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.
Highlights
G-protein-coupled receptors (GPCRs), termed seven-transmembrane receptors (7TMRs) are by far the largest family of membrane-bound receptors, which are involved in the regulation of the neurotransmitter dopamine effects as one of their targets [1]
After dopamine binds to the D1-R, the signaling pathway is canonically activated via the heterotrimeric protein Gαs and Golf G-proteins, leading to adenylate cyclase (AC) activation and cyclic adenosine monophosphate formation in the cell
Previous work had indicated that Gαi2 was selective for D2L-R [9,10], experimental data has indicated that selectivity regulation of Gαi is driven by the agonist-activated conformation of D2-R
Summary
G-protein-coupled receptors (GPCRs), termed seven-transmembrane receptors (7TMRs) are by far the largest family of membrane-bound receptors, which are involved in the regulation of the neurotransmitter dopamine effects as one of their targets [1]. Data acquired on genetically engineered D2-R mouse model indicates additional evidence for different roles of two isoforms in cognitive and motor functions [24], responsiveness to cocaine exposure [26], and therapeutic effects of antipsychotic drugs [27]. As a primary target for atypical and typical antipsychotic drugs and treatment of the Parkinson’s disease, many of those agents can cause potentially life-threatening and severe side effects due to the promiscuous activities against related D2-Rs [29] Because of this reason, it is necessary to be familiar with the details of the dopamine receptor’s complex structure and functions
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