Dopamine Receptor Oligomerization

Each dopamine (DA) receptor subtype physically interacts with its own kind (homomers) or other receptors (heteromers) in the plasma membrane of neurons in the basal ganglia to form dimeric or high-order receptor oligomers, termed dimeric or high-order receptor mosaics (RMs). Two types of heteromeric DA RMs are primarily discussed, namely type 1 receptor mosaic (RM1) formed by different DA receptor (DA-R) subtypes that display classical cooperativity and type 2 receptor mosaic (RM2) formed by DA-R subtypes physically interacting with other receptors that display non-classical cooperativity. The D2 receptor can form a RM1 with either D1 or D3 receptor subtypes as well as different types of RM2 with A2A, mGluR5, CB1, neuropeptide receptors (SSR5, NTS1, CCK-2), and N-methyl- D-aspartate (NMDA) receptors. Trimeric A2A-D2-mGluR5 and A2A-D2-CB1 RM2 may exist in striatal neuronal networks and are also discussed. D1 receptors can form RM1 with D3 receptors and different types of RM2 with A1, μ-opioid, and NMDA receptors. D3 receptors can form a RM2 with A2A receptors and D5 receptors can form a RM2 with γ-aminobutyric acid (GABA)-A receptors. Through existing as part of a horizontal molecular network, RMs fine-tune multiple effector systems already at the level of the membrane, involving Ca2+, Na+, and K+ and including G protein-regulated inwardly rectifying potassium channels (GIRK), adenylyl cyclase (AC), phospholipase C (PLC), and dopamine transporter activity. The synaptic strength is particularly modulated by DA receptors within DA receptor RM2 that involve ligand-gated ion channels such as GABA-A and NMDA receptors. The existence of a RM2 formed by D2 receptors and receptor tyrosine kinase (RTK) receptors is also likely to exist and bears high relevance for the integration of trophic and informational signals within striatal networks. A novel neuropsychopharmacology may develop on the basis of DA receptor-containing RMs in the brain from the unique pharmacological properties afforded by their receptor–receptor interactions.