Abstract
The dopamine D2 receptor belongs to rhodopsin-like G protein-coupled receptors (GPCRs) and it is an important molecular target for the treatment of many disorders, including schizophrenia and Parkinson’s disease. Here, computational methods were used to construct the full models of the dopamine D2 receptor short (D2S) and long (D2L) isoforms (differing with 29 amino acids insertion in the third intracellular loop, ICL3) and to study their coupling with Gi1 and Gi2 proteins. It was found that the D2L isoform preferentially couples with the Gi2 protein and D2S isoform with the Gi1 protein, which is in accordance with experimental data. Our findings give mechanistic insight into the interplay between isoforms of dopamine D2 receptors and Gi proteins subtypes, which is important to understand signaling by these receptors and their mediation by pharmaceuticals, in particular psychotic and antipsychotic agents.
Highlights
Dopamine receptors belong to rhodopsin-like G protein-coupled receptors (GPCRs) and share the molecular architecture typical for this family of proteins
Referring to the literature data indicating that R233 from the ICL3 of D2 receptor short (D2S) isoform is important for interaction with G protein [8], we investigated the interactions between the α subunit of G protein and R233 in ICL3 of both isoforms
As there are no reports about structural aspects of the full-length dopamine D2 receptor concerning its interactions with respective G proteins, we investigated how the length of the ICL3 loop affects the interactions with the Gi1 and Gi2 proteins and receptor activation processes
Summary
Dopamine receptors belong to rhodopsin-like G protein-coupled receptors (GPCRs) and share the molecular architecture typical for this family of proteins They consist of seven transmembrane (TM) helices, which are connected by three extracellular and three intracellular loops (ECL1, ECL2, ECL3, and ICL1, ICL2, ICL3, respectively). Dopamine receptors are divided into D1-like (D1 and D5 receptors) and D2-like (D2, D3, and D4 receptors) subfamilies based on their activation or inhibition of adenylyl cyclase These aminergic GPCRs are involved in regulation of many physiological conditions, ranging from voluntary movement and reward to hormonal regulation and hypertension [1], and they are important molecular targets for the treatment of a number of diseases: Parkinson’s disease, restless legs syndrome, sexual dysfunction, dementia, depression, bipolar disorder, Huntington’s disease, and schizophrenia [2]. It was found that dopamine D2S and D2L receptors may differentially contribute to the actions of antipsychotic and psychotic agents in mice [5]
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