Multiple signaling routes involved in the regulation of adenylyl cyclase and extracellular regulated kinase by dopamine D2 and D3 receptors

Mingli Jin, Chengchun Min, Mei Zheng, Dong Im Cho, Soo Jin Cheong, Hitosh Kurose, Kyeong Man Kim

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14 Citations (Scopus)

Abstract

Most G protein coupled receptors (GPCR) regulate multiple cellular processes by coupling to more than one kind of G protein. Furthermore, recent studies have reported G protein-independent/β-arrestin-dependent signaling pathway for some GPCRs. Dopamine D2 and D3 receptors (D2R, D3R), the major targets of currently used antipsychotic drugs, are co-expressed in some of the same dopaminergic neurons and regulate the same overlapping effectors. However, the specific subunits of G proteins that regulate each signaling pathway are not clearly identified. In addition, the existence of β-arrestin-dependent/G protein-independent signaling is not clear for these receptors. In this study, we determined the G protein subtypes and β-arrestin dependency involved in the signaling of D2R and D3R, which was measured by inhibition of adenylyl cyclase and extracellular signal-regulated kinase (ERK) activation. For the inhibition of cAMP production in HEK-293 cells, D2R used the Gαo subunit but D3R used the βγ subunit of Gi family proteins. For the regulation of ERK activation, D2R used the α subunits of Gi/o proteins both in HEK-293 cells and COS-7 cells, but D 3R used Gαo and Gβγ in HEK-293 cells and COS-7 cells, respectively. β-Arrestin-dependent/G protein-independent ERK activation was not observed for both D2R and D3R. Agonist-induced β-arrestin translocation was observed with D2R but not with D3R, and β-arrestins exerted inhibitory influences on G protein-dependent ERK activation by D2R, but not D3R. These results show that the D2R and D3R, which have overlapping cellular expressions and functional roles, employ distinct G protein subunits depending on the cell types and the effectors they control.

Original languageEnglish
Pages (from-to)31-41
Number of pages11
JournalPharmacological Research
Volume67
Issue number1
DOIs
Publication statusPublished - Jan 1 2013

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All Science Journal Classification (ASJC) codes

  • Pharmacology

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