DOPAMINE D2 RECEPTOR DIMERS AND RECEPTOR-BLOCKING PEPTIDES

Dopamine D2 receptors exist as dimers in whole cell lysate, crude memb ranes prepared from human caudate, and following solubilization and im munoprecipitation of the receptor from these tissues. Photoaffinity la belling experiments confirmed that D2 receptors exist either as monome rs that are selective targets for spiperone or as dimers that are targ ets for nemonapride. incubation of D2 dimers with peptides derived fro m the putative transmembrane (TM) domains of the D2 receptor, or incub ation under high temperatures or low pH resulted in the dissociation o f the dimer to monomer. D2-TM peptides were unable to dissociate dopam ine D1 and serotonin 5-HT1B receptor dimers, suggesting that receptor dimers are formed by specific intermolecular noncovalent interactions involving TM regions. This opens a path to new selective therapeutic r eceptor-blocking compounds based on this principle of mimicking transm embrane portions of neurotransmitter receptors. (C) 1996 Academic Pres s, Inc.