Alternative titles; symbols
HGNC Approved Gene Symbol: ADRA2A
Cytogenetic location: 10q25.2 Genomic coordinates (GRCh38): 10:111,077,029-111,080,907 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 10q25.2 | ?Lipodystrophy, familial partial, type 8 | 620679 | Autosomal dominant | 3 |
The ADRA2A gene encodes the main presynaptic inhibitory feedback G protein-coupled receptor regulating norepinephrine release. Activation of ADRA2A inhibits cAMP production and reduces lipolysis in adipocytes (summary by Garg et al., 2016).
A variety of neurotransmitter and hormone receptors elicit their responses through biochemical pathways that involve transduction elements known as guanine nucleotide regulatory (G) proteins. Among these are several types of receptors for epinephrine (adrenaline), which are termed adrenergic receptors. The alpha-2-adrenergic receptors inhibit adenylate cyclase (summary by Kobilka et al., 1987).
Kobilka et al. (1987) cloned the gene for the human platelet alpha-2-adrenergic receptor by using oligonucleotides corresponding to the partial amino acid sequence of the purified receptor. The deduced protein contains 450 amino acids. The protein sequence is most similar to those of human beta-2- and beta-1-adrenergic receptors. The greatest homology is found in the 7 putative transmembrane-spanning domains. Similarities to the muscarinic cholinergic receptors are also evident.
Garg et al. (2016) found that mRNA expression of ADRA2A was increased by 9-fold and 17-fold in human intraabdominal and subcutaneous abdominal adipose tissue, respectively, compared to ADRA2C (104250). ADRA2B (104260) was undetectable in these tissues. ADRA2A expression was about 2-fold higher in subcutaneous abdominal fat compared with intraabdominal fat.
Kobilka et al. (1987) showed that the coding block of the ADRAR gene is contained within a single exon.
Yang-Feng et al. (1987) mapped the ADRAR locus to 10q23-q25 by somatic cell hybridization and in situ hybridization. Hoehe et al. (1988) identified a DraI RFLP of the ADRAR gene.
Stumpf (2024) mapped the ADRA2A gene to chromosome 10q25.2 based on an alignment of the ADRA2A sequence (GenBank AF262016) with the genomic sequence (GRCh38).
By study of interspecific backcrosses, Oakey et al. (1991) assigned the Adra2r gene to the distal region of mouse chromosome 19.
An aspartic acid residue at position 79 is highly conserved among G protein-coupled receptors. Surprenant et al. (1992) found that when asp79 was mutated to asparagine, cells transfected with the mutant adrenoceptor showed inhibition of adenylyl cyclase and calcium currents by agonists but did not increase potassium currents. Because distinct G proteins appear to couple adrenoceptors to potassium and calcium currents, the findings suggested that the mutant adrenoceptor could not achieve the conformation necessary to activate G proteins that mediate potassium channel activation.
Xu et al. (2003) presented evidence that ADRA2A and ADRB1 (109630) form heterodimers when coexpressed in cultured cells, and that ADRA2A expression affects the internalization and ligand-binding characteristics of ADRB1.
Using congenic strains from the diabetic Goto-Kakizaki rat, Rosengren et al. (2010) identified a 1.4-Mb genomic locus that was linked to impaired insulin granule docking at the plasma membrane and reduced beta-cell exocytosis. In this locus, Adra2a was significantly overexpressed. The alpha-2A-adrenergic receptor mediates adrenergic suppression of insulin secretion. Pharmacologic receptor antagonism, silencing of receptor expression, or blockade of downstream effectors rescued insulin secretion in congenic islets.
Familial Partial Lipodystrophy Type 8
In 3 affected members of an African American family (family FPLD 122) with familial partial lipodystrophy, type 8 (FPLD8; 620679), Garg et al. (2016) identified a heterozygous missense mutation in the ADRA2A gene (L68F; 104210.0001). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Two clinically unaffected children (3 and 8 years of age) who were younger than the age of symptom onset also carried the mutation. The mutation was not present in the ExAC or dbSNP databases. Expression of the mutation in HEK293 cells showed that the mutant ADRA2A protein was expressed and localized normally to the plasma membrane, but caused slightly increased cAMP production compared to wildtype. Differentiated adipose cells (3T3-L1) transfected with the mutation had a higher rate of basal lipolysis compared to controls, as evidenced by glycerol release. Synthesis of cAMP and lipolysis in cells carrying the mutation were resistant to suppression by clonidine and not sensitive to yohimbine, suggesting that the mutation results in a loss of function. The findings suggested that excessive lipolysis from certain adipose tissue deposits is the main mechanism causing the disorder.
Associations Pending Confirmation
Halperin et al. (1997) reported a significant increase in plasma norepinephrine in attention-deficit hyperactivity disorder (ADHD; 143465) children with reading and other cognitive disabilities compared to ADHD children without learning disabilities (LD). Comings et al. (1999) examined the hypothesis that ADHD with or without LD is associated with dysfunction at a molecular genetic level by testing for associations and additive effects between polymorphisms at 3 noradrenergic genes: the adrenergic alpha-2A receptor (ADRA2A), adrenergic alpha-2C receptor (ADRA2C; 104250), and dopamine beta-hydroxylase (DBH; 223360) genes. A total of 336 subjects (274 individuals with Tourette syndrome (137580) and 62 normal controls) were genotyped. Regression analysis showed a significant correlation between scores for ADHD, a history of LD, and poor grade-school academic performance that was greatest for the additive effect of all 3 genes. Combined, these 3 genes accounted for 3.5% of the variance of the ADHD score (p = 0.0005). There was a significant increase in the number of variant norepinephrine genes progressing from subjects without ADHD (A-) or learning disabilities (LD-) to A+/LD- to A-/LD+ to A+/LD+ (p = 0.0017), but no comparable effect for dopamine genes. These data supported an association between norepinephrine genes and ADHD, especially in ADHD subjects with LD.
In a Brazilian sample of 92 ADHD patients and their biologic parents, Roman et al. (2003) studied the -1291C-G SNP (rs1800544) that was previously reported by Comings et al. (1999) to be associated with ADHD scores, particularly inattention scores. No association was observed through the Haplotype Relative Risk method, although an influence of the GG genotype on inattention and combined ADHD scores was detected. To further investigate the -1291C-G SNP, Roman et al. (2006) studied a new sample of 128 Brazilian ADHD probands. Patients were genotyped and symptoms for each ADHD cluster (inattention, hyperactivity/impulsivity, and combined) were obtained. An association with inattention symptoms was again detected in individuals with the GG genotype (p = 0.017).
Rosengren et al. (2010) identified a single-nucleotide polymorphism in the human ADRA2A gene, rs553668, for which risk allele carriers exhibited overexpression of alpha-2A-adrenergic receptor, reduced insulin secretion, and increased type 2 diabetes risk. Human pancreatic islets from risk allele carriers exhibited reduced granule docking and secreted less insulin in response to glucose; both effects were counteracted by pharmacologic alpha-2A-adrenergic receptor antagonists.
Alpha-2-adrenergic receptors have a critical role in regulating neurotransmitter release from sympathetic nerves and from adrenergic neurons in the central nervous system. To help elucidate the individual roles of the 3 highly homologous alpha-2-adrenergic receptors (ADRA2A; ADRA2B, 104260; and ADRA2C) in this process, Hein et al. (1999) studied neurotransmitter release in mice in which the genes encoding the 3 alpha-2-adrenergic receptor subtypes were disrupted. Hein et al. (1999) demonstrated that both the ADRA2A and ADRA2C subtypes are required for normal presynaptic control of transmitter release from sympathetic nerves in the heart and from central noradrenergic neurons. ADRA2A receptors inhibited transmitter release at high stimulation frequencies, whereas the ADRA2C subtype modulated neurotransmission at lower levels of nerve activity. Both low and high frequency regulation seemed to be physiologically important, as mice lacking both ADRA2A and ADRA2C receptor subtypes had elevated plasma noradrenaline concentrations and developed cardiac hypertrophy with decreased left ventricular contractility by 4 months of age.
A substantial percentage of human pregnancies are lost as spontaneous abortions after implantation. This is often caused by an inadequately developed placenta. Proper development of the placental vascular system is essential to nutrient and gas exchange between mother and developing embryo. Philipp et al. (2002) showed that alpha-2-adrenoceptors, which are activated by adrenaline and noradrenaline, are important regulators of placental structure and function. Mice with deletions in the genes Adra2a, Adra2b, and Adra2c died between embryonic days 9.5 and 11.5 from a severe defect in yolk-sac and placenta development. In wildtype placentae, alpha-2-adrenoceptors are abundantly expressed in giant cells, which secrete angiogenic factors to initiate development of the placental vascular labyrinth. In placentae deficient in the 3 adrenoceptors encoded by the 3 genes deleted in these mice, the density of fetal blood vessels in the labyrinth was markedly lower than normal, leading to death of the embryos as a result of reduced oxygen and nutrient supply. Basal phosphorylation of the extracellular signal-regulated kinases ERK1 (601795) and ERK2 (176948) was also lower than normal, suggesting that activation of the mitogen-activated protein kinase (MAP kinase) pathway by alpha-2-adrenoceptors is required for placenta and yolk-sac vascular development. Thus, alpha-2-adrenoceptors are essential at the placental interface between mother and embryo to establish the circulatory system of the placenta and thus maintain pregnancy.
In 3 affected members of an African American family (family FPLD 122) with familial partial lipodystrophy type 8 (FPLD8; 620679), Garg et al. (2016) identified a heterozygous c.202C-T transition (c.202C-T, NM_000681.3) in the ADRA2A gene, resulting in a leu68-to-phe (L68F) substitution at a highly conserved residue in the first transmembrane domain. The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Two clinically unaffected children (3 and 8 years of age) who were younger than the age of symptom onset also carried the mutation. The mutation was not present in the ExAC or dbSNP databases. In vitro functional expression studies in cells transfected with the mutation showed that the mutant protein was expressed and localized normally to the plasma membrane, but resulted in increased cAMP production and increased lipolysis compared to controls, and showed resistance to the ADRA2A agonist clonidine and the antagonist yohimbine. The findings were consistent with a loss-of-function effect.
Comings, D. E., Gade-Andavolu, R., Gonzalez, N., Blake, H., Wu, S., MacMurray, J. P. Additive effect of three noradrenergic genes (ADRA2A, ADRA2C, DBH) on attention-deficit hyperactivity disorder and learning disabilities in Tourette syndrome subjects. Clin. Genet. 55: 160-172, 1999. [PubMed: 10334470] [Full Text: https://doi.org/10.1034/j.1399-0004.1999.550304.x]
Garg, A., Sankella, S., Xing, C., Agarwal, A. K. Whole-exome sequencing identifies ADRA2A mutation in atypical familial partial lipodystrophy. JCI Insight 1: e86870, 2016. [PubMed: 27376152] [Full Text: https://doi.org/10.1172/jci.insight.86870]
Halperin, J. M., Newcorn, J. H., Koda, V. H., Pick, L., McKay, K. E., Knott, P. Noradrenergic mechanisms in ADHD children with and without reading disabilities: a replication and extension. J. Am. Acad. Child Adolesc. Psychiat. 36: 1688-1697, 1997. [PubMed: 9401330] [Full Text: https://doi.org/10.1097/00004583-199712000-00017]
Hein, L., Altman, J. D., Kobilka, B. K. Two functionally distinct alpha-2-adrenergic receptors regulate sympathetic neurotransmission. Nature 402: 181-184, 1999. [PubMed: 10647009] [Full Text: https://doi.org/10.1038/46040]
Hoehe, M., Berrettini, W., Leppert, M., Lalouel, J.-M., Byerley, W., Gershon, E., White, R. Genetic mapping of adrenergic receptor genes. (Abstract) Am. J. Hum. Genet. 45 (suppl.): A143 only, 1989.
Hoehe, M. R., Berrettini, W. H., Lentes, K.-U. Dra I identifies a two allele DNA polymorphism in the human alpha-2-adrenergic receptor gene (ADRAR), using a 5.5 kb probe (p ADRAR). Nucleic Acids Res. 16: 9070 only, 1988. [PubMed: 2902571] [Full Text: https://doi.org/10.1093/nar/16.18.9070]
Kobilka, B. K., Matsui, H., Kobilka, T. S., Yang-Feng, T. L., Francke, U., Caron, M. G., Lefkowitz, R. J., Regan, J. W. Cloning, sequencing, and expression of the gene coding for the human platelet alpha-2-adrenergic receptor. Science 238: 650-656, 1987. [PubMed: 2823383] [Full Text: https://doi.org/10.1126/science.2823383]
Oakey, R. J., Caron, M. G., Lefkowitz, R. J., Seldin, M. F. Genomic organization of adrenergic and serotonin receptors in the mouse: linkage mapping of sequence-related genes provides a method for examining mammalian chromosome evolution. Genomics 10: 338-344, 1991. [PubMed: 1676978] [Full Text: https://doi.org/10.1016/0888-7543(91)90317-8]
Philipp, M., Brede, M. E., Hadamek, K., Gessler, M., Lohse, M. J., Hein, L. Placental alpha-2-adrenoceptors control vascular development at the interface between mother and embryo. Nature Genet. 31: 311-315, 2002. [PubMed: 12068299] [Full Text: https://doi.org/10.1038/ng919]
Roman, T., Polanczyk, G. V., Zeni, C., Genro, J. P., Rohde, L. A., Hutz, M. H. Further evidence of the involvement of alpha-2A-adrenergic receptor gene (ADRA2A) in inattentive dimensional scores of attention-deficit/hyperactivity disorder. Molec. Psychiat. 11: 8-10, 2006. [PubMed: 16172611] [Full Text: https://doi.org/10.1038/sj.mp.4001743]
Roman, T., Schmitz, M., Polanczyk, G. V., Eizirik, M., Rhode, L. A., Hutz, M. H. Is the alpha-2A adrenergic receptor gene (ADRA2A) associated with attention-deficit/hyperactivity disorder? Am. J. Med. Genet. 120B: 116-120, 2003. [PubMed: 12815749] [Full Text: https://doi.org/10.1002/ajmg.b.20018]
Rosengren, A. H., Jokubka, R., Tojjar, D., Granhall, C., Hansson, O., Li, D.-Q., Nagaraj, V., Reinbothe, T. M., Tuncel, J., Eliasson, L., Groop, L., Rorsman, P., Salehi, A., Lyssenko, V., Luthman, H., Renstrom, E. Overexpression of alpha2A-adrenergic receptors contributes to type 2 diabetes. Science 327: 217-220, 2010. [PubMed: 19965390] [Full Text: https://doi.org/10.1126/science.1176827]
Stumpf, A. M. Personal Communication. Baltimore, Md. 01/18/2024.
Surprenant, A., Horstman, D. A., Akbarali, H., Limbird, L. E. A point mutation of the alpha-2-adrenoceptor that blocks coupling to potassium but not calcium currents. Science 257: 977-980, 1992. [PubMed: 1354394] [Full Text: https://doi.org/10.1126/science.1354394]
Xu, J., He, J., Castleberry, A. M., Balasubramanian, S., Lau, A. G., Hall, R. A. Heterodimerization of alpha-2A- and beta-1-adrenergic receptors. J. Biol. Chem. 278: 10770-10777, 2003. [PubMed: 12529373] [Full Text: https://doi.org/10.1074/jbc.M207968200]
Yang-Feng, T. L., Kobilka, B. K., Caron, M. G., Lefkowitz, R. J., Francke, U. Chromosomal assignment of genes for an alpha-adrenergic receptor (ADRAR) and for another member of this receptor family coupled to guanine nucleotide regulatory proteins (RG21). (Abstract) Cytogenet. Cell Genet. 46: 722-723, 1987.