Biomol Ther.  2019 Nov;27(6):514-521. 10.4062/biomolther.2019.026.

Role of Helix 8 in Dopamine Receptor Signaling

• Yang HS
• Sun N
• Zhao X
• Kim HR
• Park HJ
• Kim KM
• Chung KY

• KMID: 2462878
• DOI: http://doi.org/10.4062/biomolther.2019.026

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.

Keyword

GPCR; G protein; Helix 8; Dopamine receptor; Arrestin

MeSH Terms

Arrestin
Arrestins
Computational Biology
Cytosol
Dopamine*
Family Characteristics
GTP-Binding Proteins
Membranes
Phosphorylation
Receptors, Dopamine D1
Receptors, Dopamine D2
Receptors, Dopamine*
Arrestin
Arrestins
Dopamine
GTP-Binding Proteins
Receptors, Dopamine
Receptors, Dopamine D1
Receptors, Dopamine D2