Details for: ADRA2A

Gene ID: 150

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: ADRA2A

Ensembl ID: ENSG00000150594

Description: adrenoceptor alpha 2A

Selected Context(s):  Overall

Cell Significance Landscape

Contexts:

Associated with

Significant Cells

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

  • progenitor cell CL0011026
    CSI 7.51
    rCSI 15.96%
    PRS 92.14
  • microcirculation associated smooth muscle cell CL0008035
    CSI 5.42
    rCSI 15.69%
    PRS 95.8
  • epithelial cell of lower respiratory tract CL0002632
    CSI 5.11
    rCSI 3.96%
    PRS 97.57
  • perivascular cell CL4033054
    CSI 4.97
    rCSI 6.79%
    PRS 97.83
  • glutamatergic neuron CL0000679
    CSI 4.03
    rCSI 8.29%
    PRS 88.07
  • stem cell CL0000034
    CSI 3.31
    rCSI 3.19%
    PRS 94.45
  • BEST4+ enteroycte CL4030026
    CSI 2.97
    rCSI 3.69%
    PRS 95.38
  • vascular associated smooth muscle cell CL0000359
    CSI 2.94
    rCSI 9.55%
    PRS 95.68
  • sst GABAergic cortical interneuron CL4023017
    CSI 2.88
    rCSI 3.71%
    PRS 90.08
  • megakaryocyte-erythroid progenitor cell CL0000050
    CSI 2.74
    rCSI 2.48%
    PRS 95.79
  • pancreatic ductal cell CL0002079
    CSI 2.2
    rCSI 4.29%
    PRS 96.43
  • intestinal crypt stem cell of small intestine CL0009017
    CSI 1.97
    rCSI 5.32%
    PRS 96.84
  • peripheral nervous system neuron CL2000032
    CSI 1.91
    rCSI 2.61%
    PRS 92.59
  • Cajal-Retzius cell CL0000695
    CSI 1.1
    rCSI 8.62%
    PRS 96.16
  • bronchial goblet cell CL1000312
    CSI 1.04
    rCSI 4.16%
    PRS 97.5
  • L6b glutamatergic cortical neuron CL4023038
    CSI 0.7
    rCSI 2.19%
    PRS 90.05
  • respiratory goblet cell CL0002370
    CSI 0.5
    rCSI 5.39%
    PRS 97.4
  • paneth cell of colon CL0009009
    CSI 0.47
    rCSI 4.58%
    PRS 97.06
  • blood vessel smooth muscle cell CL0019018
    CSI 0.46
    rCSI 3.74%
    PRS 95.51

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.

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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 [ADRA2A](/details-gene/150) encodes the alpha-2A adrenergic receptor, a member of the G protein-coupled receptor (GPCR) superfamily. This receptor is a critical mediator of the physiological effects of catecholamines, primarily norepinephrine and epinephrine. Functionally, it acts predominantly through G(i) proteins to inhibit adenylate cyclase, leading to decreased intracellular cAMP levels and subsequent modulation of downstream signaling cascades. Its expression profile indicates a significant role in the nervous system, vascular smooth muscle regulation, and progenitor cell populations. The **Overall** expression data highlights [ADRA2A](/details-gene/150) as a top significance marker in '[progenitor cell](/details-cell/CL0011026)', '[microcirculation associated smooth muscle cell](/details-cell/CL0008035)', and '[epithelial cell of lower respiratory tract](/details-cell/CL0002632)', underscoring its broad involvement in cellular homeostasis, development, and tissue-specific functions. Clinically, mutations in [ADRA2A](/details-gene/150) have been associated with conditions such as atypical familial partial lipodystrophy, as reported in OMIM ([104210](https://omim.org/entry/104210)). ## Cellular Roles and Expression Landscape The expression pattern of [ADRA2A](/details-gene/150) reveals its multifaceted roles across diverse cell lineages. **Overall**, its most significant expression is observed in '[progenitor cell](/details-cell/CL0011026)' (CSI: 7.51) and '[stem cell](/details-cell/CL0000034)' (CSI: 3.31), including more specific populations like '[megakaryocyte-erythroid progenitor cell](/details-cell/CL0000050)' and '[intestinal crypt stem cell of small intestine](/details-cell/CL0009017)'. This suggests a fundamental role for adrenergic signaling in regulating cell fate decisions, proliferation, or the maintenance of undifferentiated states. A second major functional axis for [ADRA2A](/details-gene/150) is the regulation of vascular tone. It is highly significant in '[microcirculation associated smooth muscle cell](/details-cell/CL0008035)' (CSI: 5.42) and '[vascular associated smooth muscle cell](/details-cell/CL0000359)' (CSI: 2.94), consistent with its well-established role in mediating vasoconstriction in response to sympathetic stimulation. Its presence in '[perivascular cell](/details-cell/CL4033054)' further supports its involvement in blood flow regulation. Thirdly, [ADRA2A](/details-gene/150) is a key component of the nervous system. Its significance in '[glutamatergic neuron](/details-cell/CL0000679)' (CSI: 4.03), '[sst GABAergic cortical interneuron](/details-cell/CL4023017)' (CSI: 2.88), and '[peripheral nervous system neuron](/details-cell/CL2000032)' (CSI: 1.91) points to its function as a presynaptic autoreceptor that provides negative feedback to inhibit further neurotransmitter release, thereby modulating synaptic transmission. Finally, notable expression in secretory and epithelial tissues, such as '[epithelial cell of lower respiratory tract](/details-cell/CL0002632)' and '[pancreatic ductal cell](/details-cell/CL0002079)', suggests roles in processes like fluid secretion and hormone regulation, particularly the inhibition of insulin release from the pancreas. ## Pathways and Molecular Function The functions of [ADRA2A](/details-gene/150) are primarily executed through its role as a G(i)-coupled receptor. This is captured by its annotation in Reactome pathways such as '[Adrenaline signalling through alpha-2 adrenergic receptor](https://reactome.org/content/detail/R-HSA-392023)' and '[G alpha (i) signalling events](https://reactome.org/content/detail/R-HSA-418594)'. Upon binding ligands like epinephrine ([GO:0051379](https://www.ebi.ac.uk/QuickGO/term/GO:0051379)) or norepinephrine ([GO:0051380](https://www.ebi.ac.uk/QuickGO/term/GO:0051380)), the receptor inhibits adenylate cyclase, a process central to its function ([GO:0007193](https://www.ebi.ac.uk/QuickGO/term/GO:0007193)). This central mechanism underlies its diverse physiological effects. Its expression in vascular smooth muscle is directly linked to its role in the '[Regulation of vasoconstriction](https://www.ebi.ac.uk/QuickGO/term/GO:0019229)'. In the context of pancreatic cells, it drives the '[Negative regulation of insulin secretion](https://www.ebi.ac.uk/QuickGO/term/GO:0046676)', a key process in '[Glucose homeostasis](https://www.ebi.ac.uk/QuickGO/term/GO:0042593)'. In the nervous system, its localization to the '[Presynaptic active zone membrane](https://www.ebi.ac.uk/QuickGO/term/GO:0048787)' is consistent with its role in the '[Presynaptic modulation of chemical synaptic transmission](https://www.ebi.ac.uk/QuickGO/term/GO:0099171)'. Furthermore, [ADRA2A](/details-gene/150) is a key player in hemostasis, as evidenced by its involvement in '[Platelet activation](https://www.ebi.ac.uk/QuickGO/term/GO:0030168)' and '[Platelet activation, signaling and aggregation](https://reactome.org/content/detail/R-HSA-76002)', a function first highlighted by early cloning studies ([Link](https://doi.org/10.1126/science.2823383)). Mutations in this gene have been identified in cases of atypical familial partial lipodystrophy, suggesting a role in metabolic regulation beyond glucose control ([Link](https://doi.org/10.1172/jci.insight.86870)). ## Research Directions The widespread expression of [ADRA2A](/details-gene/150) in critical cell types, particularly progenitors, presents several avenues for future research. The data suggests that beyond its classical roles in neurotransmission and vascular control, adrenergic signaling may be a fundamental regulator of cell fate and tissue homeostasis. ### Proposed Hypotheses: 1. Given its exceptionally high significance in '[progenitor cell](/details-cell/CL0011026)', [ADRA2A](/details-gene/150) signaling acts as a critical brake on differentiation in multiple stem cell niches. Activation of the receptor by endogenous catecholamines may maintain cells in a quiescent or undifferentiated state, and its downregulation is a prerequisite for lineage commitment. 2. The known role of [ADRA2A](/details-gene/150) in inhibiting lipolysis, combined with its association with lipodystrophy ([Link](https://doi.org/10.1172/jci.insight.86870)), suggests that overactive [ADRA2A](/details-gene/150) signaling in adipose-derived stem cells or preadipocytes impairs their terminal differentiation, leading to a failure to form and maintain healthy adipose tissue. 3. In the context of the respiratory system, [ADRA2A](/details-gene/150) expression in '[epithelial cell of lower respiratory tract](/details-cell/CL0002632)' may regulate mucociliary clearance and ion transport. Dysregulation of this receptor could contribute to the pathophysiology of diseases characterized by airway dehydration or excessive mucus production, such as cystic fibrosis or chronic bronchitis. ### Key Experimental Approach: To test the hypothesis regarding the role of [ADRA2A](/details-gene/150) in adipocyte differentiation (Hypothesis 2), a robust experimental plan could be implemented. Primary human adipose-derived stem cells (ADSCs) would be cultured and induced to differentiate into mature adipocytes. A parallel group of ADSCs would be transduced with lentiviral vectors expressing either a short hairpin RNA (shRNA) to knock down [ADRA2A](/details-gene/150) or a constitutively active mutant of the receptor. Differentiation efficiency would be quantified by Oil Red O staining for lipid accumulation and by qRT-PCR for key adipogenic transcription factors (e.g., *PPARG*, *CEBPA*) and mature adipocyte markers (e.g., *ADIPOQ*, *FABP4*). Further, metabolic function could be assessed by measuring glucose uptake and lipolysis rates in response to insulin and isoproterenol, respectively. This would directly test whether [ADRA2A](/details-gene/150) activity level is a critical determinant of adipogenesis. ### Therapeutic Potential: [ADRA2A](/details-gene/150) is already a successful therapeutic target. Agonists like clonidine and dexmedetomidine are used clinically as antihypertensives and sedatives by acting on central autoreceptors to reduce sympathetic outflow. The data suggests new therapeutic applications. Given its role in negatively regulating insulin secretion and lipolysis, selective [ADRA2A](/details-gene/150) **inhibition** represents a promising strategy for treating metabolic disorders. An antagonist could potentially enhance insulin release and promote healthy lipid storage, making it a candidate for treating type 2 diabetes or specific forms of lipodystrophy. As a cell surface GPCR, it is highly druggable with small molecules, offering a well-established path for drug development.

Genular Protein ID: 1283291309

Symbol: ADA2A_HUMAN

Name: Alpha-2 adrenergic receptor subtype C10

UniProtKB Accession Codes:

P08913 B0LPF6 Q2I8G2 Q2XN99 Q86TH8 Q9BZK1

Database IDs:

AGR 1 AlphaFoldDB 1 Antibodypedia 1 BMRB 1 Bgee 1 BindingDB 1 BioGRID 1 BioGRID-ORCS 1 BioMuta 1 CCDS 1 CDD 1 CORUM 1 CTD 1 ChEMBL 1 ChiTaRS 1 DIP 1 DMDM 1 DNASU 1 DisGeNET 1 DrugBank 101 DrugCentral 1 EMBL 13 EMDB 7 Ensembl 1 EvolutionaryTrace 1 GO 64 Gene3D 1 GeneCards 1 GeneTree 1 GeneWiki 1 GenomeRNAi 1 GlyCosmos 1 GlyGen 1 GuidetoPHARMACOLOGY 1 HGNC 1 HOGENOM 1 HPA 1 InParanoid 1 IntAct 1 InterPro 4 KEGG 1 MANE-Select 1 MIM 3 MalaCards 1 MassIVE 1 NCBI Taxonomy 1 OMA 1 OpenTargets 1 OrthoDB 1 PANTHER 2 PDB 13 PDBsum 13 PIR 1 PRINTS 3 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 6 RefSeq 1 SIGNOR 1 SMART 1 SMR 1 STRING 1 SUPFAM 1 SignaLink 1 SwissPalm 1 TCDB 1 TreeFam 1 UCSC 1 VEuPathDB 1 eggNOG 1 iPTMnet 1 jPOST 1 neXtProt 1

Citations:

PubMed ID: 2568356

Title: Cloning, sequence analysis, and permanent expression of a human alpha 2-adrenergic receptor in Chinese hamster ovary cells. Evidence for independent pathways of receptor coupling to adenylate cyclase attenuation and activation.

PubMed ID: 2568356

DOI: 10.1016/s0021-9258(18)80130-2

PubMed ID: 2170371

Title: Cloning, sequencing, and expression of the gene encoding the porcine alpha 2-adrenergic receptor. Allosteric modulation by Na+, H+, and amiloride analogs.

PubMed ID: 2170371

DOI: 10.1016/s0021-9258(17)44904-0

PubMed ID: 16567612

Title: Complex haplotypes derived from noncoding polymorphisms of the intronless alpha-2A-adrenergic gene diversify receptor expression.

PubMed ID: 16567612

DOI: 10.1073/pnas.0601345103

PubMed ID: 15164054

Title: The DNA sequence and comparative analysis of human chromosome 10.

PubMed ID: 15164054

DOI: 10.1038/nature02462

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: 2823383

Title: Cloning, sequencing, and expression of the gene coding for the human platelet alpha 2-adrenergic receptor.

PubMed ID: 2823383

DOI: 10.1126/science.2823383

PubMed ID: 10948191

Title: An Asn to Lys polymorphism in the third intracellular loop of the human alpha 2A-adrenergic receptor imparts enhanced agonist-promoted Gi coupling.

PubMed ID: 10948191

DOI: 10.1074/jbc.m004550200

PubMed ID: 1849485

Title: Identification of an additional gene belonging to the alpha 2 adrenergic receptor family in the human genome by PCR.

PubMed ID: 1849485

DOI: 10.1016/0014-5793(91)80301-i

PubMed ID: 1678390

Title: A point mutation in the seventh hydrophobic domain of the alpha 2 adrenergic receptor increases its affinity for a family of beta receptor antagonists.

PubMed ID: 1678390

DOI: 10.1016/s0021-9258(18)98642-4

PubMed ID: 1678850

Title: Site-directed mutagenesis of alpha 2a-adrenergic receptors: Identification of amino acids involved in ligand binding and receptor activation by agonists.

PubMed ID: 1678850

PubMed ID: 23105096

Title: Rab26 modulates the cell surface transport of alpha2-adrenergic receptors from the Golgi.

PubMed ID: 23105096

DOI: 10.1074/jbc.m112.410936

PubMed ID: 11888275

Title: NMR structure of the second intracellular loop of the alpha 2A adrenergic receptor: evidence for a novel cytoplasmic helix.

PubMed ID: 11888275

DOI: 10.1021/bi015811+

PubMed ID: 27376152

Title: Whole-exome sequencing identifies ADRA2A mutation in atypical familial partial lipodystrophy.

PubMed ID: 27376152

DOI: 10.1172/jci.insight.86870

Sequence Information:

  • Length: 465
  • Mass: 50647
  • Checksum: 585E576149BDB696
  • Sequence:
    • MFRQEQPLAE GSFAPMGSLQ PDAGNASWNG TEAPGGGARA TPYSLQVTLT LVCLAGLLML 
LTVFGNVLVI IAVFTSRALK APQNLFLVSL ASADILVATL VIPFSLANEV MGYWYFGKAW 
CEIYLALDVL FCTSSIVHLC AISLDRYWSI TQAIEYNLKR TPRRIKAIII TVWVISAVIS 
FPPLISIEKK GGGGGPQPAE PRCEINDQKW YVISSCIGSF FAPCLIMILV YVRIYQIAKR 
RTRVPPSRRG PDAVAAPPGG TERRPNGLGP ERSAGPGGAE AEPLPTQLNG APGEPAPAGP 
RDTDALDLEE SSSSDHAERP PGPRRPERGP RGKGKARASQ VKPGDSLPRR GPGATGIGTP 
AAGPGEERVG AAKASRWRGR QNREKRFTFV LAVVIGVFVV CWFPFFFTYT LTAVGCSVPR 
TLFKFFFWFG YCNSSLNPVI YTIFNHDFRR AFKKILCRGD RKRIV