Adenosine A2A receptor antagonists represent a new way forward in the symptomatic treatment of Parkinson's disease (PD) through a non-dopaminergic mechanism. As a class, adenosine A2A antagonists are effective in reversing motor deficits in haloperidol-treated rodents, 6-OHDA-lesioned rats, and MPTP-treated primates when combined with low doses of l-dopa or dopamine agonist drugs. Importantly, they improve motor function without worsening dyskinesia and they may prevent the onset of involuntary movements. Adenosine A2A receptor antagonists are active in animal models of reduced cognition, anxiety, and depression and so this drug class may also be effective in controlling the neuropsychiatric components of nonmotor symptoms in PD.
Seattle, WA -- (SBWIRE) -- 12/04/2019 -- Structure
This protein is a member of the G protein-coupled receptor (GPCR) family which possess seven transmembrane alpha helices, as well as an extracellular N-terminus and an intracellular C-terminus. Furthermore, located in the intracellular side close to the membrane is a small alpha helix, often referred to as helix 8 (H8). The crystallographic structure of the adenosine A2A receptor reveals a ligand binding pocket distinct from that of other structurally determined GPCRs (i.e., the beta-2 adrenergic receptor and rhodopsin). Below this primary (orthosteric) binding pocket lies a secondary (allosteric) binding pocket.
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The gene encodes a protein which is one of several receptor subtypes for adenosine. The activity of the encoded protein, a G protein-coupled receptor family member, is mediated by G proteins which activate adenylyl cyclase, which induce synthesis of intracellular cAMP. The A2A receptor binds with the Gs protein at the intracellular site of the receptor.
A1 and A2A receptors are believed to regulate myocardial oxygen demand and to increase coronary circulation by vasodilation. In addition, A2A receptor can suppress immune cells, thereby protecting tissue from inflammation.
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, and Parkinson's disease.
In cancer immunotherapy
The adenosine A2A receptor has also been shown to play a regulatory role in the adaptive immune system. In this role, A2AR functions similarly to programmed cell death-1 (PD-1) and cytotoxic t-lymphocyte associated protein-4 (CTLA-4) receptors, namely to suppress immunologic response and prevent associated tissue damage. Extracellular adenosine gathers in response to cellular stress and breakdown through interactions with hypoxia induced HIF-1?.
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