title: Adenosine A(2A) receptors, dopamine D(2) receptors and their interactions in Parkinson's disease.
abstract: Future therapies in Parkinson's disease may substantially build on the existence of intra-membrane receptor-receptor interactions in DA receptor containing heteromeric receptor complexes. The A(2A)/D(2) heteromer is of substantial interest in view of its specific location in cortico-striatal glutamate terminals and in striato-pallidal GABA neurons. Antagonistic A(2A)/D(2) receptor interactions in this heteromer demonstrated at the cellular level, and at the level of the striato-pallidal GABA neuron and at the network level made it possible to suggest A(2A) antagonists as anti-parkinsonian drugs. The major mechanism is an enhancement of D(2) signaling leading to attenuation of hypokinesia, tremor, and rigidity in models of Parkinson's disease with inspiring results in two clinical trials. Other interactions are antagonism at the level of the adenylyl cyclase; heterologous sensitization at the A(2A) activated adenylyl cyclase by persistent D(2) activation and a compensatory up-regulation of A(2A) receptors in response to intermittent Levodopa treatment. An increased dominance of A(2A) homomers over D(2) homomers and A(2A)/D(2) heteromers after intermittent Levodopa treatment may therefore contribute to development of Levodopa induced dyskinesias and to the wearing off of the therapeutic actions of Levodopa giving additional therapeutic roles of A(2A) antagonists. Their neuroprotective actions may involve an increase in the retrograde trophic signaling in the nigro-striatal DA system.
authors.affiliation: Division of Cellular and Molecular Neurochemistry, Department of Neuroscience, Karolinska Institutet, 17177 Stockholm, Sweden. Kjell.Fuxe@ki.se
authors.forename: Kjell
authors.initials: K
authors.lastname: Fuxe
authors.forename: Daniel
authors.initials: D
authors.lastname: Marcellino
authors.forename: Susanna
authors.initials: S
authors.lastname: Genedani
authors.forename: Luigi
authors.initials: L
authors.lastname: Agnati
mesh_terms: D000818:Animals; D006801:Humans; D008954:Models, Biological; D010300:Parkinson Disease / Q000378:metabolism* / Q000503:physiopathology*; D043705:Receptor, Adenosine A2A / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000502:physiology*
chemical_list: D043705:Receptor, Adenosine A2A; D017448:Receptors, Dopamine D2