| Summary: | The type 2 dopamine receptor D<sub>2</sub> (D<sub>2</sub>-R), member of the G protein-coupled receptor (GPCR) superfamily, exists in two isoforms, short (D<sub>2S</sub>-R) and long (D<sub>2L</sub>-R). They differ by an additional 29 amino acids (AA) in the third cytoplasmic loop (ICL3) of the D<sub>2L</sub>-R. These isoforms differ in their intracellular localization and trafficking functionality, as D<sub>2L</sub>-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 D<sub>2</sub>-R and proteins interacting with the ICL3 of both isoforms, specifically with the 29 AA insert. These motifs might be involved in D<sub>2</sub>-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 D<sub>2</sub>-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.
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