Brain Receptor Mosaics and Their Intramembrane Receptor-Receptor Interactions: Molecular Integration in Transmission and Novel Targets for Drug Development

Illustration of the electrostatic epitope-epitope interactions in the intracellular parts of the A2A-D2 heteromers (seen in the box). Two epitopes with negative charges (in bold) exist in the C terminal tail of the A2A receptor, the one with the phosphorylated serine (SAQEpSQGNT) being of special interest, since it underlines the role of phosphorylation processes in the electrostatic interactions. Positive charges (in bold) exist in the arginine rich epitope (VLRRRRKRVN) in the N terminal part of the intracellular loop 3 of the D2 receptor which interacts with the negatively charged epitopes seen in this figure. These non-covalent interactions in the intracellular part of the two receptors are strong and represent an important part of the A2A/D2 interface (see text for references).

Scheme of receptor-receptor interactions in putative trimeric CB1/D2/A2A receptor mosaics in Parkinson's disease (PD) mainly located on dorsal striatal glutamate terminals with (right) or without (left) combined treatment with low doses of L-dopa and A2A and CB1 receptor antagonists. Left panel: Reduced tone of DA in PD leads to reduced signaling of D2 receptors to AC (inhibited by D2) and to ion channels (not shown). Instead dominance of A2A and CB1 receptor signaling will develop with increased inhibition of D2 receptor activity via antagonistic A2A/D2 and CB1/D2 receptor-receptor interactions and increased AC activity over the A2A activated AC. As a result PKA is strongly activated mediating increases in P-MEK (MAPK kinase), P-CREB and increased phosphorylation of Thr³⁴ in DARPP-32 turning it into a protein phosphatase type-1 inhibitor. This will cause inter alia increases in striatal excitability with increased release of glutamate leading to inhibition of motor function. Right panel: By means of combined therapy with A2A and/or CB1 receptor antagonists and removal of the antagonistic A2A/D2 and CB1/D2 receptor interactions it will be possible to use very low doses of L-dopa with reduced side-effects like L-dopa induced dyskinesias. A proper tone of D2 receptor activity can therefore be restored to ion channels (not shown) and to Gi/o regulated AC with normalization of the activity of the A2A activated AC and reduction in the activity of PKA and thus in P-MEK, P-CREB and the activity of DARPP-32 and normalization of glutamate release.

Scheme of the molecular mechanism for the receptor-receptor interactions in the D1/NMDA (A) and D2/NMDA (B) receptor mosaics. (A) One epitope of the C-terminal region of D1 can directly interact with the C-terminal of the NR2A and reduce its plasma membrane expression resulting in reduction of NMDA currents and in reduced excitability; another epitope of the C-terminal region of D1 can directly interact with the NR1–1a increasing the ability of the NR1–1 to form a complex with calmodulin and PI-3 kinase resulting in increased activity of the PI-3 kinase and increased cell survival (see text for reference). (B) The N terminal part of the third intracellular loop of D2 directly interacts with C terminal part of the NR2B subunit of synaptic NMDA receptors. This interaction is increased by D2 activation and reduces the binding of the calcium/calmodulin dependent protein kinase II to the NR2B which results in reduced phophorylation of the NR2B subunit, reduction of NMDA currents and thus reduced excitability (see text for reference).