Critical Impact of Different Conserved Endoplasmic Retention Motifs and Dopamine Receptor Interacting Proteins (DRIPs) on Intracellular Localization and Trafficking of the D2 Dopamine Receptor (D2-R) Isoforms

Abstract

The type 2 dopamine receptor D2 (D2-R), member of the G protein-coupled receptor (GPCR) superfamily, exists in two isoforms, short (D2S-R) and long (D2L-R). They differ by an additional 29 amino acids (AA) in the third cytoplasmic loop (ICL3) of the D2L-R. These isoforms differ in their intracellular localization and trafficking functionality, as D2L-R possesses a larger intracellular pool, mostly in the endoplasmic reticulum (ER). This review focuses on the evolutionarily conserved motifs in the ICL3 of the D2-R and proteins interacting with the ICL3 of both isoforms, specifically with the 29 AA insert. These motifs might be involved in D2-R exit from the ER and have an impact on cell-surface and intracellular localization and, therefore, also play a role in the function of dopamine receptor signaling, ligand binding and possible homo/heterodimerization. Our recent bioinformatic data on potential new interaction partners for the ICL3 of D2-Rs are also presented. Both are highly relevant, and have clinical impacts on the pathophysiology of several diseases such as Parkinson’s disease, schizophrenia, Tourette’s syndrome, Huntington’s disease, manic depression, and others, as they are connected to a variety of essential motifs and differences in communication with interaction partners.

Evidence for Protein–Protein Interaction between Dopamine Receptors and the G Protein-Coupled Receptor 143

“…DRs regulate numerous physiological functions and have been linked to numerous pathological conditions [7,8]. DRs have been shown to be very promiscuous and complex with many other GPCRs in order to carry out these multiple functions with specificity [7,14,16,19,[51][52][53][54][55].…”

“…Dopamine receptors (DRs, DRD 1 -DRD 5 ) are a family of GPCRs that regulate numerous physiological functions including vision, cognitive function, and voluntary movement. They have been associated with pathological conditions and mental disorders such as Parkinson's disease, schizophrenia, and nicotine addiction [6][7][8]. DR activity can be modulated by dimerization and/or oligomerization with other DRs as well as other GPCRs such as adenosine A 1 receptors, glutamate N-methyl-D-aspartate receptors, or cannabinoid 1 receptors, which can further diversify and fine-tune their function [9][10][11][12][13][14].…”

Cell-to-cell variations in subcellular localisation of V2R are independent of its expression level

“…Moreover, a dependence on the cell type with respect to the subcellular localisation of a GPCR has been reported. (Blagotinšek Cokan, Mavri et al 2020)…”

“…Moreover, a dependence on the cell type with respect to the subcellular localisation of a GPCR has been reported. (Blagotinšek Cokan, Mavri et al 2020) We hypothesise that the interplay of a specific mutation and the cellular environment is a strong factor in determining receptor fate and biogenesis efficiency. To test this, we systematically probed a large panel of mutants for expression and localisation in the same cell type.…”

“…Protein degradation pathways also may play an important role in ability of GPCRs to reach cell surface, exemplified by the proteosome inhibitor bortezomib being able to rescue cell-surface expression of ER-retained mutants of GPCRs in a universal matter (Morfa et al, 2018). Many potential effectors that are involved in GPCR folding and quality control may affect trafficking of GPCRs to the cell surface (Achour, Labbé-Jullié, Scott, & Marullo, 2008) and a dependence on the cell type with respect to the subcellular localisation of a GPCR has been reported (Blagotinšek Cokan et al, 2020).…”