The A2A/D2 heteromeric receptor complexes of the striatopallidal gaba neurons. From molecular mechanisms to relevance for Parkinson's disease and schizophrenia

During recent years, a large number of observations indicate that heptaspanning membrane receptors formdimers and heterodimers in neuronal membranes of the CNS, where they together with receptor interacting proteins form horizontal molecular networks making possible integration of signals already at the membrane level. Early behavioral findings indicated the existence in the brain of antagonistic adenosine/dopamine interactions and more specifically of A2A/D2 and A1/D1 receptor interactions. In the last couple of years, it has been possible by coimmunoprecipitation technology to obtain evidence in neuronal and other cell lines and in striatal tissue for the existence of A2A/D2 and A1/D1 heteromeric receptor complexes. Studies in A2A/D2 cotransfected HEK-293T cells using BRET and FRET techniques give evidence for the existence of A2A/D2 heterodimers. Evidence has been obtained in a large number of studies in the ventral and dorsal striatum and in cell lines that A2AR activation in the A2A/D2 heteromer leads to a substantial reduction of the affinity of the high affinity D2 binding and of the D2-G protein coupling and D2 signaling (second messenger measurements). Also prolonged A2A and/or D2 agonist activation of the A2A/D2 heteromers leads to coaggregation, cointernalization and codesensitization of the A2A/D2 heterodimers. In a series of behavioral and microdialysis experiments evidence has been obtained that the A2A agonist CGS 21680 has the characteristics of being an atypical antipsychotic drug probably in part by preferentially acting on the A2A/D2 heterodimer located in the ventral striatopallidal GABA pathway leading to reduction of D2 signaling and increasing activity in this GABA pathway regulating the input to the prefrontal cortex. The antiparkinsonian actions of A2A antagonists are probably mainly produced by blockade of A2A