Multiple signaling routes involved in the regulation of adenylyl cyclase and extracellular regulated kinase by dopamine D-2 and D-3 receptors

作者：Jin Mingli; Min Chengchun; Zheng Mei; Cho Dong Im; Cheong Soo Jin; Kurose Hitosh; Kim Kyeong Man^*

来源：Pharmacological Research, 2013, 67(1): 31-41.

DOI：10.1016/j.phrs.2012.09.012

• Angiotensin receptor
• Vasopressin receptor
• Pertussis toxin
• Ubiquitination

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/beta-arrestin-dependent signaling pathway for some GPCRs. Dopamine D-2 and D-3 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 beta-arrestin-dependent/G protein-independent signaling is not clear for these receptors. In this study, we determined the G protein subtypes and beta-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 G alpha o subunit but D3R used the beta gamma subunit of Gi family proteins. For the regulation of ERK activation, D2R used the alpha subunits of Gi/o proteins both in HEK-293 cells and COS-7 cells, but D3R used G alpha o and G beta gamma in HEK-293 cells and COS-7 cells, respectively. beta-Arrestin-dependent/G protein-independent ERK activation was not observed for both D2R and D3R. Agonist-induced beta-arrestin translocation was observed with D2R but not with D3R, and beta-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.

• 出版日期2013-1