Adenosine A1 receptor

The adenosine A₁ receptor (A1AR) ^[5] is one member of the adenosine receptor group of G protein-coupled receptors with adenosine as endogenous ligand.

ADORA1
Identifiers
Aliases	ADORA1, RDC7, adenosine A1 receptor
External IDs	OMIM: 102775; MGI: 99401; HomoloGene: 20165; GeneCards: ADORA1; OMA:ADORA1 - orthologs
Gene location (Human) Chr. Chromosome 1 (human)[1] Band 1q32.1 Start 203,090,654 bp[1] End 203,167,405 bp[1]
Gene location (Mouse) Chr. Chromosome 1 (mouse)[2] Band 1|1 E4 Start 134,126,961 bp[2] End 134,163,169 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in inferior ganglion of vagus nerve prefrontal cortex C1 segment lateral nuclear group of thalamus Brodmann area 10 putamen Pons Amygdala ventral tegmental area right frontal lobe Top expressed in pontine nuclei dentate gyrus of hippocampal formation granule cell medial geniculate nucleus cerebellar cortex cerebellar vermis subiculum facial motor nucleus lobe of cerebellum superior frontal gyrus barrel cortex More reference expression data BioGPS More reference expression data
Gene ontology Molecular function G-protein beta/gamma-subunit complex binding G protein-coupled adenosine receptor activity G protein-coupled receptor activity signal transducer activity purine nucleoside binding protein binding protein heterodimerization activity phospholipase C activity heterotrimeric G-protein binding G protein-coupled receptor binding heat shock protein binding neurotransmitter receptor activity involved in regulation of presynaptic cytosolic calcium ion concentration Cellular component integral component of membrane cell body postsynaptic membrane membrane postsynaptic density dendritic spine synapse integral component of plasma membrane presynaptic active zone terminal bouton soma dendrite basolateral plasma membrane endoplasmic reticulum axolemma asymmetric synapse presynaptic membrane endomembrane system plasma membrane integral component of postsynaptic membrane integral component of presynaptic membrane calyx of Held Biological process negative regulation of circadian sleep/wake cycle, non-REM sleep positive regulation of nucleoside transport positive regulation of epidermal growth factor-activated receptor activity G protein-coupled adenosine receptor signaling pathway negative regulation of neurotrophin production negative regulation of glutamate secretion response to hypoxia negative regulation of acute inflammatory response adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway regulation of sensory perception of pain cognition positive regulation of protein dephosphorylation negative regulation of blood pressure negative regulation of heart contraction protein targeting to membrane positive regulation of potassium ion transport regulation of glomerular filtration cell-cell signaling positive regulation of peptide secretion negative regulation of apoptotic process nervous system development detection of temperature stimulus involved in sensory perception of pain regulation of respiratory gaseous exchange by nervous system process lipid catabolic process negative regulation of circadian sleep/wake cycle, sleep positive regulation of blood pressure negative regulation of synaptic transmission, GABAergic negative regulation of renal sodium excretion excitatory postsynaptic potential phagocytosis relaxation of vascular associated smooth muscle apoptotic signaling pathway regulation of cardiac muscle contraction negative regulation of long-term synaptic depression temperature homeostasis inflammatory response negative regulation of mucus secretion negative regulation of hormone secretion negative regulation of lipid catabolic process negative regulation of inflammatory response negative regulation of leukocyte migration negative regulation of synaptic transmission, glutamatergic signal transduction negative regulation of cell population proliferation negative regulation of cardiac muscle contraction G protein-coupled receptor signaling pathway positive regulation of systemic arterial blood pressure negative regulation of systemic arterial blood pressure positive regulation of lipid catabolic process fatty acid homeostasis triglyceride homeostasis negative regulation of long-term synaptic potentiation positive regulation of neuron death regulation of cardiac muscle cell contraction regulation of presynaptic cytosolic calcium ion concentration Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 134 11539 Ensembl ENSG00000163485 ENSMUSG00000042429 UniProt P30542 Q60612 RefSeq (mRNA) NM_000674 NM_001048230 NM_001365065 NM_001365066 NM_001008533 NM_001039510 NM_009629 NM_001282945 NM_001291928 NM_001291930 RefSeq (protein) NP_000665 NP_001041695 NP_001351994 NP_001351995 NP_001008533 NP_001034599 NP_001269874 NP_001278857 NP_001278859 Location (UCSC) Chr 1: 203.09 – 203.17 Mb Chr 1: 134.13 – 134.16 Mb PubMed search [3] [4]
Wikidata
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Biochemistry

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]}

Signaling

Activation of the adenosine A₁ receptor by an agonist causes binding of G_i1/2/3 or G_o protein. Binding of G_i1/2/3 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]

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.^{[citation needed]}

Ligands

Caffeine, as well as theophylline, has been found to antagonize both A₁ and A_2A receptors in the brain.^{[citation needed]}

Agonists

• 2-Chloro-N(6)-cyclopentyladenosine (CCPA).^{[citation needed]}
• N6-Cyclopentyladenosine^{[citation needed]}
• N(6)-cyclohexyladenosine^{[citation needed]}
• Tecadenoson ((2R,3S,4R)-2-(hydroxymethyl)-5-(6-

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

• Selodenoson ((2S,3S,4R)-5-(6-(cyclopentylamino)-9Hpurin-9-yl)-N-ethyl-3,4-dihydroxytetrahydrofuran-2-carboxamide) ^[9]
• Capadenoson (BAY68-4986) ^[9]
• Benzyloxy-cyclopentyladenosine (BnOCPA) is an A1R selective agonist.^[10]

PAMs

• 2‑Amino-3-(4′-chlorobenzoyl)-4-substituted-5-arylethynyl thiophene # 4e^[11]

Antagonists

Non-selective

• Caffeine
• Theophylline
• CGS-15943^{[citation needed]}

Selective

• 8-Cyclopentyl-1,3-dimethylxanthine (CPX / 8-cyclopentyltheophylline)^{[citation needed]}
• 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX)^{[citation needed]}
• 8-Phenyl-1,3-dipropylxanthine ^{[citation needed]}
• Bamifylline ^{[citation needed]}
• BG-9719^[12]
• BG-9928^[13]
• FK-453 ^{[citation needed]}
• FK-838 ^{[citation needed]}
• Rolofylline (KW-3902)^[14][15]
• N-0861 ^{[citation needed]}
• ISAM-CV202^[16]

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 (I_Ca) and the 'funny' hyperpolarization-activated current (I_f).^[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]