Dopamine D3 receptor modulates D2 receptor effects on cAMP and GABA release at striatopallidal terminals-Modulation...

Dopamine D2 receptor (D₂R) is expressed in striatopallidal neurons and decreases forskolin-stimulated cyclic adenine monophosphate (cAMP) accumulation and gamma-aminobutyric acid (GABA) release. Dopamine D3 receptor (D₃R) mRNA is expressed in a population of striatal D₂R-expressing neurons. Also, D₃R protein and binding have been reported in the neuropil of globus pallidus. We explore whether D₂R and D₃R colocalize in striatopallidal terminals and whether D₃R modulates the D₂R effect on forskolin-stimulated [³H]cAMP accumulation in pallidal synaptosomes and high K⁺ stimulated-[³H]GABA release in pallidal slices. Previous reports in heterologous systems indicate that calmodulin (CaM) and CaMKII modulate D₂R and D₃R functions; thus, we study whether this system regulates its functional interaction. D₂R immunoprecipitates with CaM, and pretreatment with ophiobolin A or depolarization of synaptosomes with 15 mM of K⁺ decreases it. Both treatments increase the D₂R inhibition of forskolin-stimulated [³H]cAMP accumulation when activated with quinpirole, indicating a negative modulation of CaM on D₂R function. Quinpirole also activates D₃R, potentiating D₂R inhibition of cAMP accumulation in the ophiobolin A-treated synaptosomes. D₂R and D₃R immunoprecipitate in pallidal synaptosomes and decrease after the kainic acid striatal lesion, indicating the striatal origin of the presynaptic receptors. CaM-kinase II alfa (CaMKIIα) immunoprecipitates with D₃R and increases after high K⁺ depolarization. In the presence of KN62, a CaMKIIα blocker, D₃R potentiates D₂R effects on cAMP accumulation in depolarized synaptosomes and GABA release in pallidal slices, indicating D₃R function regulation by CaMKIIα. Our data indicate that D₃R potentiates the D₂R effect on cAMP accumulation and GABA release at pallidal terminals, an interaction regulated by the CaM-CaMKIIα system.