis plus co-immunopurification and two-hybrid, single lab, multiple orthogonal methods","pmids":["12482973"],"is_preprint":false},{"year":1997,"finding":"CGRP-RCP protein expression in mouse myometrium correlates with the biological efficacy of CGRP in inhibiting smooth muscle contractions: CGRP-RCP protein (but not mRNA) was greatly diminished at parturition, paralleling the loss of CGRP inhibitory activity, indicating post-transcriptional regulation of RCP protein abundance controls CGRP responsiveness.","method":"Isometric force measurements on myometrial strips, Northern blot, Western blot, cDNA cloning","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Western/Northern blot combined with functional force measurements, single lab, two orthogonal methods","pmids":["9322931"],"is_preprint":false},{"year":2000,"finding":"CGRP-RCP protein levels (not mRNA) in mouse myometrium vary across the estrous cycle and in response to progesterone, correlating with changes in myometrial sensitivity to CGRP inhibition, demonstrating that regulation of CGRP-RCP does not occur at the transcriptional level.","method":"Isometric force measurements, Western blot, Northern blot, ovariectomy with steroid hormone treatment","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional assay plus Western/Northern blot, single lab, two orthogonal methods","pmids":["10712245"],"is_preprint":false},{"year":1999,"finding":"CGRP-RCP protein is localized to the head (acrosomal) region of murine spermatozoa and is lost upon acrosome reaction, suggesting a role in reproduction linked to acrosomal function. Northern blot showed highest CGRP-RCP mRNA abundance in testis among human and mouse tissues.","method":"Northern blot, immunohistochemistry with multiple antisera including one against recombinant hCGRP-RCP, experimentally induced acrosome reaction","journal":"Endocrinology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — immunohistochemical localization with functional observation (loss on acrosome reaction), single lab, replicated with multiple antisera","pmids":["10067875"],"is_preprint":false},{"year":2016,"finding":"Maturation of suprathreshold auditory nerve activity in mice requires formation of a complete cochlear CGRP receptor complex (CLR/RAMP1/RCP): CGRP null mice lacked the developmental increase in sound-evoked nerve activity, and the increase in wild-type animals correlated temporally with completion of cochlear CGRP receptor complex formation (incomplete at 1 month, complete by 3 months).","method":"Auditory nerve recordings in wild-type and CGRP knockout mice, developmental immunohistochemistry/expression analysis of receptor complex components","journal":"Physiological reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function (CGRP KO) with defined electrophysiological phenotype correlated with receptor complex formation, single lab","pmids":["27440744"],"is_preprint":false},{"year":2018,"finding":"RCP (CRCP) is involved in the caveolin-1/ERK1/2 signaling pathway in vascular smooth muscle cell (VSMC) proliferation induced by static pressure: siRNA-mediated knockdown of RCP increased VSMC proliferation and phospho-ERK1/2 expression under static pressure; RCP expression was upregulated by static pressure and inversely correlated with caveolin-1 levels.","method":"siRNA knockdown, Western blot for p-ERK1/2 and caveolin-1, PCNA expression, static pressure model in A10 VSMCs","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — siRNA knockdown with defined proliferative phenotype and pathway readout, single lab, single method set","pmids":["29741760"],"is_preprint":false},{"year":2024,"finding":"Loss of RCP specifically in the nervous system (nestinRCP -/- mouse) does not abolish CGRP-mediated behavioral effects (sway, tail vasodilation) but prevents antagonism by the CGRP receptor antagonist olcegepant, indicating RCP mediates Gα-stimulatory pathway coupling and its loss biases receptor pharmacology such that gepant-class antagonists lose efficacy.","method":"Tamoxifen-inducible neural-specific RCP knockout mouse (nestinRCP -/-), behavioral assays (motion-induced thermoregulation, center of pressure), systemic CGRP and olcegepant injections","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — conditional KO with two behavioral readouts and pharmacological challenge, single lab, preprint","pmids":["39484482"],"is_preprint":true}],"current_model":"CRCP (CGRP-RCP) encodes a ~148-residue intracellular protein that functions as a required coupling component of the heterotrimeric CGRP/adrenomedullin receptor complex (CRLR–RAMP–RCP), physically interacting with CRLR to link receptor activation to Gα-stimulatory downstream signaling without affecting ligand binding; it is also a bona fide subunit of RNA Polymerase III (orthologous to yeast C17/RPC17, forming a Rpb4/Rpb7-like heterodimer with RPC25), and its protein abundance—regulated post-transcriptionally—governs CGRP responsiveness in smooth muscle and cochlear tissues, with its loss in neurons impairing gepant-class antagonist efficacy."},"narrative":{"mechanistic_narrative":"CRCP encodes a dual-function intracellular protein that operates both as a signal-coupling component of the CGRP/adrenomedullin receptor and as a subunit of RNA polymerase III [PMID:10903324, PMID:12482973]. As CGRP receptor component protein (RCP), it is required for CGRP- and adrenomedullin-stimulated cAMP signaling but is dispensable for ligand binding or receptor density; it physically associates with calcitonin receptor-like receptor (CRLR), so that a functional receptor requires CRLR, RAMP, and RCP together, with RCP linking the activated receptor to Gα-stimulatory downstream effectors [PMID:10903324]. Independently, CRCP is the genuine human orthologue of yeast Pol III subunit C17/RPC17—it rescues Δrpc17 yeast, supports faithful transcription initiation in reconstituted Pol III, copurifies with human Pol III, and forms a Rpb4/Rpb7-like heterodimer with the C25/RPC25 subunit [PMID:12482973]. The cellular abundance of RCP protein is controlled post-transcriptionally and sets tissue CGRP responsiveness: RCP protein but not mRNA tracks CGRP inhibitory efficacy in myometrium across parturition and the estrous/progesterone cycle [PMID:9322931, PMID:10712245], and complete cochlear CLR/RAMP1/RCP complex formation accompanies maturation of auditory nerve activity [PMID:27440744]. Functionally, RCP knockdown modulates caveolin-1/ERK1/2-dependent vascular smooth muscle proliferation [PMID:29741760], and neural-specific loss of RCP preserves CGRP behavioral effects while abolishing the efficacy of gepant-class CGRP receptor antagonists [PMID:39484482].","teleology":[{"year":1997,"claim":"Established that RCP protein abundance, rather than transcript level, gates the physiological efficacy of CGRP, introducing post-transcriptional control of an unknown signaling component.","evidence":"Western/Northern blot with isometric force measurements on mouse myometrial strips across parturition","pmids":["9322931"],"confidence":"Medium","gaps":["Molecular function of RCP not yet defined at this stage","Mechanism of post-transcriptional regulation unidentified","Correlative link between protein level and contractility, not causal manipulation"]},{"year":1999,"claim":"Mapped RCP protein to the acrosomal region of spermatozoa and its loss on the acrosome reaction, and showed highest mRNA in testis, hinting at a reproductive role beyond smooth muscle.","evidence":"Northern blot and immunohistochemistry with multiple antisera plus induced acrosome reaction in murine sperm","pmids":["10067875"],"confidence":"Medium","gaps":["Functional role in acrosomal physiology untested","No mechanistic link to a receptor or signaling pathway established here","Whether localization reflects receptor coupling or another activity unknown"]},{"year":2000,"claim":"Defined RCP molecularly as a coupling protein required for CGRP/adrenomedullin signal transduction but not ligand binding, and demonstrated direct physical interaction with the receptor CRLR.","evidence":"Stable antisense cell lines, cAMP and radioligand binding assays, and co-immunoprecipitation","pmids":["10903324"],"confidence":"High","gaps":["Structural basis of the RCP–CRLR interaction unresolved","Identity of the Gα-coupling step downstream of RCP not detailed","Stoichiometry within the CRLR–RAMP–RCP complex undefined"]},{"year":2000,"claim":"Confirmed that hormonal modulation of CGRP sensitivity in myometrium operates through post-transcriptional control of RCP protein, reinforcing RCP abundance as a tunable rheostat of receptor responsiveness.","evidence":"Isometric force, Western/Northern blot, and ovariectomy with steroid replacement in mice","pmids":["10712245"],"confidence":"Medium","gaps":["The post-transcriptional mechanism (translation vs stability) not identified","Direct demonstration that RCP level limits signaling output absent","Generalizability beyond myometrium unaddressed"]},{"year":2003,"claim":"Revealed an entirely separate function by showing CRCP is the bona fide human orthologue of Pol III subunit C17/RPC17, establishing it as a core transcription machinery component.","evidence":"Yeast Δrpc17 complementation, in vitro transcription of reconstituted Pol III, and mass spectrometry of purified human Pol III","pmids":["12482973"],"confidence":"High","gaps":["Relationship, if any, between the Pol III role and the receptor-coupling role unknown","Whether the same protein pool serves both functions unresolved","Pol III gene targets dependent on this subunit not enumerated"]},{"year":2003,"claim":"Placed C17/CRCP architecturally within Pol III as a heterodimer partner of C25/RPC25, paralleling the Rpb4/Rpb7 stalk of Pol II.","evidence":"Genetic suppression screens, co-immunopurification, two-hybrid, and molecular modeling in yeast","pmids":["12482973"],"confidence":"Medium","gaps":["Human C17–C25 interaction inferred from yeast, not directly shown","Functional consequence of the heterodimer for transcription initiation only partly resolved","No structure of the human subcomplex"]},{"year":2016,"claim":"Linked assembly of the complete cochlear CLR/RAMP1/RCP receptor complex to a developmental milestone, implicating RCP-dependent CGRP signaling in maturation of auditory nerve function.","evidence":"Auditory nerve recordings in CGRP knockout vs wild-type mice with developmental expression analysis of receptor components","pmids":["27440744"],"confidence":"Medium","gaps":["Effect attributed to CGRP loss, not direct RCP deletion","Causal role of RCP timing not isolated from CLR/RAMP1","Mechanism connecting receptor coupling to nerve maturation unknown"]},{"year":2018,"claim":"Connected RCP to a caveolin-1/ERK1/2 axis governing pressure-induced vascular smooth muscle proliferation, broadening its signaling reach beyond cAMP coupling.","evidence":"siRNA knockdown with Western blot for p-ERK1/2, caveolin-1, and PCNA in a static pressure model in A10 VSMCs","pmids":["29741760"],"confidence":"Medium","gaps":["Direct molecular partner mediating the caveolin-1/ERK link unidentified","Single cell-line model without in vivo confirmation","Relation to canonical CGRP receptor coupling unclear"]},{"year":2024,"claim":"Demonstrated in vivo that neural RCP biases CGRP receptor pharmacology: its loss spares agonist-driven behaviors but abolishes gepant-class antagonist efficacy, defining RCP as a determinant of antagonist responsiveness.","evidence":"Tamoxifen-inducible neural-specific RCP knockout mouse with behavioral assays and systemic CGRP/olcegepant challenge (preprint)","pmids":["39484482"],"confidence":"Medium","gaps":["Preprint, not peer-reviewed","Molecular basis for the antagonist-specific pharmacology shift unresolved","Single lab with two behavioral readouts"]},{"year":null,"claim":"How a single small protein partitions between its role as a Pol III subunit and its role as a membrane-receptor signal-coupling protein, and whether these functions are coordinated, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No study reconciles the nuclear Pol III and receptor-coupling pools","Structural basis of RCP–CRLR coupling and Gα activation undefined","Post-transcriptional regulatory mechanism setting RCP abundance unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060089","term_label":"molecular transducer activity","supporting_discovery_ids":[0]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,2]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,2]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,8]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[1,2]}],"complexes":["RNA Polymerase III","CGRP receptor complex (CRLR-RAMP-RCP)"],"partners":["CALCRL","RPC25"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O75575","full_name":"DNA-directed RNA polymerase III subunit RPC9","aliases":["Calcitonin gene-related peptide-receptor component protein","CGRP-RCP","CGRP-receptor component protein","CGRPRCP","HsC17"],"length_aa":148,"mass_kda":16.9,"function":"DNA-dependent RNA polymerase catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates (PubMed:20413673, PubMed:33558764, PubMed:34675218). Specific peripheric component of RNA polymerase III (Pol III) which synthesizes small non-coding RNAs including 5S rRNA, snRNAs, tRNAs and miRNAs from at least 500 distinct genomic loci. With POLR3H/RPC8 forms a mobile stalk that protrudes from Pol III core and functions primarily in transcription initiation (By similarity) (PubMed:20413673, PubMed:33558764, PubMed:33558766, PubMed:34675218). Pol III plays a key role in sensing and limiting infection by intracellular bacteria and DNA viruses. Acts as nuclear and cytosolic DNA sensor involved in innate immune response. Can sense non-self dsDNA that serves as template for transcription into dsRNA. The non-self RNA polymerase III transcripts, such as Epstein-Barr virus-encoded RNAs (EBERs) induce type I interferon and NF-kappa-B through the RIG-I pathway (PubMed:19609254, PubMed:19631370) Accessory protein for the calcitonin gene-related peptide (CGRP) receptor. It modulates CGRP responsiveness in a variety of tissues","subcellular_location":"Nucleus; Cell membrane","url":"https://www.uniprot.org/uniprotkb/O75575/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":true,"resolved_as":"","url":"https://depmap.org/portal/gene/CRCP","classification":"Common Essential","n_dependent_lines":1189,"n_total_lines":1208,"dependency_fraction":0.984271523178808},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"POLR1C","stoichiometry":10.0},{"gene":"POLR2F","stoichiometry":10.0},{"gene":"POLR2H","stoichiometry":10.0},{"gene":"POLR2K","stoichiometry":10.0},{"gene":"POLR3A","stoichiometry":10.0},{"gene":"POLR3B","stoichiometry":10.0},{"gene":"POLR3F","stoichiometry":10.0},{"gene":"POLR3H","stoichiometry":10.0},{"gene":"TRMT1L","stoichiometry":10.0},{"gene":"POLR2E","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/CRCP","total_profiled":1310},"omim":[{"mim_id":"619801","title":"RNA POLYMERASE III, SUBUNIT H; POLR3H","url":"https://www.omim.org/entry/619801"},{"mim_id":"606121","title":"CGRP RECEPTOR COMPONENT; CRCP","url":"https://www.omim.org/entry/606121"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/CRCP"},"hgnc":{"alias_symbol":["CGRP-RCP","RCP","RCP9","C17","POLR3I"],"prev_symbol":[]},"alphafold":{"accession":"O75575","domains":[{"cath_id":"-","chopping":"12-28_38-58","consensus_level":"medium","plddt":90.2395,"start":12,"end":58},{"cath_id":"1.20.1250.40","chopping":"60-122","consensus_level":"medium","plddt":92.3251,"start":60,"end":122}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75575","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75575-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75575-F1-predicted_aligned_error_v6.png","plddt_mean":82.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=CRCP","jax_strain_url":"https://www.jax.org/strain/search?query=CRCP"},"sequence":{"accession":"O75575","fasta_url":"https://rest.uniprot.org/uniprotkb/O75575.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75575/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75575"}},"corpus_meta":[{"pmid":"10903324","id":"PMC_10903324","title":"CGRP-RCP, a novel protein required for signal transduction at calcitonin gene-related peptide and adrenomedullin receptors.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10903324","citation_count":256,"is_preprint":false},{"pmid":"9236222","id":"PMC_9236222","title":"The role of CED-3-related cysteine proteases in apoptosis of cerebellar granule cells.","date":"1997","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/9236222","citation_count":125,"is_preprint":false},{"pmid":"15254341","id":"PMC_15254341","title":"Human respiratory tract cancer risks of inhaled formaldehyde: dose-response predictions derived from biologically-motivated computational modeling of a combined rodent and human dataset.","date":"2004","source":"Toxicological sciences : an official journal of the Society of Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/15254341","citation_count":80,"is_preprint":false},{"pmid":"12857938","id":"PMC_12857938","title":"Biologically motivated computational modeling of formaldehyde carcinogenicity in the F344 rat.","date":"2003","source":"Toxicological sciences : an official journal of the Society of Toxicology","url":"https://pubmed.ncbi.nlm.nih.gov/12857938","citation_count":72,"is_preprint":false},{"pmid":"27775942","id":"PMC_27775942","title":"PET/CT With 68Ga-DOTA-TATE for Diagnosis of Neuroendocrine: Differentiation in Patients With Castrate-Resistant Prostate Cancer.","date":"2017","source":"Clinical nuclear medicine","url":"https://pubmed.ncbi.nlm.nih.gov/27775942","citation_count":56,"is_preprint":false},{"pmid":"27787597","id":"PMC_27787597","title":"Stromal factors involved in human prostate cancer development, progression and castration resistance.","date":"2016","source":"Journal of cancer research and clinical oncology","url":"https://pubmed.ncbi.nlm.nih.gov/27787597","citation_count":46,"is_preprint":false},{"pmid":"12176916","id":"PMC_12176916","title":"Cyclosporine inhibition of P-glycoprotein in chronic myeloid leukemia blast phase.","date":"2002","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12176916","citation_count":43,"is_preprint":false},{"pmid":"12482973","id":"PMC_12482973","title":"An Rpb4/Rpb7-like complex in yeast RNA polymerase III contains the orthologue of mammalian CGRP-RCP.","date":"2003","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/12482973","citation_count":38,"is_preprint":false},{"pmid":"22578777","id":"PMC_22578777","title":"Allogeneic stem cell transplantation for myeloproliferative neoplasm in blast phase.","date":"2012","source":"Leukemia research","url":"https://pubmed.ncbi.nlm.nih.gov/22578777","citation_count":38,"is_preprint":false},{"pmid":"32450824","id":"PMC_32450824","title":"Independence of HIF1a and androgen signaling pathways in prostate cancer.","date":"2020","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/32450824","citation_count":33,"is_preprint":false},{"pmid":"9322931","id":"PMC_9322931","title":"Inhibitory effect of calcitonin gene-related peptide on myometrial contractility is diminished at parturition.","date":"1997","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/9322931","citation_count":31,"is_preprint":false},{"pmid":"9538931","id":"PMC_9538931","title":"Heart failure: is there an energy deficit contributing to contractile dysfunction?","date":"1998","source":"Basic research in cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/9538931","citation_count":31,"is_preprint":false},{"pmid":"10889296","id":"PMC_10889296","title":"Immunological and inflammatory characterisation of three canine cell lines: K1, K6 and DH82.","date":"2000","source":"Veterinary immunology and immunopathology","url":"https://pubmed.ncbi.nlm.nih.gov/10889296","citation_count":30,"is_preprint":false},{"pmid":"30188709","id":"PMC_30188709","title":"Down-Regulation of the Androgen Receptor by G-Quadruplex Ligands Sensitizes Castration-Resistant Prostate Cancer Cells to Enzalutamide.","date":"2018","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/30188709","citation_count":29,"is_preprint":false},{"pmid":"11937264","id":"PMC_11937264","title":"Regulation and function of the CGRP receptor complex in human granulopoiesis.","date":"2002","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/11937264","citation_count":28,"is_preprint":false},{"pmid":"29607467","id":"PMC_29607467","title":"New NO- and H2S-releasing doxorubicins as targeted therapy against chemoresistance in castration-resistant prostate cancer: in vitro and in vivo evaluations.","date":"2018","source":"Investigational new drugs","url":"https://pubmed.ncbi.nlm.nih.gov/29607467","citation_count":25,"is_preprint":false},{"pmid":"28384600","id":"PMC_28384600","title":"A prospective study of fungal biomarkers to improve management of invasive fungal diseases in a mixed specialty critical care unit.","date":"2017","source":"Journal of critical care","url":"https://pubmed.ncbi.nlm.nih.gov/28384600","citation_count":25,"is_preprint":false},{"pmid":"21426013","id":"PMC_21426013","title":"Novel, potent anti-androgens of therapeutic potential: recent advances and promising developments.","date":"2010","source":"Future medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21426013","citation_count":24,"is_preprint":false},{"pmid":"3430484","id":"PMC_3430484","title":"Pregnancy suppression in the bonnet monkey by active immunisation with chicken riboflavin carrier protein.","date":"1987","source":"Journal of reproductive immunology","url":"https://pubmed.ncbi.nlm.nih.gov/3430484","citation_count":24,"is_preprint":false},{"pmid":"24609082","id":"PMC_24609082","title":"Methylation of migraine-related genes in different tissues of the rat.","date":"2014","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24609082","citation_count":22,"is_preprint":false},{"pmid":"27440744","id":"PMC_27440744","title":"Maturation of suprathreshold auditory nerve activity involves cochlear CGRP-receptor complex formation.","date":"2016","source":"Physiological reports","url":"https://pubmed.ncbi.nlm.nih.gov/27440744","citation_count":22,"is_preprint":false},{"pmid":"27431942","id":"PMC_27431942","title":"miRNA-30a functions as a tumor suppressor by downregulating cyclin E2 expression in castration-resistant prostate cancer.","date":"2016","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/27431942","citation_count":21,"is_preprint":false},{"pmid":"4726090","id":"PMC_4726090","title":"The effect of scald injury upon the distribution of glucose between red cells and plasma and upon the turnover of glucose in red cells in the rat.","date":"1973","source":"British journal of experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/4726090","citation_count":20,"is_preprint":false},{"pmid":"18253034","id":"PMC_18253034","title":"Characterization of a balanced reciprocal translocation, rcp(9;11)(q27;q11) in cattle.","date":"2008","source":"Cytogenetic and genome research","url":"https://pubmed.ncbi.nlm.nih.gov/18253034","citation_count":19,"is_preprint":false},{"pmid":"12439699","id":"PMC_12439699","title":"The graft-versus-leukaemia effect in haematopoietic stem cell transplantation using unrelated donors.","date":"2002","source":"Bone marrow transplantation","url":"https://pubmed.ncbi.nlm.nih.gov/12439699","citation_count":19,"is_preprint":false},{"pmid":"33985539","id":"PMC_33985539","title":"Identification of sensory and motor nerve fascicles by immunofluorescence staining after peripheral nerve injury.","date":"2021","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/33985539","citation_count":18,"is_preprint":false},{"pmid":"10712245","id":"PMC_10712245","title":"Sensitivity of myometrium to CGRP varies during mouse estrous cycle and in response to progesterone.","date":"2000","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/10712245","citation_count":17,"is_preprint":false},{"pmid":"16399883","id":"PMC_16399883","title":"Recognition, co-internalization, and recycling of an avian riboflavin carrier protein in human placental trophoblasts.","date":"2006","source":"The Journal of pharmacology and experimental therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/16399883","citation_count":17,"is_preprint":false},{"pmid":"40225580","id":"PMC_40225580","title":"FOS-driven inflammatory CAFs promote colorectal cancer liver metastasis via the SFRP1-FGFR2-HIF1 axis.","date":"2025","source":"Theranostics","url":"https://pubmed.ncbi.nlm.nih.gov/40225580","citation_count":16,"is_preprint":false},{"pmid":"7535246","id":"PMC_7535246","title":"Enhancing peptide antigenicity by helix stabilization.","date":"1995","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/7535246","citation_count":15,"is_preprint":false},{"pmid":"3418615","id":"PMC_3418615","title":"Isolation and partial characterisation of human riboflavin carrier protein and the estimation of its levels during human pregnancy.","date":"1988","source":"Journal of reproductive immunology","url":"https://pubmed.ncbi.nlm.nih.gov/3418615","citation_count":14,"is_preprint":false},{"pmid":"10095096","id":"PMC_10095096","title":"Regional and cellular localization of calcitonin gene-related peptide-receptor component protein mRNA in the guinea-pig central nervous system.","date":"1999","source":"Brain research. Molecular brain research","url":"https://pubmed.ncbi.nlm.nih.gov/10095096","citation_count":14,"is_preprint":false},{"pmid":"21223598","id":"PMC_21223598","title":"Genome-wide joint SNP and CNV analysis of aortic root diameter in African Americans: the HyperGEN study.","date":"2011","source":"BMC medical genomics","url":"https://pubmed.ncbi.nlm.nih.gov/21223598","citation_count":14,"is_preprint":false},{"pmid":"15636430","id":"PMC_15636430","title":"Preliminary data suggest that mutations in the CgRP pathway are not involved in human sporadic cryptorchidism.","date":"2004","source":"Journal of endocrinological investigation","url":"https://pubmed.ncbi.nlm.nih.gov/15636430","citation_count":13,"is_preprint":false},{"pmid":"7517603","id":"PMC_7517603","title":"Termination of pregnancy in mice following administration of antibodies to the pentadecapeptide 10-24 of chicken riboflavin carrier protein: identification of a bioneutralizing epitope of chicken riboflavin carrier protein.","date":"1994","source":"Vaccine","url":"https://pubmed.ncbi.nlm.nih.gov/7517603","citation_count":12,"is_preprint":false},{"pmid":"8621956","id":"PMC_8621956","title":"Comparison of antibodies raised against the peptide 10-24 of chicken riboflavin carrier protein (cRCP) by classical and multiple antigen peptide (MAP) approaches.","date":"1996","source":"Journal of immunological methods","url":"https://pubmed.ncbi.nlm.nih.gov/8621956","citation_count":11,"is_preprint":false},{"pmid":"10067875","id":"PMC_10067875","title":"Testes exhibit elevated expression of calcitonin gene-related peptide receptor component protein.","date":"1999","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/10067875","citation_count":10,"is_preprint":false},{"pmid":"36835316","id":"PMC_36835316","title":"Low-Energy Shock Wave Suppresses Prostatic Pain and Inflammation by Modulating Mitochondrial Dynamics Regulators on a Carrageenan-Induced Prostatitis Model in Rats.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36835316","citation_count":8,"is_preprint":false},{"pmid":"9540794","id":"PMC_9540794","title":"Identification and characterization of receptors for riboflavin carrier protein in the chicken oocyte. Role of the phosphopeptide in mediating receptor interaction.","date":"1998","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/9540794","citation_count":8,"is_preprint":false},{"pmid":"31400517","id":"PMC_31400517","title":"Clinical exome sequencing vs. usual care for hereditary colorectal cancer diagnosis: A pilot comparative effectiveness study.","date":"2019","source":"Contemporary clinical trials","url":"https://pubmed.ncbi.nlm.nih.gov/31400517","citation_count":8,"is_preprint":false},{"pmid":"14979575","id":"PMC_14979575","title":"Effectiveness of twenty, twenty-five diazacholesterol, avian gonadotropin-releasing hormone, and chicken riboflavin carrier protein for inhibiting reproduction in Coturnix quail.","date":"2004","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/14979575","citation_count":7,"is_preprint":false},{"pmid":"28502171","id":"PMC_28502171","title":"Complexation of a Globular Protein, β-Lactoglobulin, with an Anionic Surfactant in Aqueous Solution.","date":"2017","source":"Langmuir : the ACS journal of surfaces and colloids","url":"https://pubmed.ncbi.nlm.nih.gov/28502171","citation_count":7,"is_preprint":false},{"pmid":"39918307","id":"PMC_39918307","title":"Genome-scale CRISPR/Cas9 screening reveals the role of PSMD4 in colibactin-mediated cell cycle arrest.","date":"2025","source":"mSphere","url":"https://pubmed.ncbi.nlm.nih.gov/39918307","citation_count":6,"is_preprint":false},{"pmid":"39227669","id":"PMC_39227669","title":"Exploration and validation of ceRNA regulatory networks in colorectal cancer based on associations whole transcriptome sequencing.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/39227669","citation_count":6,"is_preprint":false},{"pmid":"36213442","id":"PMC_36213442","title":"NK-cell dysfunction of acute myeloid leukemia in relation to the renin-angiotensin system and neurotransmitter genes.","date":"2022","source":"Open medicine (Warsaw, Poland)","url":"https://pubmed.ncbi.nlm.nih.gov/36213442","citation_count":6,"is_preprint":false},{"pmid":"20068298","id":"PMC_20068298","title":"A cytogenetic study of breeding boars in Canada.","date":"2010","source":"Cytogenetic and genome research","url":"https://pubmed.ncbi.nlm.nih.gov/20068298","citation_count":6,"is_preprint":false},{"pmid":"9135669","id":"PMC_9135669","title":"Immunohistochemical localization of riboflavin carrier protein in testicular cells of mammals.","date":"1995","source":"Indian journal of experimental biology","url":"https://pubmed.ncbi.nlm.nih.gov/9135669","citation_count":6,"is_preprint":false},{"pmid":"2460089","id":"PMC_2460089","title":"Characterization of antibodies to chicken riboflavin carrier protein. Immunoneutralizing ability of antibodies to a sequence-specific region of the protein.","date":"1988","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/2460089","citation_count":6,"is_preprint":false},{"pmid":"7679667","id":"PMC_7679667","title":"Studies on the delineation of the antigenic determinants of chicken riboflavin carrier protein (cRCP). Identification of a determinant in the region 10-24 of the protein.","date":"1993","source":"International journal of peptide and protein research","url":"https://pubmed.ncbi.nlm.nih.gov/7679667","citation_count":5,"is_preprint":false},{"pmid":"37180721","id":"PMC_37180721","title":"The molecular mechanism for inhibiting the growth of nasopharyngeal carcinoma cells using polymethoxyflavonoids purified from pericarp of Citrus reticulata 'Chachi' via HSCCC.","date":"2023","source":"Frontiers in pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/37180721","citation_count":5,"is_preprint":false},{"pmid":"17891525","id":"PMC_17891525","title":"Biochemical characterization of recombinant chicken Riboflavin carrier protein.","date":"2007","source":"Molecular and cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17891525","citation_count":5,"is_preprint":false},{"pmid":"17853344","id":"PMC_17853344","title":"Expression of calcitonin gene-related peptide-receptor component protein (CGRP-RCP) in human myometrium in differing physiological states and following misoprostol administration.","date":"2007","source":"American journal of perinatology","url":"https://pubmed.ncbi.nlm.nih.gov/17853344","citation_count":4,"is_preprint":false},{"pmid":"32290587","id":"PMC_32290587","title":"Identification of an LPS-Induced Chemo-Attractive Peptide from Ciona robusta.","date":"2020","source":"Marine drugs","url":"https://pubmed.ncbi.nlm.nih.gov/32290587","citation_count":4,"is_preprint":false},{"pmid":"32179489","id":"PMC_32179489","title":"Integrating transcriptome-wide association study and copy number variation study identifies candidate genes and pathways for diffuse non-Hodgkin's lymphoma.","date":"2020","source":"Cancer genetics","url":"https://pubmed.ncbi.nlm.nih.gov/32179489","citation_count":4,"is_preprint":false},{"pmid":"31422818","id":"PMC_31422818","title":"Rates of Actionable Genetic Findings in Individuals with Colorectal Cancer or Polyps Ascertained from a Community Medical Setting.","date":"2019","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31422818","citation_count":3,"is_preprint":false},{"pmid":"2765133","id":"PMC_2765133","title":"Effects of antibodies against chicken riboflavin carrier protein on fetal hepatic cell ultrastructure.","date":"1989","source":"American journal of reproductive immunology (New York, N.Y. : 1989)","url":"https://pubmed.ncbi.nlm.nih.gov/2765133","citation_count":3,"is_preprint":false},{"pmid":"29741760","id":"PMC_29741760","title":"Involvement of CGRP-RCP in the caveolin-1/ERK1/2 signal pathway in the static pressure-induced proliferation of vascular smooth muscle cells.","date":"2018","source":"Journal of cellular physiology","url":"https://pubmed.ncbi.nlm.nih.gov/29741760","citation_count":2,"is_preprint":false},{"pmid":"1380947","id":"PMC_1380947","title":"Enzyme-linked immunosorbent assay for riboflavin carrier protein and modified protein: application for epitope analysis.","date":"1992","source":"Indian journal of biochemistry & biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/1380947","citation_count":2,"is_preprint":false},{"pmid":"37835624","id":"PMC_37835624","title":"Characterization of Robertsonian and Reciprocal Translocations in Cattle through NGS.","date":"2023","source":"Animals : an open access journal from MDPI","url":"https://pubmed.ncbi.nlm.nih.gov/37835624","citation_count":1,"is_preprint":false},{"pmid":"38602755","id":"PMC_38602755","title":"[Mechanism study on the effect of androgen antagonism in prostate cancer].","date":"2023","source":"Zhonghua nan ke xue = National journal of andrology","url":"https://pubmed.ncbi.nlm.nih.gov/38602755","citation_count":1,"is_preprint":false},{"pmid":"41154025","id":"PMC_41154025","title":"4-Vinylguaiacol in Citri Reticulatae 'Chachiensis' Pericarpium Volatile Oil: A Microbial-Mediated Aging Marker Enhances Glucose Metabolism.","date":"2025","source":"Foods (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/41154025","citation_count":1,"is_preprint":false},{"pmid":"7506230","id":"PMC_7506230","title":"Improved presentation of antigenic sites in enzyme-linked immunosorbent assay: antigenicity of reduced and carboxymethylated riboflavin carrier protein.","date":"1993","source":"Indian journal of biochemistry & biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/7506230","citation_count":1,"is_preprint":false},{"pmid":"20577925","id":"PMC_20577925","title":"[Demethylation of the gamma-synuclein gene CpG island in colorectal cancer and its clinical significance].","date":"2010","source":"Zhonghua wei chang wai ke za zhi = Chinese journal of gastrointestinal surgery","url":"https://pubmed.ncbi.nlm.nih.gov/20577925","citation_count":1,"is_preprint":false},{"pmid":"30505899","id":"PMC_30505899","title":"Microbiome dataset from Clara Cave and Empalme Sinkhole waters in Puerto Rico.","date":"2018","source":"Data in brief","url":"https://pubmed.ncbi.nlm.nih.gov/30505899","citation_count":1,"is_preprint":false},{"pmid":"8361111","id":"PMC_8361111","title":"[A case report of graft replacement of the ascending and transverse aorta without homologous red blood cell transfusion].","date":"1993","source":"Kyobu geka. The Japanese journal of thoracic surgery","url":"https://pubmed.ncbi.nlm.nih.gov/8361111","citation_count":1,"is_preprint":false},{"pmid":"39484482","id":"PMC_39484482","title":"Loss of Calcitonin Gene Related Receptor component protein (RCP) in nervous system can bias \"gepant\" antagonism.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/39484482","citation_count":0,"is_preprint":false},{"pmid":"9717443","id":"PMC_9717443","title":"Immunoreactive riboflavin carrier protein concentration during ovulatory cycle in the common marmoset (Callithrix jachhus): role of estrogen.","date":"1998","source":"Indian journal of experimental biology","url":"https://pubmed.ncbi.nlm.nih.gov/9717443","citation_count":0,"is_preprint":false},{"pmid":"42154421","id":"PMC_42154421","title":"Differential Metabolic and Transcriptional Responses of PBMCs to Blastocystis sp. Subtypes in Chemotherapy-Treated Colorectal Cancer Patients.","date":"2026","source":"Acta parasitologica","url":"https://pubmed.ncbi.nlm.nih.gov/42154421","citation_count":0,"is_preprint":false},{"pmid":"11128028","id":"PMC_11128028","title":"Development and characterization of monoclonal antibodies to chicken riboflavin carrier protein.","date":"2000","source":"Hybridoma","url":"https://pubmed.ncbi.nlm.nih.gov/11128028","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.09.13.676040","title":"Single-Cell Integration of Chromatin Accessibility and Transcriptomics Reveals Regulatory Networks in Ovarian Tumor-Infiltrating Adaptive NK Cells","date":"2025-09-15","source":"bioRxiv","url":"https://doi.org/10.1101/2025.09.13.676040","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.10.25.620369","title":"Loss of Calcitonin Gene Related Receptor component protein (RCP) in nervous system can bias “gepant” antagonism","date":"2024-10-26","source":"bioRxiv","url":"https://doi.org/10.1101/2024.10.25.620369","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":37337,"output_tokens":2440,"usd":0.074305,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9625,"output_tokens":3413,"usd":0.066725,"stage2_stop_reason":"end_turn"},"total_usd":0.14103,"stage1_batch_id":"msgbatch_01ACAxJQabDsht39JXeWG22d","stage2_batch_id":"msgbatch_01QEU22A9U5sbPTgsMzTmvSf","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"CGRP-RCP (CRCP) is required for CGRP- and adrenomedullin-mediated signal transduction but not for CGRP binding or receptor density: antisense suppression of RCP greatly reduced cAMP signaling without affecting ligand binding, demonstrating RCP acts as a coupling protein that links the CGRP receptor to downstream effectors rather than as a chaperone. RCP co-immunoprecipitated with calcitonin receptor-like receptor (CRLR), indicating direct physical interaction. A functional CGRP or adrenomedullin receptor complex thus requires at least three proteins: CRLR (receptor), RAMP (chaperone), and RCP (signal coupling).\",\n      \"method\": \"Stable antisense cell lines, cAMP signaling assays, radioligand binding assays, co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP plus functional antisense knockdown with specific phenotypic readout (loss of signaling without loss of binding), multiple orthogonal methods in a single focused study\",\n      \"pmids\": [\"10903324\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Human CGRP-RCP (CRCP) is the genuine orthologue of yeast RNA polymerase III subunit C17 (RPC17): CGRP-RCP functionally rescued a Δrpc17 yeast strain, and the purified mutant Pol III contained CGRP-RCP with decreased but faithful transcription initiation activity. CGRP-RCP was also identified by mass spectrometry in a highly purified human RNA Pol III preparation, indicating it is a bona fide subunit of human Pol III.\",\n      \"method\": \"Yeast complementation assay, in vitro transcription of reconstituted Pol III, mass spectrometry of purified human Pol III\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — functional reconstitution in yeast complementation, in vitro transcription activity, and mass spectrometry identification, multiple orthogonal methods\",\n      \"pmids\": [\"12482973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"In yeast, C17 (the CRCP orthologue) forms a heterodimer with C25 (RPC25) analogous to the Rpb4/Rpb7 subcomplex of RNA Pol II: genetic suppression screens and co-immunopurification/two-hybrid experiments established the C17–C25 interaction, and sequence/molecular modeling indicated structural similarity to the archaeal RpoE/RpoF heterodimer.\",\n      \"method\": \"Genetic suppression screens, co-immunopurification, two-hybrid assay, sequence analysis and molecular modeling\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis plus co-immunopurification and two-hybrid, single lab, multiple orthogonal methods\",\n      \"pmids\": [\"12482973\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"CGRP-RCP protein expression in mouse myometrium correlates with the biological efficacy of CGRP in inhibiting smooth muscle contractions: CGRP-RCP protein (but not mRNA) was greatly diminished at parturition, paralleling the loss of CGRP inhibitory activity, indicating post-transcriptional regulation of RCP protein abundance controls CGRP responsiveness.\",\n      \"method\": \"Isometric force measurements on myometrial strips, Northern blot, Western blot, cDNA cloning\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Western/Northern blot combined with functional force measurements, single lab, two orthogonal methods\",\n      \"pmids\": [\"9322931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"CGRP-RCP protein levels (not mRNA) in mouse myometrium vary across the estrous cycle and in response to progesterone, correlating with changes in myometrial sensitivity to CGRP inhibition, demonstrating that regulation of CGRP-RCP does not occur at the transcriptional level.\",\n      \"method\": \"Isometric force measurements, Western blot, Northern blot, ovariectomy with steroid hormone treatment\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional assay plus Western/Northern blot, single lab, two orthogonal methods\",\n      \"pmids\": [\"10712245\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"CGRP-RCP protein is localized to the head (acrosomal) region of murine spermatozoa and is lost upon acrosome reaction, suggesting a role in reproduction linked to acrosomal function. Northern blot showed highest CGRP-RCP mRNA abundance in testis among human and mouse tissues.\",\n      \"method\": \"Northern blot, immunohistochemistry with multiple antisera including one against recombinant hCGRP-RCP, experimentally induced acrosome reaction\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — immunohistochemical localization with functional observation (loss on acrosome reaction), single lab, replicated with multiple antisera\",\n      \"pmids\": [\"10067875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Maturation of suprathreshold auditory nerve activity in mice requires formation of a complete cochlear CGRP receptor complex (CLR/RAMP1/RCP): CGRP null mice lacked the developmental increase in sound-evoked nerve activity, and the increase in wild-type animals correlated temporally with completion of cochlear CGRP receptor complex formation (incomplete at 1 month, complete by 3 months).\",\n      \"method\": \"Auditory nerve recordings in wild-type and CGRP knockout mice, developmental immunohistochemistry/expression analysis of receptor complex components\",\n      \"journal\": \"Physiological reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function (CGRP KO) with defined electrophysiological phenotype correlated with receptor complex formation, single lab\",\n      \"pmids\": [\"27440744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"RCP (CRCP) is involved in the caveolin-1/ERK1/2 signaling pathway in vascular smooth muscle cell (VSMC) proliferation induced by static pressure: siRNA-mediated knockdown of RCP increased VSMC proliferation and phospho-ERK1/2 expression under static pressure; RCP expression was upregulated by static pressure and inversely correlated with caveolin-1 levels.\",\n      \"method\": \"siRNA knockdown, Western blot for p-ERK1/2 and caveolin-1, PCNA expression, static pressure model in A10 VSMCs\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — siRNA knockdown with defined proliferative phenotype and pathway readout, single lab, single method set\",\n      \"pmids\": [\"29741760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Loss of RCP specifically in the nervous system (nestinRCP -/- mouse) does not abolish CGRP-mediated behavioral effects (sway, tail vasodilation) but prevents antagonism by the CGRP receptor antagonist olcegepant, indicating RCP mediates Gα-stimulatory pathway coupling and its loss biases receptor pharmacology such that gepant-class antagonists lose efficacy.\",\n      \"method\": \"Tamoxifen-inducible neural-specific RCP knockout mouse (nestinRCP -/-), behavioral assays (motion-induced thermoregulation, center of pressure), systemic CGRP and olcegepant injections\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — conditional KO with two behavioral readouts and pharmacological challenge, single lab, preprint\",\n      \"pmids\": [\"39484482\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"CRCP (CGRP-RCP) encodes a ~148-residue intracellular protein that functions as a required coupling component of the heterotrimeric CGRP/adrenomedullin receptor complex (CRLR–RAMP–RCP), physically interacting with CRLR to link receptor activation to Gα-stimulatory downstream signaling without affecting ligand binding; it is also a bona fide subunit of RNA Polymerase III (orthologous to yeast C17/RPC17, forming a Rpb4/Rpb7-like heterodimer with RPC25), and its protein abundance—regulated post-transcriptionally—governs CGRP responsiveness in smooth muscle and cochlear tissues, with its loss in neurons impairing gepant-class antagonist efficacy.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"CRCP encodes a dual-function intracellular protein that operates both as a signal-coupling component of the CGRP/adrenomedullin receptor and as a subunit of RNA polymerase III [#0, #1]. As CGRP receptor component protein (RCP), it is required for CGRP- and adrenomedullin-stimulated cAMP signaling but is dispensable for ligand binding or receptor density; it physically associates with calcitonin receptor-like receptor (CRLR), so that a functional receptor requires CRLR, RAMP, and RCP together, with RCP linking the activated receptor to Gα-stimulatory downstream effectors [#0]. Independently, CRCP is the genuine human orthologue of yeast Pol III subunit C17/RPC17—it rescues Δrpc17 yeast, supports faithful transcription initiation in reconstituted Pol III, copurifies with human Pol III, and forms a Rpb4/Rpb7-like heterodimer with the C25/RPC25 subunit [#1, #2]. The cellular abundance of RCP protein is controlled post-transcriptionally and sets tissue CGRP responsiveness: RCP protein but not mRNA tracks CGRP inhibitory efficacy in myometrium across parturition and the estrous/progesterone cycle [#3, #4], and complete cochlear CLR/RAMP1/RCP complex formation accompanies maturation of auditory nerve activity [#6]. Functionally, RCP knockdown modulates caveolin-1/ERK1/2-dependent vascular smooth muscle proliferation [#7], and neural-specific loss of RCP preserves CGRP behavioral effects while abolishing the efficacy of gepant-class CGRP receptor antagonists [#8].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that RCP protein abundance, rather than transcript level, gates the physiological efficacy of CGRP, introducing post-transcriptional control of an unknown signaling component.\",\n      \"evidence\": \"Western/Northern blot with isometric force measurements on mouse myometrial strips across parturition\",\n      \"pmids\": [\"9322931\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular function of RCP not yet defined at this stage\", \"Mechanism of post-transcriptional regulation unidentified\", \"Correlative link between protein level and contractility, not causal manipulation\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Mapped RCP protein to the acrosomal region of spermatozoa and its loss on the acrosome reaction, and showed highest mRNA in testis, hinting at a reproductive role beyond smooth muscle.\",\n      \"evidence\": \"Northern blot and immunohistochemistry with multiple antisera plus induced acrosome reaction in murine sperm\",\n      \"pmids\": [\"10067875\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional role in acrosomal physiology untested\", \"No mechanistic link to a receptor or signaling pathway established here\", \"Whether localization reflects receptor coupling or another activity unknown\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Defined RCP molecularly as a coupling protein required for CGRP/adrenomedullin signal transduction but not ligand binding, and demonstrated direct physical interaction with the receptor CRLR.\",\n      \"evidence\": \"Stable antisense cell lines, cAMP and radioligand binding assays, and co-immunoprecipitation\",\n      \"pmids\": [\"10903324\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the RCP–CRLR interaction unresolved\", \"Identity of the Gα-coupling step downstream of RCP not detailed\", \"Stoichiometry within the CRLR–RAMP–RCP complex undefined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Confirmed that hormonal modulation of CGRP sensitivity in myometrium operates through post-transcriptional control of RCP protein, reinforcing RCP abundance as a tunable rheostat of receptor responsiveness.\",\n      \"evidence\": \"Isometric force, Western/Northern blot, and ovariectomy with steroid replacement in mice\",\n      \"pmids\": [\"10712245\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The post-transcriptional mechanism (translation vs stability) not identified\", \"Direct demonstration that RCP level limits signaling output absent\", \"Generalizability beyond myometrium unaddressed\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Revealed an entirely separate function by showing CRCP is the bona fide human orthologue of Pol III subunit C17/RPC17, establishing it as a core transcription machinery component.\",\n      \"evidence\": \"Yeast Δrpc17 complementation, in vitro transcription of reconstituted Pol III, and mass spectrometry of purified human Pol III\",\n      \"pmids\": [\"12482973\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship, if any, between the Pol III role and the receptor-coupling role unknown\", \"Whether the same protein pool serves both functions unresolved\", \"Pol III gene targets dependent on this subunit not enumerated\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Placed C17/CRCP architecturally within Pol III as a heterodimer partner of C25/RPC25, paralleling the Rpb4/Rpb7 stalk of Pol II.\",\n      \"evidence\": \"Genetic suppression screens, co-immunopurification, two-hybrid, and molecular modeling in yeast\",\n      \"pmids\": [\"12482973\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Human C17–C25 interaction inferred from yeast, not directly shown\", \"Functional consequence of the heterodimer for transcription initiation only partly resolved\", \"No structure of the human subcomplex\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Linked assembly of the complete cochlear CLR/RAMP1/RCP receptor complex to a developmental milestone, implicating RCP-dependent CGRP signaling in maturation of auditory nerve function.\",\n      \"evidence\": \"Auditory nerve recordings in CGRP knockout vs wild-type mice with developmental expression analysis of receptor components\",\n      \"pmids\": [\"27440744\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Effect attributed to CGRP loss, not direct RCP deletion\", \"Causal role of RCP timing not isolated from CLR/RAMP1\", \"Mechanism connecting receptor coupling to nerve maturation unknown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Connected RCP to a caveolin-1/ERK1/2 axis governing pressure-induced vascular smooth muscle proliferation, broadening its signaling reach beyond cAMP coupling.\",\n      \"evidence\": \"siRNA knockdown with Western blot for p-ERK1/2, caveolin-1, and PCNA in a static pressure model in A10 VSMCs\",\n      \"pmids\": [\"29741760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular partner mediating the caveolin-1/ERK link unidentified\", \"Single cell-line model without in vivo confirmation\", \"Relation to canonical CGRP receptor coupling unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated in vivo that neural RCP biases CGRP receptor pharmacology: its loss spares agonist-driven behaviors but abolishes gepant-class antagonist efficacy, defining RCP as a determinant of antagonist responsiveness.\",\n      \"evidence\": \"Tamoxifen-inducible neural-specific RCP knockout mouse with behavioral assays and systemic CGRP/olcegepant challenge (preprint)\",\n      \"pmids\": [\"39484482\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not peer-reviewed\", \"Molecular basis for the antagonist-specific pharmacology shift unresolved\", \"Single lab with two behavioral readouts\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single small protein partitions between its role as a Pol III subunit and its role as a membrane-receptor signal-coupling protein, and whether these functions are coordinated, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No study reconciles the nuclear Pol III and receptor-coupling pools\", \"Structural basis of RCP–CRLR coupling and Gα activation undefined\", \"Post-transcriptional regulatory mechanism setting RCP abundance unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060089\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 2]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 8]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [1, 2]}\n    ],\n    \"complexes\": [\n      \"RNA Polymerase III\",\n      \"CGRP receptor complex (CRLR-RAMP-RCP)\"\n    ],\n    \"partners\": [\n      \"CALCRL\",\n      \"RPC25\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}