Adenosine A1 receptor explained

The adenosine A1 receptor (A1AR) [1] is one member of the adenosine receptor group of G protein-coupled receptors with adenosine as endogenous ligand.

Biochemistry

A1 receptors are implicated in sleep promotion by inhibiting wake-promoting cholinergic neurons in the basal forebrain.[2] A1 receptors are also present in smooth muscle throughout the vascular system.[3]

The adenosine A1 receptor has been found to be ubiquitous throughout the entire body.

Signaling

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.[4]

Effect

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.

Ligands

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

Agonists

((R)-tetrahydrofuran-3-ylamino)-9H-purin-9-yl)-tetrashydrofuran3,4-diol) [5]

PAMs

Antagonists

Non-selective
Selective

In the heart

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

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).[5] Specifically, A1 receptor activation leads to inactivation of the inwardly rectifying K+ current and inhibition of the inward Ca2+ current (ICa) andthe 'funny' hyperpolarization-activated current (If).[13] Adenosine agonism of A1ARs also inhibits release of norepinephrine from cardiac nerves.[14] Norepinephrine is a positive chronotrope, inotrope, and dromotrope, through its agonism of β adrenergic receptors on pacemaker cells and ventricular myocytes.[15] [16]

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. 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.

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.[17] 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.[18]

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.[19] Excess A1AR expression can induce cardiomyopathy, cardiac dilatation, and cardiac hypertrophy.[20] Cardiac failure may involve increased A1AR expression and decreased adenosine in physical models of cardiac overload and in dysfunction induced by TNFα.[21] 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.[22] [23]

External links

Notes and References

  1. Townsend-Nicholson A, Baker E, Schofield PR, Sutherland GR . Localization of the adenosine A1 receptor subtype gene (ADORA1) to chromosome 1q32.1 . Genomics . 26 . 2 . 423–425 . March 1995 . 7601478 . 10.1016/0888-7543(95)80236-F . Grant Robert Sutherland .
  2. Elmenhorst D, Meyer PT, Winz OH, Matusch A, Ermert J, Coenen HH, Basheer R, Haas HL, Zilles K, Bauer A . Sleep deprivation increases A1 adenosine receptor binding in the human brain: a positron emission tomography study . The Journal of Neuroscience . 27 . 9 . 2410–2415 . February 2007 . 17329439 . 6673478 . 10.1523/JNEUROSCI.5066-06.2007 . free .
  3. Tawfik HE, Schnermann J, Oldenburg PJ, Mustafa SJ . Role of A1 adenosine receptors in regulation of vascular tone . American Journal of Physiology. Heart and Circulatory Physiology . 288 . 3 . H1411–H1416 . March 2005 . 15539423 . 10.1152/ajpheart.00684.2004 . 916788 .
  4. Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J . International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors . Pharmacological Reviews . 53 . 4 . 527–552 . December 2001 . 11734617 . 9389454 .
  5. Headrick JP, Peart JN, Reichelt ME, Haseler LJ . Adenosine and its receptors in the heart: regulation, retaliation and adaptation . Biochimica et Biophysica Acta (BBA) - Biomembranes . 1808 . 5 . 1413–1428 . May 2011 . 21094127 . 10.1016/j.bbamem.2010.11.016 . 10072/35871. free .
  6. Wall MJ, Hill E, Huckstepp R, Barkan K, Deganutti G, Leuenberger M, Preti B, Winfield I, Carvalho S, Suchankova A, Wei H, Safitri D, Huang X, Imlach W, La Mache C, Dean E, Hume C, Hayward S, Oliver J, Zhao FY, Spanswick D, Reynolds CA, Lochner M, Ladds G, Frenguelli BG . Selective activation of Gαob by an adenosine A1 receptor agonist elicits analgesia without cardiorespiratory depression . Nature Communications . 13 . 1 . 4150 . July 2022 . 35851064 . 9293909 . 10.1038/s41467-022-31652-2 . 2022NatCo..13.4150W .
  7. Romagnoli R, Baraldi PG, IJzerman AP, Massink A, Cruz-Lopez O, Lopez-Cara LC, Saponaro G, Preti D, Aghazadeh Tabrizi M, Baraldi S, Moorman AR, Vincenzi F, Borea PA, Varani K . 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 . September 2014 . 25181013 . 10.1021/jm5008853 .
  8. Gottlieb SS, Brater DC, Thomas I, Havranek E, Bourge R, Goldman S, Dyer F, Gomez M, Bennett D, Ticho B, Beckman E, Abraham WT . BG9719 (CVT-124), an A1 adenosine receptor antagonist, protects against the decline in renal function observed with diuretic therapy . Circulation . 105 . 11 . 1348–1353 . March 2002 . 11901047 . 10.1161/hc1102.105264 . 14866962 .
  9. Greenberg B, Thomas I, Banish D, Goldman S, Havranek E, Massie BM, Zhu Y, Ticho B, Abraham WT . 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 . August 2007 . 17692744 . 10.1016/j.jacc.2007.03.059 . 37858957 .
  10. Givertz MM, Massie BM, Fields TK, Pearson LL, Dittrich HC . 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 . October 2007 . 17936154 . 10.1016/j.jacc.2007.07.019 .
  11. Cotter G, Dittrich HC, Weatherley BD, Bloomfield DM, O'Connor CM, Metra M, Massie BM . 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 . October 2008 . 18926433 . 10.1016/j.cardfail.2008.08.010 .
  12. Val C, Rodríguez-García C, Prieto-Díaz R, Crespo A, Azuaje J, Carbajales C, Majellaro M, Díaz-Holguín A, Brea JM, Loza MI, Gioé-Gallo C, Contino M, Stefanachi A, García-Mera X, Estévez JC, Gutiérrez-de-Terán H, Sotelo E . Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A1 Antagonists . Journal of Medicinal Chemistry . 65 . 3 . 2091–2106 . February 2022 . 35068155 . 8842224 . 10.1021/acs.jmedchem.1c01636 .
  13. Belardinelli L, Shryock JC, Song Y, Wang D, Srinivas M . Ionic basis of the electrophysiological actions of adenosine on cardiomyocytes . FASEB Journal . 9 . 5 . 359–365 . March 1995 . 7896004 . 10.1096/fasebj.9.5.7896004 . free . 26061166 .
  14. Lorbar M, Chung ES, Nabi A, Skalova K, Fenton RA, Dobson JG, Meyer TE . Receptors subtypes involved in adenosine-mediated modulation of norepinephrine release from cardiac nerve terminals . Canadian Journal of Physiology and Pharmacology . 82 . 11 . 1026–1031 . November 2004 . 15644943 . 10.1139/y04-108 .
  15. Chan SA, Vaseghi M, Kluge N, Shivkumar K, Ardell JL, Smith C . 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 . May 2020 . 32216617 . 10.1152/ajpheart.00574.2019 . 7346543 .
  16. Lakatta EG . Beyond Bowditch: the convergence of cardiac chronotropy and inotropy . Cell Calcium . 35 . 6 . 629–642 . June 2004 . 15110153 . 10.1016/j.ceca.2004.01.017 .
  17. Maeda T, Koos BJ . 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 . March 2009 . 19118101 . 2665841 . 10.1152/ajpregu.90363.2008 .
  18. Fraser H, Lopaschuk GD, Clanachan AS . 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 . September 1999 . 10498852 . 1571606 . 10.1038/sj.bjp.0702765 .
  19. Perlini S, Arosio B, Parmeggiani L, Santambrogio D, Palladini G, Tozzi R, Gatti C, Annoni G, Meyer TE, Ferrari AU . Adenosine A1 receptor expression during the transition from compensated pressure overload hypertrophy to heart failure . Journal of Hypertension . 25 . 2 . 449–454 . February 2007 . 17211253 . 10.1097/HJH.0b013e3280110de3 . 36575444 .
  20. Funakoshi H, Chan TO, Good JC, Libonati JR, Piuhola J, Chen X, MacDonnell SM, Lee LL, Herrmann DE, Zhang J, Martini J, Palmer TM, Sanbe A, Robbins J, Houser SR, Koch WJ, Feldman AM . 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 . November 2006 . 17088462 . 10.1161/CIRCULATIONAHA.106.620211 . 37115831 . free .
  21. Funakoshi H, Zacharia LC, Tang Z, Zhang J, Lee LL, Good JC, Herrmann DE, Higuchi Y, Koch WJ, Jackson EK, Chan TO, Feldman AM . A1 adenosine receptor upregulation accompanies decreasing myocardial adenosine levels in mice with left ventricular dysfunction . Circulation . 115 . 17 . 2307–2315 . May 2007 . 17438146 . 10.1161/CIRCULATIONAHA.107.694596 . 31096844 . free .
  22. Yuan K, Bai GY, Park WH, Kim SZ, Kim SH . Stimulation of ANP secretion by 2-Cl-IB-MECA through A(3) receptor and CaMKII . Peptides . 29 . 12 . 2216–2224 . December 2008 . 18838091 . 10.1016/j.peptides.2008.09.003 . 12321885 .
  23. Yuan K, Cao C, Han JH, Kim SZ, Kim SH . Adenosine-stimulated atrial natriuretic peptide release through A1 receptor subtype . Hypertension . 46 . 6 . 1381–1387 . December 2005 . 16286581 . 10.1161/01.HYP.0000190041.61737.fd . 21514416 . free .

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