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Allosteric Interactions between Adenosine A 2A and Dopamine D 2 Receptors in Heteromeric Complexes: Biochemical and Pharmacological Characteristics, and Opportunities for PET Imaging.
- Source :
-
International journal of molecular sciences [Int J Mol Sci] 2021 Feb 09; Vol. 22 (4). Date of Electronic Publication: 2021 Feb 09. - Publication Year :
- 2021
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Abstract
- Adenosine and dopamine interact antagonistically in living mammals. These interactions are mediated via adenosine A <subscript>2A</subscript> and dopamine D <subscript>2</subscript> receptors (R). Stimulation of A <subscript>2A</subscript> R inhibits and blockade of A <subscript>2A</subscript> R enhances D <subscript>2</subscript> R-mediated locomotor activation and goal-directed behavior in rodents. In striatal membrane preparations, adenosine decreases both the affinity and the signal transduction of D <subscript>2</subscript> R via its interaction with A <subscript>2A</subscript> R. Reciprocal A <subscript>2A</subscript> R/D <subscript>2</subscript> R 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. A <subscript>2A</subscript> R and D <subscript>2</subscript> R 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 A <subscript>2A</subscript> R/D <subscript>2</subscript> R 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 A <subscript>2A</subscript> R/D <subscript>2</subscript> R 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.
- Subjects :
- Adenosine A2 Receptor Agonists pharmacology
Adenosine A2 Receptor Agonists therapeutic use
Adenosine A2 Receptor Antagonists pharmacology
Adenosine A2 Receptor Antagonists therapeutic use
Allosteric Regulation drug effects
Animals
Astrocytes metabolism
Cyclic AMP metabolism
Disease Models, Animal
GABAergic Neurons metabolism
Globus Pallidus cytology
Globus Pallidus diagnostic imaging
Globus Pallidus metabolism
Humans
Ligands
Locomotion drug effects
Locomotion physiology
Mice
Nucleus Accumbens cytology
Nucleus Accumbens diagnostic imaging
Nucleus Accumbens metabolism
Parkinson Disease diagnosis
Parkinson Disease drug therapy
Protein Multimerization drug effects
Rats
Reward
Schizophrenia diagnosis
Schizophrenia drug therapy
Substance-Related Disorders diagnosis
Substance-Related Disorders drug therapy
Molecular Imaging methods
Positron-Emission Tomography methods
Receptor, Adenosine A2A metabolism
Receptors, Dopamine D2 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1422-0067
- Volume :
- 22
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- International journal of molecular sciences
- Publication Type :
- Academic Journal
- Accession number :
- 33572077
- Full Text :
- https://doi.org/10.3390/ijms22041719