Adenosine A1 receptor

Adenosine A1 receptor
Identifiers
Symbols	ADORA1 ; RDC7
External IDs	OMIM: 102775 MGI: 99401 HomoloGene: 20165 IUPHAR: 18 ChEMBL: 226 GeneCards: ADORA1 Gene
Gene ontology Molecular function • G-protein coupled adenosine receptor activity • G-protein coupled receptor binding • purine nucleoside binding • phospholipase C activity • protein binding • G-protein beta/gamma-subunit complex binding • heterotrimeric G-protein binding • protein heterodimerization activity Cellular component • endoplasmic reticulum • plasma membrane • integral component of plasma membrane • postsynaptic density • basolateral plasma membrane • axolemma • asymmetric synapse • presynaptic membrane • neuronal cell body • terminal bouton • dendritic spine • postsynaptic membrane • presynaptic active zone Biological process • activation of MAPKK activity • temperature homeostasis • response to hypoxia • adenosine receptor signaling pathway • regulation of respiratory gaseous exchange by neurological system process • negative regulation of acute inflammatory response • negative regulation of leukocyte migration • positive regulation of peptide secretion • regulation of glomerular filtration • protein targeting to membrane • phagocytosis • inflammatory response • signal transduction • adenylate cyclase-inhibiting G-protein coupled receptor signaling pathway • cell-cell signaling • nervous system development • negative regulation of cell proliferation • negative regulation of glutamate secretion • lipid catabolic process • negative regulation of synaptic transmission, GABAergic • positive regulation of nucleoside transport • negative regulation of neurotrophin production • positive regulation of protein dephosphorylation • negative regulation of renal sodium excretion • negative regulation of circadian sleep/wake cycle, non-REM sleep • negative regulation of apoptotic process • positive regulation of potassium ion transport • positive regulation of epidermal growth factor-activated receptor activity • negative regulation of blood pressure • positive regulation of blood pressure • negative regulation of vasodilation • negative regulation of hormone secretion • regulation of synaptic plasticity • cognition • detection of temperature stimulus involved in sensory perception of pain • negative regulation of lipid catabolic process • regulation of sensory perception of pain • negative regulation of synaptic transmission, glutamatergic • negative regulation of cardiac muscle contraction • regulation of excitatory postsynaptic membrane potential • relaxation of vascular smooth muscle • negative regulation of mucus secretion • apoptotic signaling pathway • negative regulation of long term synaptic depression Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	134	11539
Ensembl	ENSG00000163485	ENSMUSG00000042429
UniProt	P30542	Q60612
RefSeq (mRNA)	NM_000674	NM_001008533
RefSeq (protein)	NP_000665	NP_001008533
Location (UCSC)	Chr 1: 203.09 – 203.17 Mb	Chr 1: 134.2 – 134.24 Mb
PubMed search

The adenosine A₁ receptor^[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 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.^[4]

Mechanism

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 A_2A receptors in the brain.

Agonists

• 2-Chloro-N(6)-cyclopentyladenosine (CCPA).
• N6-Cyclopentyladenosine
• N(6)-cyclohexyladenosine

PAMs

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

Antagonists

Non-selective

• Caffeine
• Theophylline
• CGS-15943

Selective

• 8-Cyclopentyl-1,3-dimethylxanthine (CPX / 8-cyclopentyltheophylline)
• 8-Cyclopentyl-1,3-dipropylxanthine (DPCPX)
• 8-Phenyl-1,3-dipropylxanthine
• Bamifylline
• BG-9719^[6]
• BG-9928^[7]
• FK-453
• FK-838
• Rolofylline (KW-3902)^[8][9]
• N-0861

In heart

The A₁ and A_2A receptors of endogenous adenosine are believed to play a role in regulating myocardial oxygen consumption and coronary blood flow. Stimulation of the A₁ receptor has a myocardial depressant effect by decreasing the conduction of electrical impulses and suppressing pacemaker cell 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.

In neonatal medicine

Adenosine antagonists are widely used in neonatal medicine;

Because a reduction in A₁ expression appears to prevent hypoxia-induced ventriculomegaly and loss of white matter, the pharmacological blockade of A₁ may have clinical utility.

Theophylline and caffeine are nonselective adenosine antagonists that are used to stimulate respiration in premature infants.

However, we are unaware of clinical studies that have examined the incidence of periventricular leukomalacia (PVL) as related to neonatal caffeine use. Caffeine may reduce cerebral blood flow in premature infants, it is presumed by blocking vascular A₂ ARs. Thus, it may prove more advantageous to use selective A₁ antagonists to help reduce adenosine-induced brain injury.

References

1. Townsend-Nicholson A, Baker E, Schofield PR, Sutherland GR (1995). "Localization of the adenosine A₁ receptor subtype gene (ADORA1) to chromosome 1q32.1". Genomics 26 (2): 423–5. doi:10.1016/0888-7543(95)80236-F. PMID 7601478.
2. Elmenhorst D, Meyer PT, Winz OH, Matusch A, Ermert J, Coenen HH, Basheer R, Haas HL, Zilles K, Bauer A (2007). "Sleep deprivation increases A₁ adenosine receptor binding in the human brain: a positron emission tomography study". J. Neurosci. 27 (9): 2410–5. doi:10.1523/JNEUROSCI.5066-06.2007. PMID 17329439.
3. Tawfik HE, Schnermann J, Oldenburg PJ, Mustafa SJ (2005). "Role of A₁ adenosine receptors in regulation of vascular tone". Am. J. Physiol. Heart Circ. Physiol. 288 (3): H1411–6. doi:10.1152/ajpheart.00684.2004. PMID 15539423.
4. Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J (December 2001). "International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors". Pharmacol. Rev. 53 (4): 527–52. PMID 11734617.
5. Romagnoli R, Baraldi PG, IJzerman AP; et al. (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". J. Med. Chem. 57: 7673–86. doi:10.1021/jm5008853. PMID 25181013.
6. Gottlieb SS, Brater DC, Thomas I, Havranek E, Bourge R, Goldman S, Dyer F, Gomez M, Bennett D, Ticho B, Beckman E, Abraham WT (March 2002). "BG9719 (CVT-124), an A1 adenosine receptor antagonist, protects against the decline in renal function observed with diuretic therapy". Circulation 105 (11): 1348–53. doi:10.1161/hc1102.105264. PMID 11901047.
7. Greenberg B, Thomas I, Banish D, Goldman S, Havranek E, Massie BM, Zhu Y, Ticho B, Abraham WT (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): 600–6. doi:10.1016/j.jacc.2007.03.059. PMID 17692744.
8. 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): 1551–60. doi:10.1016/j.jacc.2007.07.019. PMID 17936154.
9. Cotter G, Dittrich HC, Weatherley BD, Bloomfield DM, O'Connor CM, Metra M, Massie BM (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): 631–40. doi:10.1016/j.cardfail.2008.08.010. PMID 18926433.

External links

• "Adenosine Receptors: A₁". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology.
• Adenosine A1 Receptor at the US National Library of Medicine Medical Subject Headings (MeSH)