Alternative titles; symbols
HGNC Approved Gene Symbol: ADORA1
Cytogenetic location: 1q32.1 Genomic coordinates (GRCh38): 1:203,127,726-203,167,405 (from NCBI)
The adenosine A1 receptor (ADORA1), in conjunction with its physiologic ligand adenosine, affects neuronal excitability, synaptic plasticity, and release of neurotransmitters (summary by Jaberi et al., 2016).
Diverse physiologic effects of adenosine were recognized as early as the 1920s (Drury and Szent-Gyorgyi, 1929; Berne, 1963). Once released, adenosine activates adenosine receptors, which in turn regulate a diverse set of physiologic functions including cardiac rate and contractility, smooth muscle tone, sedation, release of neurotransmitters, platelet function, lipolysis, renal function, and white blood cell function. Stiles (1992) reviewed the structure and function of adenosine receptors important in the mediation of these multiple effects. Also see adenosine A2 receptor (ADORA2A; 102776). Libert et al. (1991) obtained cDNA clones for 4 receptors of the G protein-coupled receptor family by selective amplification of cloning from thyroid cDNA and termed them RDC1 (VIPR1; 192321), RDC4 (HTR1D; 182133), RDC7, and RDC8 (ADORA2A). RDC7 and RDC8 were identified as A1 and A2 adenosine receptors, respectively.
Allegrucci et al. (2000) reviewed the role of the A1 adenosine receptor in the fertilization process. A1 adenosine receptors are ubiquitously expressed in the central nervous system, with high expression in the cerebral cortex, hippocampus, cerebellum, thalamus, and brainstem. They are also widely distributed in peripheral tissues such as vas deferens, testis, adipose tissue, stomach, spleen, pituitary, adrenal, heart, liver, eye, bladder, lung, kidney, and intestine. The variability of the primary sequence of the A1 receptor is less than 10% in dog, rat, and cow. Bovine and human A1AR sequences differ less than 5%. These differences, although minimal, seem to be sufficient to cause interspecies differences in ligand binding and in the desensitization mechanism. Mammalian spermatozoa express ADORA1. Immunostaining experiments in human sperm cells showed a localization of ADORA1 in the acrosomal domain, the equatorial segment, and the middle piece. Human sperm ADORA1 is functionally active. A1-specific agonists induce calcium release and transient inositol 1,4,5-triphosphate (IP3) increase. Moreover, a capacitative effect on uncapacitated human spermatozoa was detected, whereas a small, although significant, increase of acrosome reaction rate was observed in capacitated spermatozoa. ADORA1 is highly colocalized with adenosine deaminase (ADA; 608958), which seems to be necessary for the high affinity binding of agonists.
By in situ hybridization, Libert et al. (1991) assigned the RDC7 gene to chromosome 22q11.2-q13.1. However, using fluorescence in situ hybridization, Townsend-Nicholson et al. (1995) demonstrated that the ADORA1 gene is located on chromosome 1q32.1.
Adenosine is an important mediator of ethanol intoxication and exerts some of its effects via the A1 adenosine receptor in the central nervous system. In vitro, acute ethanol exposure increases extracellular adenosine levels by inhibiting the nucleoside transporter ENT1 (602193); chronic ethanol exposure results in a decrease of ENT1 expression (Nagy et al., 1990). Choi et al. (2004) found that Ent1-null mice showed reduced hypnotic and ataxic responses to ethanol and increased voluntary ethanol self-administration compared to wildtype littermates. These features were associated with a decrease in the activation of A1 receptors in the nucleus accumbens. Treatment with an A1 receptor agonist reduced ethanol consumption in the Ent1-null mice. These findings supported a role for ENT1 in ethanol-mediated behaviors and suggested that decreased A1 receptor function promotes alcohol consumption.
Associations Pending Confirmation
For discussion of a possible association between variation in the ADORA1 gene and early-onset parkinsonism with cognitive dysfunction (see, e.g., PARK16, 613164), see 102775.0001.
Sun et al. (2001) used homologous recombination to generate viable mice without gross behavioral or anatomic defects that were deficient in the 2-exon A1ar gene, which encodes a protein 87% identical to the human protein. Tubuloglomerular feedback (TGF), the vasoconstriction of afferent arterioles resulting from an increase in NaCl concentration at the macula densa cells of the distal nephron, was abolished in these knockout mice. The authors concluded that adenosine acts as the major mediator of the renal TGF response.
In a model of adenosine-mediated pulmonary injury involving Ada-deficient mice, Sun et al. (2005) found that A1ar transcript levels were elevated in the lungs, particularly in alveolar macrophages. Ada/A1ar double knockout mice developed increased pulmonary inflammation, mucus metaplasia, and alveolar destruction, in association with increased expression of cytokines, chemokines, and matrix metalloproteinases. Sun et al. (2005) concluded that A1ar plays an antiinflammatory and/or protective role in the pulmonary phenotype seen in Ada-deficient mice and suggested that A1AR signaling may regulate the severity of the pulmonary inflammation and remodeling seen in chronic lung disease.
This variant is classified as a variant of unknown significance because its contribution to early-onset Parkinson disease and cognitive dysfunction has not been confirmed.
In 2 brothers, born of consanguineous Iranian parents, with early-onset parkinsonism and cognitive dysfunction, Jaberi et al. (2016) identified a homozygous c.835G-A transition in the ADORA1 gene, resulting in a gly279-to-ser (G279S) substitution at a highly conserved residue in transmembrane 7. The mutation, which was found by a combination of homozygosity mapping and exome sequencing, was confirmed by Sanger sequencing and segregated with the disorder in the family. It was filtered against the dbSNP, 1000 Genomes Project, Exome Variant Server, and ExAC databases, and was found only once in heterozygous state among all these databases. The mutation was not found in 700 Iranian controls. In vitro functional expression studies in HEK293 cells showed that the G279S variant did not disrupt proper expression or localization of the protein, or affect its interaction with the DRD1 receptor (126449). Jaberi et al. (2016) noted that the ADORA1 gene is within the PARK16 locus (613164) on chromosome 1q32. However, screening of 100 additional patients with early-onset parkinson disease did not identify any other ADORA1 variants. The patients had onset of foot dragging and abnormal gait in their twenties. Neurologic examination showed features of parkinsonism, as well as spasticity and a distal axonal sensorimotor neuropathy. The patients had onset of psychomotor retardation in childhood and had cognitive impairment as adults; 1 was reported as having severe mental retardation. The brother who underwent exome sequencing also carried a homozygous missense variant in the PTRHD1 gene (617342.0001). Segregation and functional studies of the PTRHD1 variant were not pursued because the ADORA1 gene was considered to be the likely candidate due to its previously reported role in neurologic functions.
Allegrucci, C., Liguori, L., Mezzasoma, I., Minelli, A. A1 adenosine receptor in human spermatozoa: its role in the fertilization process. Molec. Genet. Metab. 71: 381-386, 2000. [PubMed: 11001830] [Full Text: https://doi.org/10.1006/mgme.2000.3054]
Berne, R. M. Cardiac nucleotides in hypoxia: possible role in regulation of coronary blood flow. Am. J. Physiol. 204: 317-322, 1963. [PubMed: 13971060] [Full Text: https://doi.org/10.1152/ajplegacy.1963.204.2.317]
Choi, D.-S., Cascini, M.-G., Mailliard, W., Young, H., Paredes, P., McMahon, T., Diamond, I., Bonci, A., Messing, R. O. The type 1 equilibrative nucleoside transporter regulates ethanol intoxication and preference. Nature Neurosci. 7: 855-861, 2004. [PubMed: 15258586] [Full Text: https://doi.org/10.1038/nn1288]
Drury, A. N., Szent-Gyorgyi, A. The physiological activity of adenine compounds with especial reference to their action upon the mammalian heart. J. Physiol. 68: 213-237, 1929. [PubMed: 16994064] [Full Text: https://doi.org/10.1113/jphysiol.1929.sp002608]
Jaberi, E., Rohani, M., Shahidi, G. A., Nafissi, S., Arefian, E., Soleimani, M., Moghadam, A., Arzenani, M. K., Keramatian, F., Klotzle, B., Fan, J.-B., Turk, C., Steemers, F., Elahi, E. Mutation in ADORA1 identified as likely cause of early-onset parkinsonism and cognitive dysfunction. Mov. Disord. 31: 1004-1011, 2016. [PubMed: 27134041] [Full Text: https://doi.org/10.1002/mds.26627]
Libert, F., Passage, E., Parmentier, M., Simons, M.-J., Vassart, G., Mattei, M.-G. Chromosomal mapping of A1 and A2 adenosine receptors, VIP receptor, and a new subtype of serotonin receptor. Genomics 11: 225-227, 1991. Note: Erratum: Genomics 23: 305 only, 1994. [PubMed: 1662665] [Full Text: https://doi.org/10.1016/0888-7543(91)90125-x]
Nagy, L. E., Diamond, I., Casso, D. J., Franklin, C., Gordon, A. S. Ethanol increases extracellular adenosine by inhibiting adenosine uptake via the nucleoside transporter. J. Biol. Chem. 265: 1946-1951, 1990. [PubMed: 2298733]
Stiles, G. L. Adenosine receptors. J. Biol. Chem. 267: 6451-6454, 1992. [PubMed: 1551861]
Sun, C.-X., Young, H. W., Molina, J. G., Volmer, J. B., Schnermann, J., Blackburn, M. R. A protective role for the A1 adenosine receptor in adenosine-dependent pulmonary injury. J. Clin. Invest. 115: 35-43, 2005. [PubMed: 15630442] [Full Text: https://doi.org/10.1172/JCI22656]
Sun, D., Samuelson, L. C., Yang, T., Huang, Y., Paliege, A., Saunders, T., Briggs, J., Schnermann, J. Mediation of tubuloglomerular feedback by adenosine: evidence from mice lacking adenosine 1 receptors. Proc. Nat. Acad. Sci. 98: 9983-9988, 2001. [PubMed: 11504952] [Full Text: https://doi.org/10.1073/pnas.171317998]
Townsend-Nicholson, A., Baker, E., Schofield, P. R., Sutherland, G. R. Localization of the adenosine A1 receptor subtype gene (ADORA1) to chromosome 1q32.1. Genomics 26: 423-425, 1995. [PubMed: 7601478] [Full Text: https://doi.org/10.1016/0888-7543(95)80236-f]