Details for: CALCA

Gene ID: 796

Gene Type:  Protein-coding  - A gene that serves as a template for producing a messenger RNA (mRNA) molecule, which is then translated into a functional protein.

Symbol: CALCA

Ensembl ID: ENSG00000110680

Description: calcitonin related polypeptide alpha

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

Cell Significance Index (CSI) scores for the chosen context(s)

  • lung neuroendocrine cell CL1000223
    CSI 10.67
    rCSI 15.78%
    PRS 99.5
  • microglial cell CL0000129
    CSI 7.16
    rCSI 28.83%
    PRS 99.4
  • renal alpha-intercalated cell CL0005011
    CSI 4.58
    rCSI 6.12%
    PRS 99.71
  • kidney loop of Henle thin ascending limb epithelial cell CL1001107
    CSI 2.43
    rCSI 6.27%
    PRS 99.62
  • kidney collecting duct intercalated cell CL1001432
    CSI 2.37
    rCSI 16.95%
    PRS 98.84
  • neuroendocrine cell CL0000165
    CSI 1.79
    rCSI 6.9%
    PRS 99.74

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this specific cell.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.

Cell ID: Standard Cell Ontology term used for mapping and comparing cells across experiments. Ensures consistency in analyzing cellular functions across tissues.
Fold Change: Represents the ratio of the current Cell Significance Index to the Cell Significance Index Threshold, indicating how much the gene expression has changed compared to a baseline.
Cell Significance Index: Reflects how strongly a gene is expressed in this cell type. Calculated using techniques like effect size estimation and bootstrapping for reliability.
Network Configuration

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  • Node Color (Target Cell CSI, relative to current network):
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Other Information

This section provides additional information about the gene, including a description generated by an AI language model and details about associated proteins.

## Summary The [CALCA](/details-gene/796) gene encodes a precursor protein that undergoes tissue-specific alternative splicing to produce two distinct, biologically active peptides: calcitonin and calcitonin gene-related peptide (CGRP) [Link](https://doi.org/10.1073/pnas.82.7.1994). Calcitonin is a classical hormone primarily involved in calcium homeostasis and the negative regulation of bone resorption, while CGRP functions as a potent neuropeptide and vasodilator. Reflecting these dual roles, [CALCA](/details-gene/796) shows highly specific and significant expression in neuroendocrine cells, particularly [lung neuroendocrine cell](/details-cell/CL1000223)s, as well as in central nervous system [microglial cell](/details-cell/CL0000129)s and specialized epithelial cells of the kidney. Its dysregulation is associated with certain endocrine tumors, such as medullary thyroid carcinoma [Link](https://omim.org/entry/114130). ## Cellular Roles and Expression Landscape The expression profile of [CALCA](/details-gene/796) highlights its specialized function in distinct cellular contexts. **Overall**, the gene is a preeminent marker for neuroendocrine lineages, demonstrated by its highest significance score (CSI: 10.67) in [lung neuroendocrine cell](/details-cell/CL1000223)s and its general high expression in [neuroendocrine cell](/details-cell/CL0000165)s. This is consistent with the established role of CGRP as a neuropeptide secreted from these cells. Beyond its neuroendocrine role, [CALCA](/details-gene/796) exhibits significant expression in several other key cell types, suggesting pleiotropic functions: * **Central Nervous System:** It is a highly significant gene in [microglial cell](/details-cell/CL0000129)s (CSI: 7.16). This expression suggests a direct role for [CALCA](/details-gene/796)-derived peptides in neuroinflammation, immune surveillance, and neuronal homeostasis within the brain. * **Renal System:** The gene is prominently expressed in specific segments of the kidney nephron, including [renal alpha-intercalated cell](/details-cell/CL0005011)s, [kidney loop of Henle thin ascending limb epithelial cell](/details-cell/CL1001107)s, and [kidney collecting duct intercalated cell](/details-cell/CL1001432)s. This pattern points towards a localized function in regulating renal blood flow, ion transport, and systemic blood pressure. ## Pathways and Molecular Function The functional annotations for [CALCA](/details-gene/796) align with the distinct biological activities of its peptide products, calcitonin and CGRP. Its primary molecular function is as a ligand for G protein-coupled receptors, specifically through [Calcitonin receptor binding](/details-go/GO:0031716), which initiates downstream signaling cascades. Key biological processes associated with [CALCA](/details-gene/796) include: * **Neuro-hormonal Signaling:** The gene is central to the [Neuropeptide signaling pathway](/details-go/GO:0007218) and the [Adenylate cyclase-activating g protein-coupled receptor signaling pathway](/details-go/GO:0007189), consistent with the function of CGRP. This is further supported by its involvement in the Reactome pathway [Calcitonin-like ligand receptors](/details-pathway/R-HSA-419812). * **Homeostasis and Vasoregulation:** It plays a critical role in the [Negative regulation of bone resorption](/details-go/GO:0045779), a key function of calcitonin. Furthermore, it is heavily implicated in cardiovascular control through processes like [Vasodilation](/details-go/GO:0042311) and the [Regulation of blood pressure](/details-go/GO:0008217), which are primary functions of CGRP. * **Immune Modulation:** The gene is linked to the [Innate immune response](/details-go/GO:0045087) and [Inflammatory response](/details-go/GO:0006954). This annotation is highly consistent with its significant expression in [microglial cell](/details-cell/CL0000129)s, suggesting that CGRP may act as a local modulator of immune activity in the brain and other tissues. ## Research Directions The diverse expression pattern and functional annotations of [CALCA](/details-gene/796) suggest several avenues for future research, particularly concerning its roles beyond classical endocrinology. ### Testable Hypotheses: 1. **Neuromodulation by Microglia:** Given its high significance in [microglial cell](/details-cell/CL0000129)s and its link to the [Inflammatory response](/details-go/GO:0006954), it is hypothesized that [CALCA](/details-gene/796)-derived CGRP is locally secreted by microglia to modulate neuroinflammation, potentially acting in an autocrine or paracrine manner to suppress pro-inflammatory responses and promote a shift towards a tissue-reparative phenotype following injury or infection. 2. **Intra-renal Blood Pressure Regulation:** The specific expression in [renal alpha-intercalated cell](/details-cell/CL0005011)s and other distal nephron segments suggests that locally produced CGRP acts as a paracrine regulator of afferent and efferent arteriolar tone, contributing to the fine-tuning of glomerular filtration rate and renal blood flow independent of systemic CGRP levels. 3. **Tumor Microenvironment in Lung Cancer:** Based on historical reports of its expression in lung carcinoma [Link](https://doi.org/10.1002/j.1460-2075.1985.tb03688.x) and its annotated roles in [Vasculature development](/details-go/GO:0001944) and immune response, it is hypothesized that ectopic expression of [CALCA](/details-gene/796) by lung tumor cells promotes tumor growth by enhancing local blood supply and suppressing anti-tumor immune responses. ### Key Experiment: To test the hypothesis regarding the role of [CALCA](/details-gene/796)-derived CGRP in microglial function (Hypothesis 1), a compelling experiment would be to use a CRISPR-Cas9 knockout or siRNA knockdown of [CALCA](/details-gene/796) in primary human microglia or the HMC3 microglial cell line. These modified cells, alongside wild-type controls, could be challenged with a pro-inflammatory stimulus like lipopolysaccharide (LPS). The functional consequences would be assessed by measuring the secretion of key cytokines (e.g., TNF-α, IL-6, IL-10) using ELISA and by analyzing the expression of M1/M2 polarization markers (e.g., iNOS, CD206) via qPCR or flow cytometry. This would directly test whether endogenous CGRP production is required for microglia to appropriately regulate their inflammatory state. ### Therapeutic Potential: The peptides encoded by [CALCA](/details-gene/796) are already validated therapeutic targets. CGRP receptor antagonists and monoclonal antibodies targeting CGRP are approved for the treatment of migraine, demonstrating that its signaling is highly druggable. The expression data suggests new therapeutic avenues. For instance, **inhibition** of CGRP signaling could be explored as a strategy to modulate neuroinflammatory diseases where microglia play a detrimental role. Conversely, CGRP agonists could have therapeutic potential in conditions requiring enhanced vasodilation or immunomodulation. Given its association with specific cancers, [CALCA](/details-gene/796) expression could serve as a valuable biomarker, and its signaling pathways may represent targets for **inhibition** to disrupt the tumor microenvironment.

Genular Protein ID: 4100537344

Symbol: CALC_HUMAN

Name: Calcitonin

UniProtKB Accession Codes:

P01258 B7ZL39 Q13935 Q13937 Q52LX7

Database IDs:

ABCD 1 AGR 1 AlphaFoldDB 1 Antibodypedia 1 BMRB 1 Bgee 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 EMBL 19 EMDB 1 Ensembl 3 EvolutionaryTrace 1 ExpressionAtlas 1 GO 30 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 5 KEGG 1 MANE-Select 1 MIM 1 MINT 1 MassIVE 1 MetOSite 1 NCBI Taxonomy 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 3 PDBsum 3 PIR 2 PRINTS 1 PROSITE 1 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 2 RNAct 1 Reactome 3 RefSeq 4 SMART 1 SMR 1 STRING 1 SignaLink 1 TopDownProteomics 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 6546550

Title: The complete sequence of human preprocalcitonin.

PubMed ID: 6546550

DOI: 10.1016/0014-5793(84)80839-x

PubMed ID: 3872459

Title: Alternative RNA processing events in human calcitonin/calcitonin gene-related peptide gene expression.

PubMed ID: 3872459

DOI: 10.1073/pnas.82.7.1994

PubMed ID: 3034287

Title: Expression and function of the human calcitonin/alpha-CGRP gene in health and disease.

PubMed ID: 3034287

PubMed ID: 3485540

Title: Ectopic synthesis of high-Mr calcitonin by the BEN lung carcinoma cell line reflects aberrant proteolytic processing.

PubMed ID: 3485540

DOI: 10.1016/0014-5793(86)81187-5

PubMed ID: 1761559

Title: A novel calcitonin carboxyl-terminal peptide produced in medullary thyroid carcinoma by alternative RNA processing of the calcitonin/calcitonin gene-related peptide gene.

PubMed ID: 1761559

DOI: 10.1016/s0021-9258(18)54275-7

PubMed ID: 16554811

Title: Human chromosome 11 DNA sequence and analysis including novel gene identification.

PubMed ID: 16554811

DOI: 10.1038/nature04632

PubMed ID: 15489334

Title: The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC).

PubMed ID: 15489334

DOI: 10.1101/gr.2596504

PubMed ID: 6148938

Title: Structure and expression of a gene encoding human calcitonin and calcitonin gene related peptide.

PubMed ID: 6148938

DOI: 10.1016/0006-291x(84)90278-x

PubMed ID: 2408883

Title: Expression of the human calcitonin/CGRP gene in lung and thyroid carcinoma.

PubMed ID: 2408883

DOI: 10.1002/j.1460-2075.1985.tb03688.x

PubMed ID: 5760861

Title: Human calcitonin. Structure of calcitonin M and D.

PubMed ID: 5760861

DOI: 10.1002/hlca.19680510811

PubMed ID: 2001366

Title: A 1H NMR study of human calcitonin in solution.

PubMed ID: 2001366

DOI: 10.1021/bi00223a010

PubMed ID: 6132180

Title: Katacalcin: a new plasma calcium-lowering hormone.

PubMed ID: 6132180

DOI: 10.1016/s0140-6736(83)91387-9

PubMed ID: 14759258

Title: An unappreciated role for RNA surveillance.

PubMed ID: 14759258

DOI: 10.1186/gb-2004-5-2-r8

Sequence Information:

  • Length: 141
  • Mass: 15467
  • Checksum: 99622305DD8B286F
  • Sequence:
    • MGFQKFSPFL ALSILVLLQA GSLHAAPFRS ALESSPADPA TLSEDEARLL LAALVQDYVQ 
MKASELEQEQ EREGSSLDSP RSKRCGNLST CMLGTYTQDF NKFHTFPQTA IGVGAPGKKR 
DMSSDLERDH RPHVSMPQNA N

Genular Protein ID: 2822134813

Symbol: CALCA_HUMAN

Name: Calcitonin gene-related peptide 1

UniProtKB Accession Codes:

P06881 Q93048 Q9UCP0

Database IDs:

ABCD 1 AGR 1 AlphaFoldDB 1 Antibodypedia 1 BMRB 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CTD 1 ChEMBL 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 5 DrugCentral 1 EMBL 9 EMDB 3 Ensembl 3 ExpressionAtlas 1 GO 29 Gene3D 1 GeneCards 1 GeneTree 1 GenomeRNAi 1 HGNC 1 HOGENOM 1 HPA 1 IntAct 1 InterPro 5 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 3 PDBsum 3 PIR 1 PRINTS 1 PROSITE 1 PathwayCommons 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 Proteomes 1 ProteomicsDB 1 Reactome 2 RefSeq 1 SMART 1 SMR 1 SignaLink 1 TCDB 1 UCSC 1 VEuPathDB 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 3872459

Title: Alternative RNA processing events in human calcitonin/calcitonin gene-related peptide gene expression.

PubMed ID: 3872459

DOI: 10.1073/pnas.82.7.1994

PubMed ID: 2571128

Title: Structure and methylation of the human calcitonin/alpha-CGRP gene.

PubMed ID: 2571128

DOI: 10.1093/nar/17.17.6999

PubMed ID: 16554811

Title: Human chromosome 11 DNA sequence and analysis including novel gene identification.

PubMed ID: 16554811

DOI: 10.1038/nature04632

PubMed ID: 6148938

Title: Structure and expression of a gene encoding human calcitonin and calcitonin gene related peptide.

PubMed ID: 6148938

DOI: 10.1016/0006-291x(84)90278-x

PubMed ID: 2408883

Title: Expression of the human calcitonin/CGRP gene in lung and thyroid carcinoma.

PubMed ID: 2408883

DOI: 10.1002/j.1460-2075.1985.tb03688.x

PubMed ID: 6610687

Title: Calcitonin gene related peptide coding sequence is conserved in the human genome and is expressed in medullary thyroid carcinoma.

PubMed ID: 6610687

DOI: 10.1210/jcem-59-2-358

PubMed ID: 3034287

Title: Expression and function of the human calcitonin/alpha-CGRP gene in health and disease.

PubMed ID: 3034287

PubMed ID: 6609312

Title: Isolation and characterization of human calcitonin gene-related peptide.

PubMed ID: 6609312

DOI: 10.1038/308746a0

PubMed ID: 3492492

Title: Identification in the human central nervous system, pituitary, and thyroid of a novel calcitonin gene-related peptide, and partial amino acid sequence in the spinal cord.

PubMed ID: 3492492

DOI: 10.1016/s0021-9258(19)75816-5

PubMed ID: 1318039

Title: Isolation and characterization of peptides which act on rat platelets, from a pheochromocytoma.

PubMed ID: 1318039

DOI: 10.1016/s0006-291x(05)80966-0

PubMed ID: 1988044

Title: Solution structure of human calcitonin gene-related peptide by 1H NMR and distance geometry with restrained molecular dynamics.

PubMed ID: 1988044

DOI: 10.1021/bi00216a036

PubMed ID: 2039456

Title: Solution structures of calcitonin-gene-related-peptide analogues of calcitonin-gene-related peptide and amylin.

PubMed ID: 2039456

DOI: 10.1042/bj2750785

Sequence Information:

  • Length: 128
  • Mass: 13899
  • Checksum: A003A1069260D9B8
  • Sequence:
    • MGFQKFSPFL ALSILVLLQA GSLHAAPFRS ALESSPADPA TLSEDEARLL LAALVQDYVQ 
MKASELEQEQ EREGSRIIAQ KRACDTATCV THRLAGLLSR SGGVVKNNFV PTNVGSKAFG 
RRRRDLQA