AliasesADORA1, RDC7, adenosine A1 receptor
External IDsOMIM: 102775 MGI: 99401 HomoloGene: 20165 GeneCards: ADORA1
RefSeq (mRNA)


RefSeq (protein)



Location (UCSC)Chr 1: 203.09 – 203.17 MbChr 1: 134.13 – 134.16 Mb
PubMed search[3][4]
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The adenosine A1 receptor (A1AR) [5] is one member of the adenosine receptor group of G protein-coupled receptors with adenosine as endogenous ligand.


A1 receptors are implicated in sleep promotion by inhibiting wake-promoting cholinergic neurons in the basal forebrain.[6] A1 receptors are also present in smooth muscle throughout the vascular system.[7]

The adenosine A1 receptor has been found to be ubiquitous throughout the entire body.[citation needed]


Activation of the adenosine A1 receptor by an agonist causes binding of Gi1/2/3 or Go protein. Binding of Gi1/2/3 causes an inhibition of adenylate cyclase and, therefore, a decrease in the cAMP concentration. An increase of the inositol triphosphate/diacylglycerol concentration is caused by an activation of phospholipase C, whereas the elevated levels of arachidonic acid are mediated by DAG lipase, which cleaves DAG to form arachidonic acid. Several types of potassium channels are activated but N-, P-, and Q-type calcium channels are inhibited.[8]


This receptor has an inhibitory function on most of the tissues in which it rests. In the brain, it slows metabolic activity by a combination of actions. At the neuron's synapse, it reduces synaptic vesicle release.[citation needed]


Caffeine, as well as theophylline, has been found to antagonize both A1 and A2A receptors in the brain.[citation needed]


((R)-tetrahydrofuran-3-ylamino)-9H-purin-9-yl)-tetrashydrofuran3,4-diol) [9]




In the heart

In the heart, A1 receptors play roles in electrical pacing (chronotropy and dromotropy), fluid balance, local sympathetic regulation, and metabolism.[9]

When bound by adenosine, A1 receptors inhibit impulses generated in supraventricular tissue (SA node, AV node) and the Bundle of His/Purkinje system, leading to negative chronotropy (slowing of the heart rate).[9] Specifically, A1 receptor activation leads to inactivation of the inwardly rectifying K+ current and inhibition of the inward Ca2+ current (ICa) and the 'funny' hyperpolarization-activated current (If).[17] Adenosine agonism of A1ARs also inhibits release of norepinephrine from cardiac nerves.[18] Norepinephrine is a positive chronotrope, inotrope, and dromotrope, through its agonism of β adrenergic receptors on pacemaker cells and ventricular myocytes.[19][20]

Collectively, these mechanisms lead to an myocardial depressant effect by decreasing the conduction of electrical impulses and suppressing pacemaker cells function, resulting in a decrease in heart rate. This makes adenosine a useful medication for treating and diagnosing tachyarrhythmias, or excessively fast heart rates. This effect on the A1 receptor also explains why there is a brief moment of cardiac standstill when adenosine is administered as a rapid IV push during cardiac resuscitation.[citation needed] The rapid infusion causes a momentary myocardial stunning effect.

In normal physiological states, this serves as protective mechanisms. However, in altered cardiac function, such as hypoperfusion caused by hypotension, heart attack or cardiac arrest caused by nonperfusing bradycardias, adenosine has a negative effect on physiological functioning by preventing necessary compensatory increases in heart rate and blood pressure that attempt to maintain cerebral perfusion.[citation needed]

Metabolically, A1AR activation by endogenous adenosine across the body reduces plasma glucose, lactate, and insulin levels, however A2aR activation increased glucose and lactate levels to an extent greater than the A1AR effect on glucose and lactate.[21] Thus, intravascular administration of adenosine increases the amount of glucose and lactate available in the blood for cardiac myocytes. A1AR activation also partially inhibits glycolysis, slowing its rate to align with oxidative metabolism, which limits post-ischemic damage through reduced H+ generation.[22]

In the state of myocardial hypertrophy and remodeling, interstitial adenosine and the expression of the A1AR receptor are both increased. After transition to heart failure however, overexpression of A1AR is no longer present.[23] Excess A1AR expression can induce cardiomyopathy, cardiac dilatation, and cardiac hypertrophy.[24] Cardiac failure may involve increased A1AR expression and decreased adenosine in physical models of cardiac overload and in dysfunction induced by TNFα.[25] Heart failure often involves secretion of atrial natriuretic peptide to compensate for reduced renal perfusion and thus, secretion of electrolytes. A1AR activation also increases secretion of atrial natriuretic peptide from atrial myocytes.[26][27]


  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000163485Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000042429Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Townsend-Nicholson A, Baker E, Schofield PR, Sutherland GR (March 1995). "Localization of the adenosine A1 receptor subtype gene (ADORA1) to chromosome 1q32.1". Genomics. 26 (2): 423–425. doi:10.1016/0888-7543(95)80236-F. PMID 7601478.
  6. ^ Elmenhorst D, Meyer PT, Winz OH, Matusch A, Ermert J, Coenen HH, et al. (February 2007). "Sleep deprivation increases A1 adenosine receptor binding in the human brain: a positron emission tomography study". The Journal of Neuroscience. 27 (9): 2410–2415. doi:10.1523/JNEUROSCI.5066-06.2007. PMC 6673478. PMID 17329439.
  7. ^ Tawfik HE, Schnermann J, Oldenburg PJ, Mustafa SJ (March 2005). "Role of A1 adenosine receptors in regulation of vascular tone". American Journal of Physiology. Heart and Circulatory Physiology. 288 (3): H1411–H1416. doi:10.1152/ajpheart.00684.2004. PMID 15539423. S2CID 916788.
  8. ^ Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J (December 2001). "International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors". Pharmacological Reviews. 53 (4): 527–552. PMC 9389454. PMID 11734617.
  9. ^ a b c d e Headrick JP, Peart JN, Reichelt ME, Haseler LJ (May 2011). "Adenosine and its receptors in the heart: regulation, retaliation and adaptation". Biochimica et Biophysica Acta (BBA) - Biomembranes. 1808 (5): 1413–1428. doi:10.1016/j.bbamem.2010.11.016. hdl:10072/35871. PMID 21094127.
  10. ^ Wall MJ, Hill E, Huckstepp R, Barkan K, Deganutti G, Leuenberger M, et al. (July 2022). "Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression". Nature Communications. 13 (1): 4150. Bibcode:2022NatCo..13.4150W. doi:10.1038/s41467-022-31652-2. PMC 9293909. PMID 35851064.
  11. ^ Romagnoli R, Baraldi PG, IJzerman AP, Massink A, Cruz-Lopez O, Lopez-Cara LC, et al. (September 2014). "Synthesis and biological evaluation of novel allosteric enhancers of the A1 adenosine receptor based on 2-amino-3-(4'-chlorobenzoyl)-4-substituted-5-arylethynyl thiophene". Journal of Medicinal Chemistry. 57 (18): 7673–7686. doi:10.1021/jm5008853. PMID 25181013.
  12. ^ Gottlieb SS, Brater DC, Thomas I, Havranek E, Bourge R, Goldman S, et al. (March 2002). "BG9719 (CVT-124), an A1 adenosine receptor antagonist, protects against the decline in renal function observed with diuretic therapy". Circulation. 105 (11): 1348–1353. doi:10.1161/hc1102.105264. PMID 11901047. S2CID 14866962.
  13. ^ Greenberg B, Thomas I, Banish D, Goldman S, Havranek E, Massie BM, et al. (August 2007). "Effects of multiple oral doses of an A1 adenosine antagonist, BG9928, in patients with heart failure: results of a placebo-controlled, dose-escalation study". Journal of the American College of Cardiology. 50 (7): 600–606. doi:10.1016/j.jacc.2007.03.059. PMID 17692744. S2CID 37858957.
  14. ^ Givertz MM, Massie BM, Fields TK, Pearson LL, Dittrich HC (October 2007). "The effects of KW-3902, an adenosine A1-receptor antagonist,on diuresis and renal function in patients with acute decompensated heart failure and renal impairment or diuretic resistance". Journal of the American College of Cardiology. 50 (16): 1551–1560. doi:10.1016/j.jacc.2007.07.019. PMID 17936154.
  15. ^ Cotter G, Dittrich HC, Weatherley BD, Bloomfield DM, O'Connor CM, Metra M, et al. (October 2008). "The PROTECT pilot study: a randomized, placebo-controlled, dose-finding study of the adenosine A1 receptor antagonist rolofylline in patients with acute heart failure and renal impairment". Journal of Cardiac Failure. 14 (8): 631–640. doi:10.1016/j.cardfail.2008.08.010. PMID 18926433.
  16. ^ Val C, Rodríguez-García C, Prieto-Díaz R, Crespo A, Azuaje J, Carbajales C, et al. (February 2022). "Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A1 Antagonists". Journal of Medicinal Chemistry. 65 (3): 2091–2106. doi:10.1021/acs.jmedchem.1c01636. PMC 8842224. PMID 35068155.
  17. ^ Belardinelli L, Shryock JC, Song Y, Wang D, Srinivas M (March 1995). "Ionic basis of the electrophysiological actions of adenosine on cardiomyocytes". FASEB Journal. 9 (5): 359–365. doi:10.1096/fasebj.9.5.7896004. PMID 7896004. S2CID 26061166.
  18. ^ Lorbar M, Chung ES, Nabi A, Skalova K, Fenton RA, Dobson JG, et al. (November 2004). "Receptors subtypes involved in adenosine-mediated modulation of norepinephrine release from cardiac nerve terminals". Canadian Journal of Physiology and Pharmacology. 82 (11): 1026–1031. doi:10.1139/y04-108. PMID 15644943.
  19. ^ Chan SA, Vaseghi M, Kluge N, Shivkumar K, Ardell JL, Smith C (May 2020). "Fast in vivo detection of myocardial norepinephrine levels in the beating porcine heart". American Journal of Physiology. Heart and Circulatory Physiology. 318 (5): H1091–H1099. doi:10.1152/ajpheart.00574.2019. PMC 7346543. PMID 32216617.
  20. ^ Lakatta EG (June 2004). "Beyond Bowditch: the convergence of cardiac chronotropy and inotropy". Cell Calcium. 35 (6): 629–642. doi:10.1016/j.ceca.2004.01.017. PMID 15110153.
  21. ^ Maeda T, Koos BJ (March 2009). "Adenosine A1 and A2a receptors modulate insulinemia, glycemia, and lactatemia in fetal sheep". American Journal of Physiology. Regulatory, Integrative and Comparative Physiology. 296 (3): R693–R701. doi:10.1152/ajpregu.90363.2008. PMC 2665841. PMID 19118101.
  22. ^ Fraser H, Lopaschuk GD, Clanachan AS (September 1999). "Alteration of glycogen and glucose metabolism in ischaemic and post-ischaemic working rat hearts by adenosine A1 receptor stimulation". British Journal of Pharmacology. 128 (1): 197–205. doi:10.1038/sj.bjp.0702765. PMC 1571606. PMID 10498852.
  23. ^ Perlini S, Arosio B, Parmeggiani L, Santambrogio D, Palladini G, Tozzi R, et al. (February 2007). "Adenosine A1 receptor expression during the transition from compensated pressure overload hypertrophy to heart failure". Journal of Hypertension. 25 (2): 449–454. doi:10.1097/HJH.0b013e3280110de3. PMID 17211253. S2CID 36575444.
  24. ^ Funakoshi H, Chan TO, Good JC, Libonati JR, Piuhola J, Chen X, et al. (November 2006). "Regulated overexpression of the A1-adenosine receptor in mice results in adverse but reversible changes in cardiac morphology and function". Circulation. 114 (21): 2240–2250. doi:10.1161/CIRCULATIONAHA.106.620211. PMID 17088462. S2CID 37115831.
  25. ^ Funakoshi H, Zacharia LC, Tang Z, Zhang J, Lee LL, Good JC, et al. (May 2007). "A1 adenosine receptor upregulation accompanies decreasing myocardial adenosine levels in mice with left ventricular dysfunction". Circulation. 115 (17): 2307–2315. doi:10.1161/CIRCULATIONAHA.107.694596. PMID 17438146. S2CID 31096844.
  26. ^ Yuan K, Bai GY, Park WH, Kim SZ, Kim SH (December 2008). "Stimulation of ANP secretion by 2-Cl-IB-MECA through A(3) receptor and CaMKII". Peptides. 29 (12): 2216–2224. doi:10.1016/j.peptides.2008.09.003. PMID 18838091. S2CID 12321885.
  27. ^ Yuan K, Cao C, Han JH, Kim SZ, Kim SH (December 2005). "Adenosine-stimulated atrial natriuretic peptide release through A1 receptor subtype". Hypertension. 46 (6): 1381–1387. doi:10.1161/01.HYP.0000190041.61737.fd. PMID 16286581. S2CID 21514416.