Adenosine A2A receptor

The adenosine A2A receptor, also known as ADORA2A, is an is_associated_with::adenosine receptor, and also denotes the human is_associated_with::gene encoding it.

Structure
This protein is a member of the is_associated_with::G protein-coupled receptor (GPCR) family which possess seven transmembrane alpha helices. The crystallographic structure of the adenosine A2A receptor reveals a ligand binding pocket distinct from that of other structurally determined GPCRs (i.e., the is_associated_with::beta-2 adrenergic receptor and is_associated_with::rhodopsin).

Heteromers
The actions of the A2A receptor are complicated by the fact that a variety of functional is_associated_with::heteromers composed of a mixture of A2A subunits with subunits from other unrelated G-protein coupled receptors have been found in the brain, adding a further degree of complexity to the role of adenosine in modulation of neuronal activity. Hetereomers consisting of adenosine A1/A2A, dopamine D2/A2A and D3/A2A, glutamate mGluR5/A2A and cannabinoid CB1/A2A have all been observed, as well as CB1/A2A/D2 heterotrimers, and the functional significance and endogenous role of these hybrid receptors is still only starting to be unravelled.

The receptor's role in immunomodulation in the context of cancer has suggested that it is an important is_associated_with::immune checkpoint molecule.

Function
The gene encodes a protein which is one of several receptor subtypes for is_associated_with::adenosine. The activity of the encoded protein, a is_associated_with::G protein-coupled receptor family member, is mediated by is_associated_with::G proteins which activate is_associated_with::adenylyl cyclase, which induce synthesis of intracellular cAMP. The encoded protein is abundant in is_associated_with::basal ganglia, vasculature, is_associated_with::T lymphocytes, and is_associated_with::platelets and it is a major target of is_associated_with::caffeine, which is a competitive antagonist of this protein.

Physiological role
As with the A1, the A2A receptors are believed to play a role in regulating myocardial oxygen consumption and coronary blood flow. In addition, A2A receptor can negatively regulate overreactive immune cells, thereby protecting tissues from collateral inflammatory damage.

The A2A receptor is responsible for regulating myocardial blood flow by vasodilating the coronary arteries, which increases blood flow to the is_associated_with::myocardium, but may lead to hypotension. Just as in A1 receptors, this normally serves as a protective mechanism, but may be destructive in altered cardiac function.

The A2A receptor is also expressed in the brain, where it has important roles in the regulation of glutamate and dopamine release, making it a potential therapeutic target for the treatment of conditions such as insomnia, pain, depression, drug addiction and Parkinson's disease.

Ligands
A number of selective A2A ligands have been developed,           with several possible therapeutic applications. Older research on adenosine receptor function, and non-selective adenosine receptor antagonists such as is_associated_with::aminophylline, focused mainly on the role of adenosine receptors in the heart, and led to several is_associated_with::randomized controlled trials using these receptor antagonists to treat bradyasystolic arrest.

However the development of more highly selective A2A ligands has led towards other applications, with the most significant focus of research currently being the potential therapeutic role for A2A antagonists in the treatment of is_associated_with::Parkinson's disease.

Agonists

 * ATL-146e
 * YT-146 (2-(1-octynyl)adenosine)
 * is_associated_with::CGS-21680
 * DPMA (N6-(2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl)adenosine)
 * is_associated_with::Regadenoson
 * is_associated_with::UK-432,097
 * is_associated_with::Limonene
 * NECA (5′-(N-Ethylcarboxamido)adenosine)

Antagonists

 * is_associated_with::ATL-444
 * is_associated_with::Istradefylline (KW-6002)
 * MSX-3
 * is_associated_with::Preladenant (SCH-420,814)
 * is_associated_with::SCH-58261
 * SCH-412,348
 * is_associated_with::SCH-442,416
 * ST-1535
 * is_associated_with::Caffeine
 * VER-6623
 * VER-6947
 * VER-7835
 * Vipadenant (BIIB-014)
 * is_associated_with::ZM-241,385

Interactions
Adenosine A2A receptor has been shown to interact with is_associated_with::Dopamine receptor D2. As a result, Adenosine receptor A2A decreases activity in the Dopamine D2 receptors.