Movatterモバイル変換

[0]ホーム
URL:

Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
Thehttps:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

NIH NLM Logo
Log inShow account info
Access keysNCBI HomepageMyNCBI HomepageMain ContentMain Navigation
pubmed logo
Advanced Clipboard
User Guide

Full text links

MDPI full text link MDPI Free PMC article
Full text links

Actions

Review
.2021 Feb 9;22(4):1719.
doi: 10.3390/ijms22041719.

Allosteric Interactions between Adenosine A2A and Dopamine D2 Receptors in Heteromeric Complexes: Biochemical and Pharmacological Characteristics, and Opportunities for PET Imaging

Affiliations
Review

Allosteric Interactions between Adenosine A2A and Dopamine D2 Receptors in Heteromeric Complexes: Biochemical and Pharmacological Characteristics, and Opportunities for PET Imaging

Kavya Prasad et al. Int J Mol Sci..

Abstract

Adenosine and dopamine interact antagonistically in living mammals. These interactions are mediated via adenosine A2A and dopamine D2 receptors (R). Stimulation of A2AR inhibits and blockade of A2AR enhances D2R-mediated locomotor activation and goal-directed behavior in rodents. In striatal membrane preparations, adenosine decreases both the affinity and the signal transduction of D2R via its interaction with A2AR. Reciprocal A2AR/D2R interactions occur mainly in striatopallidal GABAergic medium spiny neurons (MSNs) of the indirect pathway that are involved in motor control, and in striatal astrocytes. In the nucleus accumbens, they also take place in MSNs involved in reward-related behavior. A2AR and D2R co-aggregate, co-internalize, and co-desensitize. They are at very close distance in biomembranes and form heteromers. Antagonistic interactions between adenosine and dopamine are (at least partially) caused by allosteric receptor-receptor interactions within A2AR/D2R heteromeric complexes. Such interactions may be exploited in novel strategies for the treatment of Parkinson's disease, schizophrenia, substance abuse, and perhaps also attention deficit-hyperactivity disorder. Little is known about shifting A2AR/D2R heteromer/homodimer equilibria in the brain. Positron emission tomography with suitable ligands may provide in vivo information about receptor crosstalk in the living organism. Some experimental approaches, and strategies for the design of novel imaging agents (e.g., heterobivalent ligands) are proposed in this review.

Keywords: GABAergic enkephalinergic neuron; adenosine A2A receptor; allosteric interaction; dopamine D2 receptor; heteromers; receptor–receptor interactions; striatum.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Metabolic pathways involved in the formation and removal of adenosine. 1 = Oxidative phosphorylation (and creatine kinase), 2 = Energy-consuming processes, 3 = Adenylate kinase, 4 = Apyrase, 5 = Adenylate cyclase, 6 = Phosphodiesterase, 7 = 5′-Nucleotidase, 8 = S-adenosyl homocysteine hydrolase, 9 = Adenosine kinase, 10 = Adenosine deaminase, 11 = Purine phosphorylase, 12 = Xanthine oxidase. ATP = adenosine 5’-triphosphate, ADP = adenosine 5’-diphosphate, AMP = adenosine 5’-monophosphate, cAMP = 3’.5’-cyclic adenosine monophosphate.
Figure 2
Figure 2
Schematic drawing of the direct and indirect pathways for motor control. Solid and faded lines represent direct and indirect pathways, respectively. Blue lines represent excitatory connections and red lines represent inhibitory connections. Pu = putamen, Gpe = globus pallidus externus, Gpi = globus pallidus internus, STN = subthalamic nucleus, SNc = substantia nigra pars compacta, VA/VL = ventral anterior/ventral lateral thalamic nucleus. Created with BioRender.com.
Figure 3
Figure 3
Chemical structures of the A2A antagonist XCC (A) and the D2 agonist PPHT-NH2 (B). By attaching a linker to the atomic positions indicated by the arrowheads, a bivalent ligand for A2AR/D2R heteromers can be created [392].
Figure 4
Figure 4
Conjugation of dopamine with the A2A antagonist 7-amino-5-(aminomethyl)-cyclohexylmethyl-amino-2-(2-furyl)-1,2,4-triazolo[1,5-a]-1,3,5-triazine trifluoroacetate via a succinate spacer, to obtain the prodrug DP-L-A2AANT, a bivalent ligand [394].
Figure 5
Figure 5
Conjugation of the adenosine A2AR antagonist ZM241385 (A) and the dopamine D2 agonist ropinirole (B) to form a heterobivalent ligand (C). Dual action drugs can be prepared by using cyclic (D) or non-cyclic (E) spacers, and the latter may contain an ionizable tertiary amine [395].
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Latini S., Corsi C., Pedata F., Pepeu G. The Source of Brain Adenosine Outflow during Ischemia and Electrical Stimulation. Neurochem. Int. 1996;28:113–118. doi: 10.1016/0197-0186(95)00062-D. - DOI - PubMed
    1. Ballarín M., Fredholm B.B., Ambrosio S., Mahy N. Extracellular Levels of Adenosine and Its Metabolites in the Striatum of Awake Rats: Inhibition of Uptake and Metabolism. Acta Physiol. Scand. 1991;142:97–103. doi: 10.1111/j.1748-1716.1991.tb09133.x. - DOI - PubMed
    1. Pazzagli M., Corsi C., Fratti S., Pedata F., Pepeu G. Regulation of Extracellular Adenosine Levels in the Striatum of Aging Rats. Brain Res. 1995;684:103–106. doi: 10.1016/0006-8993(95)00471-2. - DOI - PubMed
    1. Murillo-Rodriguez E., Liu M., Blanco-Centurion C., Shiromani P.J. Effects of Hypocretin (Orexin) Neuronal Loss on Sleep and Extracellular Adenosine Levels in the Rat Basal Forebrain. Eur. J. Neurosci. 2008;28:1191–1198. doi: 10.1111/j.1460-9568.2008.06424.x. - DOI - PMC - PubMed
    1. Nelson A.M., Battersby A.S., Baghdoyan H.A., Lydic R. Opioid-Induced Decreases in Rat Brain Adenosine Levels Are Reversed by Inhibiting Adenosine Deaminase. Anesthesiology. 2009;111:1327–1333. doi: 10.1097/ALN.0b013e3181bdf894. - DOI - PMC - PubMed

Publication types

MeSH terms

Substances

Related information

LinkOut - more resources

Full text links
MDPI full text link MDPI Free PMC article
Cite
Send To

NCBI Literature Resources

MeSHPMCBookshelfDisclaimer

The PubMed wordmark and PubMed logo are registered trademarks of the U.S. Department of Health and Human Services (HHS). Unauthorized use of these marks is strictly prohibited.

[8]ページ先頭
©2009-2025 Movatter.jp