View source for Adenosine A1 receptor

{{Short description|Cell surface receptor found in humans}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{DISPLAYTITLE:Adenosine A<sub>1</sub> receptor}}
{{Infobox_gene}}
The '''adenosine A<sub>1</sub> receptor''' (A1AR) <ref name="pmid7601478">{{cite journal | vauthors = Townsend-Nicholson A, Baker E, Schofield PR, Sutherland GR | title = Localization of the adenosine A1 receptor subtype gene (ADORA1) to chromosome 1q32.1 | journal = Genomics | volume = 26 | issue = 2 | pages = 423–425 | date = March 1995 | pmid = 7601478 | doi = 10.1016/0888-7543(95)80236-F | author-link4 = Grant Robert Sutherland }}</ref> is one member of the [[adenosine receptor]] group of [[G protein-coupled]] receptors with [[adenosine]] as [[endogenous]] [[ligand]].

==Biochemistry==
A<sub>1</sub> receptors are implicated in sleep promotion by inhibiting wake-promoting [[cholinergic]] neurons in the [[basal forebrain]].<ref name="pmid17329439">{{cite journal | vauthors = Elmenhorst D, Meyer PT, Winz OH, Matusch A, Ermert J, Coenen HH, Basheer R, Haas HL, Zilles K, Bauer A | title = Sleep deprivation increases A1 adenosine receptor binding in the human brain: a positron emission tomography study | journal = The Journal of Neuroscience | volume = 27 | issue = 9 | pages = 2410–2415 | date = February 2007 | pmid = 17329439 | pmc = 6673478 | doi = 10.1523/JNEUROSCI.5066-06.2007 | doi-access = free }}</ref> A<sub>1</sub> receptors are also present in smooth muscle throughout the vascular system.<ref name="pmid15539423">{{cite journal | vauthors = Tawfik HE, Schnermann J, Oldenburg PJ, Mustafa SJ | title = Role of A1 adenosine receptors in regulation of vascular tone | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 288 | issue = 3 | pages = H1411–H1416 | date = March 2005 | pmid = 15539423 | doi = 10.1152/ajpheart.00684.2004 | s2cid = 916788 }}</ref>

The adenosine A<sub>1</sub> receptor has been found to be ubiquitous throughout the entire body.{{Citation needed|date=November 2023}}

==Signaling==
Activation of the adenosine A<sub>1</sub> receptor by an [[agonist]] causes binding of G<sub>i1/2/3</sub> or G<sub>o</sub> protein. Binding of G<sub>i1/2/3</sub> causes an inhibition of [[adenylate cyclase]] and, therefore, a decrease in the [[Cyclic adenosine monophosphate|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 [[Diacylglycerol lipase|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.<ref name="pmid11734617">{{cite journal | vauthors = Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J | title = International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors | journal = Pharmacological Reviews | volume = 53 | issue = 4 | pages = 527–552 | date = December 2001 | pmid = 11734617 | pmc = 9389454 }}</ref>

==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 [[Chemical synapse#Structure|synapse]], it reduces [[synaptic vesicle]] release.{{Citation needed|date=April 2023}}

==Ligands==
[[Caffeine]], as well as [[theophylline]], has been found to antagonize both A<sub>1</sub> and [[Adenosine A2A receptor|A<sub>2A</sub>]] receptors in the brain.{{Citation needed|date=November 2023}}

===Agonists===
* 2-Chloro-N(6)-cyclopentyladenosine ([[CCPA (biochemistry)|CCPA]]).{{Citation needed|date=November 2023}}
* [[N6-Cyclopentyladenosine]]{{Citation needed|date=November 2023}}
* N(6)-cyclohexyladenosine{{Citation needed|date=November 2023}}
*Tecadenoson ((2R,3S,4R)-2-(hydroxymethyl)-5-(6-
((R)-tetrahydrofuran-3-ylamino)-9H-purin-9-yl)-tetrashydrofuran3,4-diol) <ref name="pmid21094127">{{cite journal |vauthors=Headrick JP, Peart JN, Reichelt ME, Haseler LJ |title=Adenosine and its receptors in the heart: regulation, retaliation and adaptation |journal=Biochimica et Biophysica Acta (BBA) - Biomembranes |volume=1808 |issue=5 |pages=1413–1428 |date=May 2011 |pmid=21094127 |doi=10.1016/j.bbamem.2010.11.016 |hdl=10072/35871|hdl-access=free }}</ref>
* Selodenoson ((2S,3S,4R)-5-(6-(cyclopentylamino)-9Hpurin-9-yl)-N-ethyl-3,4-dihydroxytetrahydrofuran-2-carboxamide) <ref name="pmid21094127"/>
* Capadenoson (BAY68-4986) <ref name="pmid21094127"/>
* Benzyloxy-cyclopentyladenosine (BnOCPA) is an A1R selective agonist.<ref>{{cite journal | vauthors = 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 | title = Selective activation of Gαob by an adenosine A<sub>1</sub> receptor agonist elicits analgesia without cardiorespiratory depression | journal = Nature Communications | volume = 13 | issue = 1 | page = 4150 | date = July 2022 | pmid = 35851064 | pmc = 9293909 | doi = 10.1038/s41467-022-31652-2 | bibcode = 2022NatCo..13.4150W }}</ref>

=== PAMs ===
* 2‑Amino-3-(4′-chlorobenzoyl)-4-substituted-5-arylethynyl thiophene # 4e<ref name="pmid25181013">{{cite journal | vauthors = 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 | title = 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 = Journal of Medicinal Chemistry | volume = 57 | issue = 18 | pages = 7673–7686 | date = September 2014 | pmid = 25181013 | doi = 10.1021/jm5008853 | hdl = 10481/87954 | hdl-access = free }}</ref>

===Antagonists===
;Non-selective
* [[Caffeine]]
* [[Theophylline]]
* [[CGS-15943]]{{Citation needed|date=November 2023}}

;Selective
* [[8-Cyclopentyl-1,3-dimethylxanthine]] (CPX / 8-cyclopentyltheophylline){{Citation needed|date=November 2023}}
* [[8-Cyclopentyl-1,3-dipropylxanthine]] (DPCPX){{Citation needed|date=November 2023}}
* 8-Phenyl-1,3-dipropylxanthine {{Citation needed|date=November 2023}}
* [[Bamifylline]] {{Citation needed|date=November 2023}}
* BG-9719<ref name="pmid11901047">{{cite journal | vauthors = Gottlieb SS, Brater DC, Thomas I, Havranek E, Bourge R, Goldman S, Dyer F, Gomez M, Bennett D, Ticho B, Beckman E, Abraham WT | title = BG9719 (CVT-124), an A1 adenosine receptor antagonist, protects against the decline in renal function observed with diuretic therapy | journal = Circulation | volume = 105 | issue = 11 | pages = 1348–1353 | date = March 2002 | pmid = 11901047 | doi = 10.1161/hc1102.105264 | s2cid = 14866962 | doi-access =  }}</ref>
* [[Tonapofylline]] (BG-9928)<ref name="pmid17692744">{{cite journal | vauthors = Greenberg B, Thomas I, Banish D, Goldman S, Havranek E, Massie BM, Zhu Y, Ticho B, Abraham WT | title = 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 = Journal of the American College of Cardiology | volume = 50 | issue = 7 | pages = 600–606 | date = August 2007 | pmid = 17692744 | doi = 10.1016/j.jacc.2007.03.059 | s2cid = 37858957 | doi-access =  }}</ref>
* FK-453 {{Citation needed|date=November 2023}}
* FK-838 {{Citation needed|date=November 2023}}
* [[Rolofylline]] (KW-3902)<ref name="pmid17936154">{{cite journal | vauthors = Givertz MM, Massie BM, Fields TK, Pearson LL, Dittrich HC | title = 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 = Journal of the American College of Cardiology | volume = 50 | issue = 16 | pages = 1551–1560 | date = October 2007 | pmid = 17936154 | doi = 10.1016/j.jacc.2007.07.019 | doi-access =  }}</ref><ref name="pmid18926433">{{cite journal | vauthors = Cotter G, Dittrich HC, Weatherley BD, Bloomfield DM, O'Connor CM, Metra M, Massie BM | title = 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 = Journal of Cardiac Failure | volume = 14 | issue = 8 | pages = 631–640 | date = October 2008 | pmid = 18926433 | doi = 10.1016/j.cardfail.2008.08.010 }}</ref>
* N-0861 {{Citation needed|date=November 2023}}
* ISAM-CV202<ref>{{cite journal | vauthors = 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 | title = Optimization of 2-Amino-4,6-diarylpyrimidine-5-carbonitriles as Potent and Selective A<sub>1</sub> Antagonists | journal = Journal of Medicinal Chemistry | volume = 65 | issue = 3 | pages = 2091–2106 | date = February 2022 | pmid = 35068155 | pmc = 8842224 | doi = 10.1021/acs.jmedchem.1c01636 }}</ref>

==In the heart ==

In the heart, A<sub>1</sub> receptors play roles in electrical pacing ([[chronotropy]] and [[dromotropy]]), fluid balance, local sympathetic regulation, and metabolism.<ref name="pmid21094127" />

When bound by adenosine, A<sub>1</sub> receptors inhibit impulses generated in supraventricular tissue ([[SA node]], [[AV node]]) and the [[Bundle of His]]/[[Purkinje fibers|Purkinje system]], leading to negative chronotropy (slowing of the heart rate).<ref name="pmid21094127"/> Specifically, A<sub>1</sub> receptor activation leads to inactivation of the [[Inward-rectifier potassium channel|inwardly rectifying K<sup>+</sup> current]] and inhibition of the inward Ca<sup>2+</sup> current (I<sub>Ca</sub>) and
the [[Pacemaker current|'funny' hyperpolarization-activated current (I<sub>f</sub>)]].<ref name="pmid7896004">{{cite journal |vauthors=Belardinelli L, Shryock JC, Song Y, Wang D, Srinivas M | title = Ionic basis of the electrophysiological actions of adenosine on cardiomyocytes | journal = FASEB Journal | volume = 9 | issue = 5 | pages = 359–365 | date = March 1995 | pmid = 7896004 | doi = 10.1096/fasebj.9.5.7896004 | doi-access = free | s2cid = 26061166 }}</ref> Adenosine agonism of A1ARs also inhibits release of [[norepinephrine]] from cardiac nerves.<ref name="pmid15644943">{{cite journal | vauthors = Lorbar M, Chung ES, Nabi A, Skalova K, Fenton RA, Dobson JG, Meyer TE | title = Receptors subtypes involved in adenosine-mediated modulation of norepinephrine release from cardiac nerve terminals | journal = Canadian Journal of Physiology and Pharmacology | volume = 82 | issue = 11 | pages = 1026–1031 | date = November 2004 | pmid = 15644943 | doi = 10.1139/y04-108 }}</ref> Norepinephrine is a positive chronotrope, [[inotrope]], and dromotrope, through its agonism of β adrenergic receptors on [[sinoatrial node|pacemaker cells]] and ventricular myocytes.<ref name="pmid32216617">{{cite journal | vauthors = Chan SA, Vaseghi M, Kluge N, Shivkumar K, Ardell JL, Smith C | title = Fast in vivo detection of myocardial norepinephrine levels in the beating porcine heart | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 318 | issue = 5 | pages = H1091–H1099 | date = May 2020 | pmid = 32216617 | doi = 10.1152/ajpheart.00574.2019 | pmc = 7346543 }}</ref><ref name="pmid15110153">{{cite journal | vauthors = Lakatta EG | title = Beyond Bowditch: the convergence of cardiac chronotropy and inotropy | journal = Cell Calcium | volume = 35 | issue = 6 | pages = 629–642 | date = June 2004 | pmid = 15110153 | doi = 10.1016/j.ceca.2004.01.017 }}</ref>

Collectively, these mechanisms lead to an myocardial depressant effect by decreasing the conduction of electrical impulses and suppressing [[sinoatrial node|pacemaker cells]] function, resulting in a decrease in [[heart rate]]. This makes adenosine a useful medication for treating and diagnosing [[tachyarrhythmia]]s, or excessively fast heart rates. This effect on the A<sub>1</sub> receptor also explains why there is a brief moment of cardiac standstill when adenosine is administered as a rapid [[intravenous|IV]] push during [[cardiac resuscitation]].{{Citation needed|date=November 2023}} 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 [[bradycardia]]s, 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|date=November 2023}}

Metabolically, A1AR activation by endogenous adenosine across the body reduces plasma [[glucose]], [[lactic acid|lactate]], and [[insulin]] levels, however [[Adenosine A2A receptor|A2aR]] activation increased glucose and lactate levels to an extent greater than the A1AR effect on glucose and lactate.<ref name="pmid19118101">{{cite journal | vauthors = Maeda T, Koos BJ | title = Adenosine A1 and A2a receptors modulate insulinemia, glycemia, and lactatemia in fetal sheep | journal = American Journal of Physiology. Regulatory, Integrative and Comparative Physiology | volume = 296 | issue = 3 | pages = R693–R701 | date = March 2009 | pmid = 19118101 | pmc = 2665841 | doi = 10.1152/ajpregu.90363.2008 }}</ref> 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<sup>+</sup> generation.<ref name="pmid10498852">{{cite journal | vauthors = Fraser H, Lopaschuk GD, Clanachan AS | title = Alteration of glycogen and glucose metabolism in ischaemic and post-ischaemic working rat hearts by adenosine A1 receptor stimulation | journal = British Journal of Pharmacology | volume = 128 | issue = 1 | pages = 197–205 | date = September 1999 | pmid = 10498852 | pmc = 1571606 | doi = 10.1038/sj.bjp.0702765 }}</ref>
<!--The A1AR can heterodimerize with P2Y1 or D1 dopamine receptors.
<ref name="pmid11390975">{{cite journal | vauthors = Yoshioka K, Saitoh O, Nakata H | title = Heteromeric association creates a P2Y-like adenosine receptor | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 13 | pages = 7617–7622 | date = June 2001 | pmid = 11390975 | pmc = 34717 | doi = 10.1073/pnas.121587098 | bibcode = 2001PNAS...98.7617Y | doi-access = free }}</ref><ref name="pmid10890919">{{cite journal | vauthors = Ginés S, Hillion J, Torvinen M, Le Crom S, Casadó V, Canela EI, Rondin S, Lew JY, Watson S, Zoli M, Agnati LF, Verniera P, Lluis C, Ferré S, Fuxe K, Franco R | title = Dopamine D1 and adenosine A1 receptors form functionally interacting heteromeric complexes | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 97 | issue = 15 | pages = 8606–8611 | date = July 2000 | pmid = 10890919 | pmc = 26995 | doi = 10.1073/pnas.150241097 | bibcode = 2000PNAS...97.8606G | doi-access = free }}</ref>-->

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.<ref name="pmid17211253">{{cite journal | vauthors = Perlini S, Arosio B, Parmeggiani L, Santambrogio D, Palladini G, Tozzi R, Gatti C, Annoni G, Meyer TE, Ferrari AU | title = Adenosine A1 receptor expression during the transition from compensated pressure overload hypertrophy to heart failure | journal = Journal of Hypertension | volume = 25 | issue = 2 | pages = 449–454 | date = February 2007 | pmid = 17211253 | doi = 10.1097/HJH.0b013e3280110de3 | s2cid = 36575444 }}</ref> Excess A1AR expression can induce cardiomyopathy, cardiac dilatation, and cardiac hypertrophy.<ref name="pmid17088462">{{cite journal | vauthors = 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 | title = Regulated overexpression of the A1-adenosine receptor in mice results in adverse but reversible changes in cardiac morphology and function | journal = Circulation | volume = 114 | issue = 21 | pages = 2240–2250 | date = November 2006 | pmid = 17088462 | doi = 10.1161/CIRCULATIONAHA.106.620211 | s2cid = 37115831 | doi-access = free }}</ref> Cardiac failure may involve increased A1AR expression and decreased adenosine in physical models of cardiac overload and in dysfunction induced by TNFα.<ref name="pmid17438146">{{cite journal | vauthors = Funakoshi H, Zacharia LC, Tang Z, Zhang J, Lee LL, Good JC, Herrmann DE, Higuchi Y, Koch WJ, Jackson EK, Chan TO, Feldman AM | title = A1 adenosine receptor upregulation accompanies decreasing myocardial adenosine levels in mice with left ventricular dysfunction | journal = Circulation | volume = 115 | issue = 17 | pages = 2307–2315 | date = May 2007 | pmid = 17438146 | doi = 10.1161/CIRCULATIONAHA.107.694596 | s2cid = 31096844 | doi-access = free }}</ref> 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.<ref name="pmid18838091">{{cite journal | vauthors = Yuan K, Bai GY, Park WH, Kim SZ, Kim SH | title = Stimulation of ANP secretion by 2-Cl-IB-MECA through A(3) receptor and CaMKII | journal = Peptides | volume = 29 | issue = 12 | pages = 2216–2224 | date = December 2008 | pmid = 18838091 | doi = 10.1016/j.peptides.2008.09.003 | s2cid = 12321885 }}</ref><ref name="pmid16286581">{{cite journal | vauthors = Yuan K, Cao C, Han JH, Kim SZ, Kim SH | title = Adenosine-stimulated atrial natriuretic peptide release through A1 receptor subtype | journal = Hypertension | volume = 46 | issue = 6 | pages = 1381–1387 | date = December 2005 | pmid = 16286581 | doi = 10.1161/01.HYP.0000190041.61737.fd | s2cid = 21514416 | doi-access = free }}</ref>

== References ==
{{Reflist}}

== External links ==
* {{cite web | url = http://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2166 | title = Adenosine Receptors: A<sub>1</sub> | work = IUPHAR Database of Receptors and Ion Channels | publisher = International Union of Basic and Clinical Pharmacology | access-date = 2007-10-25 | archive-date = 2020-09-20 | archive-url = https://web.archive.org/web/20200920142452/https://www.iuphar-db.org/GPCR/ReceptorDisplayForward?receptorID=2166 }}
* {{MeshName|Adenosine+A1+Receptor}}
* {{UCSC gene info|ADORA1}}
* {{PDBe-KB2|P30542|Adenosine receptor A1}}

{{G protein-coupled receptors}}
{{Adenosinergics}}

[[Category:Adenosine receptors]]