Adenosine A₁ receptor

ADORA1
Identifiers
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 neuronal cell body 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

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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The adenosine A₁ receptor (A1AR)

.

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

, which cleaves DAG to form arachidonic acid. Several types of

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 (

When bound by adenosine, A₁ receptors inhibit impulses generated in supraventricular tissue (

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

] 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

]

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]

References

External links

• "Adenosine Receptors: A₁". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology. Archived from the original on 2020-09-20. Retrieved 2007-10-25.
• Adenosine+A1+Receptor at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Human ADORA1 genome location and ADORA1 gene details page in the UCSC Genome Browser.
• Overview of all the structural information available in the PDB for UniProt: P30542 (Adenosine receptor A1) at the PDBe-KB.