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Dopamine D3 receptor modulates D2 receptor effects on cAMP and GABA release at striatopallidal terminals—Modulation by the Ca 2+ –Calmodulin–CaMKII system

2023; Wiley; Volume: 59; Issue: 7 Linguagem: Inglês

10.1111/ejn.16237

1460-9568

Flor Selene Villalobos‐Escobedo, Rafael Jijón‐Lorenzo, José Arturo Ávalos‐Fuentes, Francisco Paz‐Bermúdez, Sergio Recillas‐Morales, Israel Conde Rojas, Gerardo Leyva‐Gómez, Hernán Cortés, Benjamí­n Florán,

Neurological disorders and treatments

Abstract Dopamine D2 receptor (D 2 R) is expressed in striatopallidal neurons and decreases forskolin‐stimulated cyclic adenine monophosphate (cAMP) accumulation and gamma‐aminobutyric acid (GABA) release. Dopamine D3 receptor (D 3 R) mRNA is expressed in a population of striatal D 2 R‐expressing neurons. Also, D 3 R protein and binding have been reported in the neuropil of globus pallidus. We explore whether D 2 R and D 3 R colocalize in striatopallidal terminals and whether D 3 R modulates the D 2 R effect on forskolin‐stimulated [ 3 H]cAMP accumulation in pallidal synaptosomes and high K + stimulated‐[ 3 H]GABA release in pallidal slices. Previous reports in heterologous systems indicate that calmodulin (CaM) and CaMKII modulate D 2 R and D 3 R functions; thus, we study whether this system regulates its functional interaction. D 2 R immunoprecipitates with CaM, and pretreatment with ophiobolin A or depolarization of synaptosomes with 15 mM of K + decreases it. Both treatments increase the D 2 R inhibition of forskolin‐stimulated [ 3 H]cAMP accumulation when activated with quinpirole, indicating a negative modulation of CaM on D 2 R function. Quinpirole also activates D 3 R, potentiating D 2 R inhibition of cAMP accumulation in the ophiobolin A‐treated synaptosomes. D 2 R and D 3 R 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 D 3 R and increases after high K + depolarization. In the presence of KN62, a CaMKIIα blocker, D 3 R potentiates D 2 R effects on cAMP accumulation in depolarized synaptosomes and GABA release in pallidal slices, indicating D 3 R function regulation by CaMKIIα. Our data indicate that D 3 R potentiates the D 2 R effect on cAMP accumulation and GABA release at pallidal terminals, an interaction regulated by the CaM–CaMKIIα system.