ID   CALCA_HUMAN             Reviewed;         128 AA.
AC   P06881; Q93048; Q9UCP0;
DT   01-JAN-1988, integrated into UniProtKB/Swiss-Prot.
DT   12-SEP-2018, sequence version 4.
DT   04-NOV-2026, entry version 225.
DE   RecName: Full=Calcitonin gene-related peptide 1;
DE            Short=CGRP1 {ECO:0000303|PubMed:9620797};
DE   AltName: Full=Alpha-type CGRP;
DE   AltName: Full=Calcitonin gene-related peptide I;
DE            Short=CGRP-I;
DE   Flags: Precursor;
GN   Name=CALCA {ECO:0000312|HGNC:HGNC:1437}; Synonyms=CALC1;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=3872459; DOI=10.1073/pnas.82.7.1994;
RA   Jonas V., Lin C.R., Kawashima E., Semon D., Swanson L.W., Mermod J.-J.,
RA   Evans R.M., Rosenfeld M.G.;
RT   "Alternative RNA processing events in human calcitonin/calcitonin gene-
RT   related peptide gene expression.";
RL   Proc. Natl. Acad. Sci. U.S.A. 82:1994-1998(1985).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA].
RX   PubMed=2571128; DOI=10.1093/nar/17.17.6999;
RA   Broad P.M., Symes A.J., Thakker R.V., Craig R.K.;
RT   "Structure and methylation of the human calcitonin/alpha-CGRP gene.";
RL   Nucleic Acids Res. 17:6999-7011(1989).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16554811; DOI=10.1038/nature04632;
RA   Taylor T.D., Noguchi H., Totoki Y., Toyoda A., Kuroki Y., Dewar K.,
RA   Lloyd C., Itoh T., Takeda T., Kim D.-W., She X., Barlow K.F., Bloom T.,
RA   Bruford E., Chang J.L., Cuomo C.A., Eichler E., FitzGerald M.G.,
RA   Jaffe D.B., LaButti K., Nicol R., Park H.-S., Seaman C., Sougnez C.,
RA   Yang X., Zimmer A.R., Zody M.C., Birren B.W., Nusbaum C., Fujiyama A.,
RA   Hattori M., Rogers J., Lander E.S., Sakaki Y.;
RT   "Human chromosome 11 DNA sequence and analysis including novel gene
RT   identification.";
RL   Nature 440:497-500(2006).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 48-119.
RX   PubMed=6148938; DOI=10.1016/0006-291x(84)90278-x;
RA   Nelkin B.D., Rosenfeld K.I., de Bustros A., Leong S.S., Roos B.A.,
RA   Baylin S.B.;
RT   "Structure and expression of a gene encoding human calcitonin and
RT   calcitonin gene related peptide.";
RL   Biochem. Biophys. Res. Commun. 123:648-655(1984).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [MRNA] OF 76-128, AND SUBCELLULAR LOCATION.
RX   PubMed=2408883; DOI=10.1002/j.1460-2075.1985.tb03688.x;
RA   Edbrooke M.R., Parker D., McVey J.H., Riley J.H., Sorenson G.D.,
RA   Pettengill O.S., Craig R.K.;
RT   "Expression of the human calcitonin/CGRP gene in lung and thyroid
RT   carcinoma.";
RL   EMBO J. 4:715-724(1985).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 77-128.
RC   TISSUE=Thyroid carcinoma;
RX   PubMed=6610687; DOI=10.1210/jcem-59-2-358;
RA   Steenbergh P.H., Hoppener J.W., Zandberg J., de Ven W.J., Jansz H.S.,
RA   Lips C.J.;
RT   "Calcitonin gene related peptide coding sequence is conserved in the human
RT   genome and is expressed in medullary thyroid carcinoma.";
RL   J. Clin. Endocrinol. Metab. 59:358-360(1984).
RN   [7]
RP   NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 77-128.
RX   PubMed=3034287;
RA   Craig R.K., Riley J.H., Edbrooke M.R., Broad P.M., Foord S.M.,
RA   Al-Kazwini S.J., Holman J.J., Marshall I.;
RT   "Expression and function of the human calcitonin/alpha-CGRP gene in health
RT   and disease.";
RL   Biochem. Soc. Symp. 52:91-105(1986).
RN   [8]
RP   PROTEIN SEQUENCE OF 83-119, AMIDATION AT PHE-119, AND DISULFIDE BOND.
RX   PubMed=6609312; DOI=10.1038/308746a0;
RA   Morris H.R., Panico M., Etienne T., Tippins J., Girgis S.I., McIntyre I.;
RT   "Isolation and characterization of human calcitonin gene-related peptide.";
RL   Nature 308:746-748(1984).
RN   [9]
RP   PROTEIN SEQUENCE OF 83-117.
RX   PubMed=3492492; DOI=10.1016/s0021-9258(19)75816-5;
RA   Petermann J.B., Born W., Chang J.Y., Fischer J.A.;
RT   "Identification in the human central nervous system, pituitary, and thyroid
RT   of a novel calcitonin gene-related peptide, and partial amino acid sequence
RT   in the spinal cord.";
RL   J. Biol. Chem. 262:542-545(1987).
RN   [10]
RP   PROTEIN SEQUENCE OF 83-108, AND FUNCTION.
RC   TISSUE=Pheochromocytoma;
RX   PubMed=1318039; DOI=10.1016/s0006-291x(05)80966-0;
RA   Kitamura K., Kangawa K., Kawamoto M., Ichiki Y., Matsuo H., Eto T.;
RT   "Isolation and characterization of peptides which act on rat platelets,
RT   from a pheochromocytoma.";
RL   Biochem. Biophys. Res. Commun. 185:134-141(1992).
RN   [11]
RP   FUNCTION.
RC   TISSUE=Neuroblastoma;
RX   PubMed=9620797; DOI=10.1038/30666;
RA   McLatchie L.M., Fraser N.J., Main M.J., Wise A., Brown J., Thompson N.,
RA   Solari R., Lee M.G., Foord S.M.;
RT   "RAMPs regulate the transport and ligand specificity of the calcitonin-
RT   receptor-like receptor.";
RL   Nature 393:333-339(1998).
RN   [12]
RP   STRUCTURE BY NMR OF CGRP.
RX   PubMed=1988044; DOI=10.1021/bi00216a036;
RA   Breeze A.L., Harvey T.S., Bazzo R., Campbell I.D.;
RT   "Solution structure of human calcitonin gene-related peptide by 1H NMR and
RT   distance geometry with restrained molecular dynamics.";
RL   Biochemistry 30:575-582(1991).
RN   [13]
RP   STRUCTURE BY NMR OF CGRP.
RX   PubMed=2039456; DOI=10.1042/bj2750785;
RA   Hubbard J.A.M., Martin S.R., Chaplin L.C., Bose C., Kelly S.M., Price N.C.;
RT   "Solution structures of calcitonin-gene-related-peptide analogues of
RT   calcitonin-gene-related peptide and amylin.";
RL   Biochem. J. 275:785-788(1991).
RN   [14] {ECO:0007744|PDB:7KNU}
RP   STRUCTURE BY ELECTRON MICROSCOPY IN COMPLEX WITH CALCRL; RAMP1 AND G
RP   PROTEINS, AND FUNCTION.
RX   PubMed=33602864; DOI=10.1126/science.abf7258;
RA   Josephs T.M., Belousoff M.J., Liang Y.L., Piper S.J., Cao J., Garama D.J.,
RA   Leach K., Gregory K.J., Christopoulos A., Hay D.L., Danev R., Wootten D.,
RA   Sexton P.M.;
RT   "Structure and dynamics of the CGRP receptor in apo and peptide-bound
RT   forms.";
RL   Science 372:0-0(2021).
RN   [15] {ECO:0007744|PDB:9AUC}
RP   STRUCTURE BY ELECTRON MICROSCOPY IN COMPLEX WITH CALCR; RAMP1 AND G
RP   PROTEINS, DISULFIDE BONDS, AND FUNCTION.
RX   PubMed=38603770; DOI=10.1021/acs.biochem.4c00114;
RA   Cao J., Belousoff M.J., Danev R., Christopoulos A., Wootten D.,
RA   Sexton P.M.;
RT   "Cryo-EM Structure of the Human Amylin 1 Receptor in Complex with CGRP and
RT   Gs Protein.";
RL   Biochemistry 63:1089-1096(2024).
CC   -!- FUNCTION: CGRP1/CALCA is a peptide hormone that induces vasodilation
CC       mediated by the CALCRL-RAMP1 receptor complex (PubMed:1318039,
CC       PubMed:33602864, PubMed:9620797). Dilates a variety of vessels
CC       including the coronary, cerebral and systemic vasculature. Its
CC       abundance in the CNS also points toward a neurotransmitter or
CC       neuromodulator role (PubMed:3492492). It also elevates platelet cAMP
CC       (PubMed:1318039). CGRP1 can also bind and activate CALCR-RAMP1 (AMYR1)
CC       receptor complex (PubMed:38603770). {ECO:0000269|PubMed:1318039,
CC       ECO:0000269|PubMed:33602864, ECO:0000269|PubMed:3492492,
CC       ECO:0000269|PubMed:38603770, ECO:0000269|PubMed:9620797}.
CC   -!- INTERACTION:
CC       P06881; Q16602: CALCRL; NbExp=5; IntAct=EBI-962928, EBI-962878;
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:2408883}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=3;
CC       Name=3;
CC         IsoId=P06881-1; Sequence=Displayed;
CC       Name=1;
CC         IsoId=P01258-1; Sequence=External;
CC       Name=2;
CC         IsoId=P01258-2; Sequence=External;
CC   -!- TISSUE SPECIFICITY: Expressed in spinal cord.
CC       {ECO:0000269|PubMed:3492492}.
CC   -!- MISCELLANEOUS: The CALCA gene (HGNC:1437) encodes a small family of
CC       peptides including calcitonin (UniProtKB:P01258), its C-terminal
CC       flanking peptide katacalcin (UniProtKB:P01258) and the calcitonin gene-
CC       related peptide 1/CGRP1 (UniProtKB:P06881).
CC       {ECO:0000269|PubMed:3872459, ECO:0000269|PubMed:6148938}.
CC   -!- SIMILARITY: Belongs to the calcitonin family. {ECO:0000305}.
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DR   EMBL; M12667; AAA51914.1; -; Genomic_DNA.
DR   EMBL; M12664; AAA51914.1; JOINED; Genomic_DNA.
DR   EMBL; M12665; AAA51914.1; JOINED; Genomic_DNA.
DR   EMBL; X15943; CAA34070.1; -; Genomic_DNA.
DR   EMBL; AC090835; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; K03512; AAA52011.1; -; mRNA.
DR   EMBL; X02330; CAA26190.1; -; mRNA.
DR   EMBL; M28637; AAA52012.1; -; Genomic_DNA.
DR   EMBL; M26094; AAA51912.1; -; Genomic_DNA.
DR   CCDS; CCDS31432.1; -. [P06881-1]
DR   PIR; S07644; TCHUR.
DR   RefSeq; NP_001029125.1; NM_001033953.3. [P06881-1]
DR   RefSeq; NP_001365879.1; NM_001378950.1. [P06881-1]
DR   PDB; 6E3Y; EM; 3.30 A; P=83-119.
DR   PDB; 7KNU; EM; 3.49 A; P=83-119.
DR   PDB; 9AUC; EM; 2.40 A; P=83-119.
DR   AlphaFoldDB; P06881; -.
DR   BMRB; P06881; -.
DR   EMDB; EMD-22963; -.
DR   EMDB; EMD-43877; -.
DR   EMDB; EMD-8978; -.
DR   SMR; P06881; -.
DR   BioGRID; 107247; 18.
DR   CORUM; P06881; -.
DR   IntAct; P06881; 10.
DR   NDEx; IQUERY-CP-CALCA; 6 NDEx IQuery Curated Pathways.
DR   BindingDB; P06881; -.
DR   ChEMBL; CHEMBL5293; -.
DR   DrugBank; DB14040; Eptinezumab.
DR   DrugBank; DB14041; Fremanezumab.
DR   DrugBank; DB14042; Galcanezumab.
DR   DrugBank; DB04869; Olcegepant.
DR   DrugBank; DB12228; Telcagepant.
DR   DrugCentral; P06881; -.
DR   TCDB; 1.C.49.1.2; the cytotoxic amylin (amylin) family.
DR   iPTMnet; P06881; -.
DR   BioMuta; CALCA; -.
DR   DMDM; 308153625; -.
DR   MassIVE; P06881; -.
DR   ProteomicsDB; 51940; -. [P06881-1]
DR   ABCD; P06881; 3 sequenced antibodies.
DR   Antibodypedia; 3493; 2002 antibodies from 56 providers.
DR   DNASU; 796; -.
DR   Ensembl; ENST00000486207.6; ENSP00000417833.1; ENSG00000110680.14.
DR   Ensembl; ENST00000706042.1; ENSP00000516203.1; ENSG00000110680.14.
DR   Ensembl; ENST00000706043.1; ENSP00000516204.1; ENSG00000110680.14.
DR   GeneID; 796; -.
DR   UCSC; uc001mlt.2; human. [P06881-1]
DR   AGR; HGNC:1437; -.
DR   ClinPGx; PA26029; -.
DR   CTD; 796; -.
DR   DisGeNET; 796; -.
DR   GeneCards; CALCA; -.
DR   HGNC; HGNC:1437; CALCA.
DR   HPA; ENSG00000110680; Group enriched (parathyroid gland, thyroid gland).
DR   MalaCards; CALCA; -.
DR   MIM; 114130; gene.
DR   OpenTargets; ENSG00000110680; -.
DR   VEuPathDB; HostDB:ENSG00000110680; -.
DR   GeneTree; ENSGT00940000162876; -.
DR   HOGENOM; CLU_122444_1_0_1; -.
DR   OMA; CDKSCVG; -.
DR   OrthoDB; 9929923at2759; -.
DR   PathwayCommons; P06881; -.
DR   Reactome; R-HSA-418555; G alpha (s) signalling events.
DR   Reactome; R-HSA-419812; Calcitonin-like ligand receptors.
DR   SignaLink; P06881; -.
DR   Agora; ENSG00000110680; -.
DR   BioGRID-ORCS; 796; 15 hits in 1146 CRISPR screens.
DR   ChiTaRS; CALCA; human.
DR   GenomeRNAi; 796; -.
DR   Pharos; P06881; Tclin.
DR   Proteomes; UP000005640; Chromosome 11.
DR   Bgee; ENSG00000110680; Expressed in dorsal root ganglion and 124 other cell types or tissues.
DR   ExpressionAtlas; P06881; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; IDA:UniProtKB.
DR   GO; GO:0005576; C:extracellular region; IDA:UniProt.
DR   GO; GO:0005179; F:hormone activity; IDA:UniProt.
DR   GO; GO:0044877; F:protein-containing complex binding; IDA:UniProtKB.
DR   GO; GO:0005102; F:signaling receptor binding; IDA:UniProtKB.
DR   GO; GO:0007190; P:activation of adenylate cyclase activity; IDA:UniProtKB.
DR   GO; GO:0007189; P:adenylate cyclase-activating G protein-coupled receptor signaling pathway; IDA:UniProtKB.
DR   GO; GO:0150059; P:amylin receptor 1 signaling pathway; IDA:UniProt.
DR   GO; GO:1990408; P:calcitonin gene-related peptide receptor signaling pathway; IDA:UniProt.
DR   GO; GO:0007267; P:cell-cell signaling; TAS:ProtInc.
DR   GO; GO:0043542; P:endothelial cell migration; IDA:UniProtKB.
DR   GO; GO:0001935; P:endothelial cell proliferation; IDA:UniProtKB.
DR   GO; GO:0002031; P:G protein-coupled receptor internalization; IDA:UniProtKB.
DR   GO; GO:0007159; P:leukocyte cell-cell adhesion; IDA:UniProtKB.
DR   GO; GO:0045776; P:negative regulation of blood pressure; IDA:MGI.
DR   GO; GO:0045779; P:negative regulation of bone resorption; IDA:UniProtKB.
DR   GO; GO:0010523; P:negative regulation of calcium ion transport into cytosol; IDA:UniProtKB.
DR   GO; GO:0045671; P:negative regulation of osteoclast differentiation; IDA:UniProtKB.
DR   GO; GO:0001976; P:nervous system process involved in regulation of systemic arterial blood pressure; IDA:MGI.
DR   GO; GO:0007200; P:phospholipase C-activating G protein-coupled receptor signaling pathway; IDA:UniProtKB.
DR   GO; GO:0032730; P:positive regulation of interleukin-1 alpha production; IDA:UniProtKB.
DR   GO; GO:0032757; P:positive regulation of interleukin-8 production; IDA:UniProtKB.
DR   GO; GO:0045651; P:positive regulation of macrophage differentiation; IDA:UniProtKB.
DR   GO; GO:0006468; P:protein phosphorylation; IDA:UniProtKB.
DR   GO; GO:0031623; P:receptor internalization; IDA:UniProtKB.
DR   GO; GO:0008217; P:regulation of blood pressure; NAS:UniProtKB.
DR   GO; GO:0051480; P:regulation of cytosolic calcium ion concentration; IDA:UniProtKB.
DR   GO; GO:0001944; P:vasculature development; IDA:UniProtKB.
DR   GO; GO:0042311; P:vasodilation; IDA:UniProtKB.
DR   Gene3D; 6.10.250.2190; -; 1.
DR   InterPro; IPR021117; Calcitonin-like.
DR   InterPro; IPR021116; Calcitonin/adrenomedullin.
DR   InterPro; IPR018360; Calcitonin_CS.
DR   InterPro; IPR015476; Calcitonin_gene-rel_peptide.
DR   InterPro; IPR001693; Calcitonin_peptide-like.
DR   PANTHER; PTHR10505:SF3; CALCITONIN GENE-RELATED PEPTIDE 2; 1.
DR   PANTHER; PTHR10505; CALCITONIN-RELATED; 1.
DR   Pfam; PF00214; Calc_CGRP_IAPP; 1.
DR   PRINTS; PR00817; CALCITONINB.
DR   SMART; SM00113; CALCITONIN; 1.
DR   PROSITE; PS00258; CALCITONIN; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Alternative splicing; Amidation;
KW   Cleavage on pair of basic residues; Direct protein sequencing;
KW   Disulfide bond; Hormone; Proteomics identification; Reference proteome;
KW   Secreted; Signal.
FT   SIGNAL          1..25
FT                   /evidence="ECO:0000255"
FT   PROPEP          26..80
FT                   /id="PRO_0000004053"
FT   PEPTIDE         83..119
FT                   /note="Calcitonin gene-related peptide 1"
FT                   /id="PRO_0000004054"
FT   PROPEP          125..128
FT                   /id="PRO_0000004055"
FT   MOD_RES         119
FT                   /note="Phenylalanine amide"
FT                   /evidence="ECO:0000269|PubMed:6609312"
FT   DISULFID        84..89
FT                   /evidence="ECO:0000269|PubMed:38603770,
FT                   ECO:0000269|PubMed:6609312, ECO:0007744|PDB:9AUC"
FT   VARIANT         57
FT                   /note="D -> N (in dbSNP:rs5239)"
FT                   /id="VAR_048584"
FT   HELIX           87..89
FT                   /evidence="ECO:0007829|PDB:9AUC"
FT   HELIX           90..100
FT                   /evidence="ECO:0007829|PDB:9AUC"
FT   TURN            101..103
FT                   /evidence="ECO:0007829|PDB:9AUC"
FT   STRAND          104..108
FT                   /evidence="ECO:0007829|PDB:9AUC"
FT   HELIX           110..113
FT                   /evidence="ECO:0007829|PDB:6E3Y"
FT   STRAND          115..117
FT                   /evidence="ECO:0007829|PDB:9AUC"
SQ   SEQUENCE   128 AA;  13899 MW;  A003A1069260D9B8 CRC64;
     MGFQKFSPFL ALSILVLLQA GSLHAAPFRS ALESSPADPA TLSEDEARLL LAALVQDYVQ
     MKASELEQEQ EREGSRIIAQ KRACDTATCV THRLAGLLSR SGGVVKNNFV PTNVGSKAFG
     RRRRDLQA
//