Details for: CA3

Gene ID: 761

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: CA3

Ensembl ID: ENSG00000164879

Description: carbonic anhydrase 3

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • pulmonary alveolar type 2 cell CL0002063
    CSI 12.59
    rCSI 19.53%
    PRS 93.5
  • lamp5 GABAergic cortical interneuron CL4023011
    CSI 10.76
    rCSI 18.07%
    PRS 82.57
  • alveolar type 1 fibroblast cell CL4028004
    CSI 9.61
    rCSI 10.52%
    PRS 94.43
  • fibroblast of lung CL0002553
    CSI 8.89
    rCSI 8.27%
    PRS 94.19
  • muscle cell CL0000187
    CSI 7
    rCSI 14.37%
    PRS 94.88
  • fast muscle cell CL0000190
    CSI 4.74
    rCSI 18.53%
    PRS 86.3
  • mesothelial cell CL0000077
    CSI 4.57
    rCSI 17.86%
    PRS 79.6
  • slow muscle cell CL0000189
    CSI 3.82
    rCSI 50.92%
    PRS 86.07
  • chondrocyte CL0000138
    CSI 3.66
    rCSI 5.82%
    PRS 89.28
  • cardiac muscle cell CL0000746
    CSI 3.65
    rCSI 5.24%
    PRS 86.07
  • caudal ganglionic eminence derived cortical interneuron CL4023064
    CSI 3.35
    rCSI 5.92%
    PRS 81.88
  • Schwann cell CL0002573
    CSI 3.15
    rCSI 8.94%
    PRS 90.09
  • hepatic stellate cell CL0000632
    CSI 3.12
    rCSI 11.7%
    PRS 89.8
  • hepatocyte CL0000182
    CSI 2.99
    rCSI 5.35%
    PRS 91.36
  • Mueller cell CL0000636
    CSI 2.7
    rCSI 6.17%
    PRS 87.62
  • alveolar adventitial fibroblast CL4028006
    CSI 2.55
    rCSI 4.03%
    PRS 93.96
  • conjunctival epithelial cell CL1000432
    CSI 2.55
    rCSI 3.89%
    PRS 92.13
  • lung secretory cell CL1000272
    CSI 2.47
    rCSI 6.11%
    PRS 94.06
  • epithelial cell of proximal tubule CL0002306
    CSI 2.4
    rCSI 5.86%
    PRS 87.83
  • kidney loop of Henle thin descending limb epithelial cell CL1001111
    CSI 2.39
    rCSI 3.39%
    PRS 91.63
  • cardiac neuron CL0010022
    CSI 2.33
    rCSI 7.46%
    PRS 92.14
  • retinal ganglion cell CL0000740
    CSI 2.27
    rCSI 5.02%
    PRS 84.37
  • BEST4+ enteroycte CL4030026
    CSI 2.21
    rCSI 2.75%
    PRS 92.52
  • kidney loop of Henle thin ascending limb epithelial cell CL1001107
    CSI 2.13
    rCSI 5.5%
    PRS 91.15
  • epicardial adipocyte CL1000309
    CSI 1.94
    rCSI 6.32%
    PRS 90.72
  • differentiation-committed oligodendrocyte precursor CL4023059
    CSI 1.82
    rCSI 3.31%
    PRS 87.78
  • Bergmann glial cell CL0000644
    CSI 1.78
    rCSI 2.44%
    PRS 86.84
  • renal beta-intercalated cell CL0002201
    CSI 1.7
    rCSI 4.06%
    PRS 93.39
  • retinal cone cell CL0000573
    CSI 1.63
    rCSI 2.63%
    PRS 86.33
  • suprabasal keratinocyte CL4033013
    CSI 1.63
    rCSI 2.67%
    PRS 66.85
  • kidney connecting tubule epithelial cell CL1000768
    CSI 1.62
    rCSI 4.1%
    PRS 88.43
  • near-projecting glutamatergic cortical neuron CL4023012
    CSI 1.54
    rCSI 5.83%
    PRS 82.7
  • L2/3-6 intratelencephalic projecting glutamatergic neuron CL4023040
    CSI 1.47
    rCSI 3.57%
    PRS 80.41
  • forebrain radial glial cell CL0013000
    CSI 1.36
    rCSI 4.35%
    PRS 92.74
  • L5/6 near-projecting glutamatergic neuron CL4030067
    CSI 1.31
    rCSI 4.32%
    PRS 83.36
  • regular atrial cardiac myocyte CL0002129
    CSI 1.24
    rCSI 3.98%
    PRS 89.87
  • L6b glutamatergic cortical neuron CL4023038
    CSI 1.1
    rCSI 3.45%
    PRS 83.6
  • enteroglial cell CL4040002
    CSI 0.83
    rCSI 4.38%
    PRS 93.18
  • corticothalamic-projecting glutamatergic cortical neuron CL4023013
    CSI 0.66
    rCSI 3.91%
    PRS 82.87
  • central nervous system neuron CL2000029
    CSI 0.51
    rCSI 3.75%
    PRS 86.48

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

Explore relationships of the current gene. Select an Interaction Source: 'ONTOLOGY' for shared pathways (GO/Reactome) or 'STRING' for protein-protein interactions. Further refine by selecting context genes and comparing Cell Significance Index (CSI) scores between baseline and target cell types and their specific contexts.

Comma-separated if multiple.
Comma-separated if multiple.
Legend:
  • Query Gene
  • Node Color (Target Cell CSI, relative to current network):
    • Very High
    • High
    • Medium
    • Low
    • Very Low
    • CSI N/A
  • Node Size: Proportional to Target Cell CSI magnitude
  • STRING PPI Edge
  • Shared Pathway Edge (ONTOLOGY)

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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 [CA3](/details-gene/761) encodes Carbonic Anhydrase 3, a member of the zinc metalloenzyme family responsible for the reversible hydration of carbon dioxide. Located on chromosome 8q21.2, this enzyme is historically associated with high expression in muscle tissue ([Link](https://pubmed.ncbi.nlm.nih.gov/3086182/), [Link](https://pubmed.ncbi.nlm.nih.gov/2824285/)). However, a broader analysis reveals its significance extends to metabolically active and specialized cell types in other tissues. **Overall**, [CA3](/details-gene/761) is a significant marker in [pulmonary alveolar type 2 cell](/details-cell/CL0002063), specific neuronal subtypes like the [lamp5 GABAergic cortical interneuron](/details-cell/CL4023011), and various mesenchymal cells including lung fibroblasts and muscle cells. Its primary function is tied to regulating intracellular pH and facilitating carbon dioxide transport, essential processes in these diverse cellular environments. A clinical association with this gene has been noted ([114750](https://omim.org/entry/114750)). ## Cellular Roles and Expression Landscape The expression profile of [CA3](/details-gene/761) highlights its importance in cells with high metabolic demands or specialized homeostatic functions. **Overall**, the gene shows the highest significance in [pulmonary alveolar type 2 cell](/details-cell/CL0002063) (CSI: 12.59), suggesting a critical role in the lung, potentially related to surfactant production, CO2 handling at the air-liquid interface, or cellular metabolism. A second major expression domain is within mesenchymal and structural tissues. [CA3](/details-gene/761) is a prominent marker in [alveolar type 1 fibroblast cell](/details-cell/CL4028004) (CSI: 9.61) and [fibroblast of lung](/details-cell/CL0002553) (CSI: 8.89), which may indicate a role in maintaining the lung interstitium. Consistent with early reports ([Link](https://doi.org/10.1073/pnas.83.24.9571)), it is also highly significant in various [muscle cell](/details-cell/CL0000187) types, including [fast muscle cell](/details-cell/CL0000190) and [slow muscle cell](/details-cell/CL0000189), where its enzymatic activity is likely crucial for managing the pH shifts associated with intense metabolic activity. Expression is also noted in [chondrocyte](/details-cell/CL0000138) and [cardiac muscle cell](/details-cell/CL0000746). Interestingly, [CA3](/details-gene/761) also demonstrates high significance in specific neuronal and glial populations. It is a key marker for the [lamp5 GABAergic cortical interneuron](/details-cell/CL4023011) (CSI: 10.76) and also shows relevance in [Schwann cell](/details-cell/CL0002573) and retinal [Mueller cell](/details-cell/CL0000636). This suggests a specialized role in regulating pH and ion balance within distinct microenvironments of the nervous system. Finally, its expression in liver cells, such as [hepatic stellate cell](/details-cell/CL0000632) and [hepatocyte](/details-cell/CL0000182), aligns with the liver's central metabolic role. ## Pathways and Molecular Function The function of [CA3](/details-gene/761) is primarily defined by its enzymatic activity. According to Gene Ontology annotations, its core molecular function is [carbonate dehydratase activity](/details-go/GO:0004089), which involves catalysis of the reaction CO2 + H2O ⇌ H+ + HCO3-. This function is central to the Reactome pathway [Reversible hydration of carbon dioxide](/details-pathway/R-HSA-1475029) and contributes broadly to [Metabolism](/details-pathway/R-HSA-1430728). As a metalloenzyme, its activity depends on cofactors, reflected in annotations for [zinc ion binding](/details-go/GO:0008270) and [nickel cation binding](/details-go/GO:0016151). Biologically, this enzymatic activity supports several key processes. It is integral to the [one-carbon metabolic process](/details-go/GO:0006730), which is fundamental for biosynthesis and cellular metabolism. This is consistent with its high expression in metabolically active cells like [hepatocyte](/details-cell/CL0000182) and [muscle cell](/details-cell/CL0000187). An annotation for [response to bacterium](/details-go/GO:0009617) suggests a potential, less-characterized role in cellular responses during infection, possibly through pH modulation in the cellular environment. Functionally, [CA3](/details-gene/761) is localized to the [cytoplasm](/details-go/GO:0005737) and [cytosol](/details-go/GO:0005829), where it can readily regulate intracellular pH. ## Research Directions The diverse, yet specific, expression pattern of [CA3](/details-gene/761) opens several avenues for future research, particularly concerning its role beyond muscle physiology. The high significance in cell types of the lung and central nervous system warrants further investigation. **Testable Hypotheses:** 1. Given its high significance in both [pulmonary alveolar type 2 cell](/details-cell/CL0002063) and [alveolar type 1 fibroblast cell](/details-cell/CL4028004), [CA3](/details-gene/761) may play a crucial role in the lung's response to injury. It is hypothesized that [CA3](/details-gene/761) expression is dysregulated during the development of pulmonary fibrosis, where it contributes to the altered metabolic and pH environment that promotes fibroblast activation and extracellular matrix deposition. 2. The high and specific expression of [CA3](/details-gene/761) in [lamp5 GABAergic cortical interneuron](/details-cell/CL4023011), a cell type involved in regulating cortical circuits, is a novel finding. It is hypothesized that [CA3](/details-gene/761) is essential for maintaining pH homeostasis in these interneurons during periods of high synaptic activity, thereby influencing their firing properties and the overall excitatory/inhibitory balance in the cortex. **Proposed Experimental Approach:** To test the second hypothesis regarding the role of [CA3](/details-gene/761) in cortical interneurons, a multi-step approach could be employed. First, co-localization studies using multiplex in situ hybridization or immunohistochemistry on human brain tissue would confirm the specific expression of [CA3](/details-gene/761) protein/mRNA within LAMP5-positive interneurons. Subsequently, a conditional knockout mouse model could be generated to specifically delete [CA3](/details-gene/761) in this neuronal subpopulation. Brain slices from these mice could then be analyzed using patch-clamp electrophysiology to measure changes in intrinsic firing properties, synaptic integration, and resilience to pH challenges compared to control animals. **Therapeutic Potential:** As an enzyme, [CA3](/details-gene/761) is a druggable target. The broad family of carbonic anhydrase inhibitors is already used clinically for conditions like glaucoma and altitude sickness. While [CA3](/details-gene/761) is known to be less sensitive to classical sulfonamide inhibitors than other isoforms ([Link](https://doi.org/10.1021/bi050610h)), isoform-specific inhibitors could be developed. If [CA3](/details-gene/761) is found to be overexpressed and functionally important in pathological conditions such as pulmonary fibrosis or certain cancers, targeted **inhibition** could represent a viable therapeutic strategy to normalize the cellular pH environment and impede disease progression. The development of such specific inhibitors would be critical to avoid off-target effects associated with inhibiting other, more ubiquitously expressed carbonic anhydrase isoforms.

Genular Protein ID: 3184628330

Symbol: CAH3_HUMAN

Name: N/A

UniProtKB Accession Codes:

P07451 B2R867 B3KUC8 O60842

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BRENDA 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CTD 1 ChEBI 8 ChEMBL 1 ChiTaRS 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 15 DrugCentral 1 EC 2 EMBL 7 Ensembl 1 EvolutionaryTrace 1 ExpressionAtlas 1 GO 7 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyGen 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 4 KEGG 1 MANE-Select 1 MIM 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 5 PDBsum 5 PIR 1 PRO 1 PROSITE 2 PathwayCommons 1 PaxDb 1 PeptideAtlas 1 Pfam 1 PharmGKB 1 Pharos 1 PhosphoSitePlus 1 PhylomeDB 1 Proteomes 1 ProteomicsDB 1 RNAct 1 Reactome 1 RefSeq 1 Rhea 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 TreeFam 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 neXtProt 1

Citations:

PubMed ID: 3086182

Title: Nucleotide sequence and derived amino acid sequence of a cDNA encoding human muscle carbonic anhydrase.

PubMed ID: 3086182

DOI: 10.1016/0378-1119(86)90103-4

PubMed ID: 3099285

Title: Nucleotide sequence, tissue-specific expression, and chromosome location of human carbonic anhydrase III: the human CAIII gene is located on the same chromosome as the closely linked CAI and CAII genes.

PubMed ID: 3099285

DOI: 10.1073/pnas.83.24.9571

PubMed ID: 14702039

Title: Complete sequencing and characterization of 21,243 full-length human cDNAs.

PubMed ID: 14702039

DOI: 10.1038/ng1285

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: 2824285

Title: Human muscle carbonic anhydrase: gene structure and DNA methylation patterns in fetal and adult tissues.

PubMed ID: 2824285

DOI: 10.1101/gad.1.6.594

PubMed ID: 9651514

Title: Sequence comparisons and functional studies of the proximal promoter of the carbonic anhydrase 3 (CA3) gene.

PubMed ID: 9651514

DOI: 10.1016/s0378-1119(98)00201-7

PubMed ID: 19186056

Title: A thiabendazole sulfonamide shows potent inhibitory activity against mammalian and nematode alpha-carbonic anhydrases.

PubMed ID: 19186056

DOI: 10.1016/j.bmcl.2009.01.038

PubMed ID: 19206230

Title: Non-zinc mediated inhibition of carbonic anhydrases: coumarins are a new class of suicide inhibitors.

PubMed ID: 19206230

DOI: 10.1021/ja809683v

PubMed ID: 18618712

Title: Crystal structure of human carbonic anhydrase XIII and its complex with the inhibitor acetazolamide.

PubMed ID: 18618712

DOI: 10.1002/prot.22144

PubMed ID: 24275569

Title: An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome.

PubMed ID: 24275569

DOI: 10.1016/j.jprot.2013.11.014

PubMed ID: 16042381

Title: Human carbonic anhydrase III: structural and kinetic study of catalysis and proton transfer.

PubMed ID: 16042381

DOI: 10.1021/bi050610h

PubMed ID: 17427958

Title: Structural and kinetic analysis of proton shuttle residues in the active site of human carbonic anhydrase III.

PubMed ID: 17427958

DOI: 10.1002/prot.21403

Sequence Information:

  • Length: 260
  • Mass: 29557
  • Checksum: A305334167233FCF
  • Sequence:
    • MAKEWGYASH NGPDHWHELF PNAKGENQSP VELHTKDIRH DPSLQPWSVS YDGGSAKTIL 
NNGKTCRVVF DDTYDRSMLR GGPLPGPYRL RQFHLHWGSS DDHGSEHTVD GVKYAAELHL 
VHWNPKYNTF KEALKQRDGI AVIGIFLKIG HENGEFQIFL DALDKIKTKG KEAPFTKFDP 
SCLFPACRDY WTYQGSFTTP PCEECIVWLL LKEPMTVSSD QMAKLRSLLS SAENEPPVPL 
VSNWRPPQPI NNRVVRASFK