Role of Helix 8 in Dopamine Receptor Signaling
10.4062/biomolther.2019.026
- Author:
Han Sol YANG
1
;
Ningning SUN
;
Xiaodi ZHAO
;
Hee Ryung KIM
;
Hyun Ju PARK
;
Kyeong Man KIM
;
Ka Young CHUNG
Author Information
1. School of Pharmacy, Sungkyunkwan University, Suwon 16419, Republic of Korea. kychung2@skku.edu
- Publication Type:Original Article
- Keywords:
GPCR;
G protein;
Helix 8;
Dopamine receptor;
Arrestin
- MeSH:
Arrestin;
Arrestins;
Computational Biology;
Cytosol;
Dopamine;
Family Characteristics;
GTP-Binding Proteins;
Membranes;
Phosphorylation;
Receptors, Dopamine D1;
Receptors, Dopamine D2;
Receptors, Dopamine
- From:Biomolecules & Therapeutics
2019;27(6):514-521
- CountryRepublic of Korea
- Language:English
-
Abstract:
G protein-coupled receptors (GPCRs) are membrane receptors whose agonist-induced dynamic conformational changes trigger heterotrimeric G protein activation, followed by GRK-mediated phosphorylation and arrestin-mediated desensitization. Cytosolic regions of GPCRs have been studied extensively because they are direct contact sites with G proteins, GRKs, and arrestins. Among various cytosolic regions, the role of helix 8 is least understood, although a few studies have suggested that it is involved in G protein activation, receptor localization, and/or internalization. In the present study, we investigated the role of helix 8 in dopamine receptor signaling focusing on dopamine D1 receptor (D1R) and dopamine D2 receptor (D2R). D1R couples exclusively to Gs, whereas D2R couples exclusively to Gi. Bioinformatic analysis implied that the sequences of helix 8 may affect GPCR-G protein coupling selectivity; therefore, we evaluated if swapping helix 8 between D1R and D2R changed G protein selectivity. Our results suggest that helix 8 is not involved in D1R-Gs or D2R-Gi coupling selectivity. Instead, we observed that D1R with D2R helix 8 or D1R with an increased number of hydrophobic residues in helix 8 relative to wild-type showed diminished β-arrestin-mediated desensitization, resulting in increased Gs signaling.