The Role of Lipids in Allosteric Modulation of Dopamine D2 Receptor—In Silico Study

Abstract

The dopamine D2 receptor, belonging to the class A G protein-coupled receptors (GPCRs), is an important drug target for several diseases, including schizophrenia and Parkinson’s disease. The D2 receptor can be activated by the natural neurotransmitter dopamine or by synthetic ligands, which in both cases leads to the receptor coupling with a G protein. In addition to receptor modulation by orthosteric or allosteric ligands, it has been shown that lipids may affect the behaviour of membrane proteins. We constructed a model of a D2 receptor with a long intracellular loop (ICL3) coupled with Giα1 or Giα2 proteins, embedded in a complex asymmetric membrane, and simulated it in complex with positive, negative or neutral allosteric ligands. In this study, we focused on the influence of ligand binding and G protein coupling on the membrane–receptor interactions. We show that there is a noticeable interplay between the cell membrane, G proteins, D2 receptor and its modulators.

Review on allosteric modulators of dopamine receptors so far

“…The dopamine D 2 receptor is a key drug target for the treatment of many central nervous system diseases 48,49 . This receptor has been an important target for Parkinson's disease 50–52 and a therapeutic strategy in Alzheimer's disease 53,54 .…”

Allosteric Modulators of Dopamine D2 Receptors for Fine-Tuning of Dopaminergic Neurotransmission in CNS Diseases: Overview, Pharmacology, Structural Aspects and Synthesis

“…Next, the presence of the positive allosteric modulator affected the W7.40 conformation. In the subsequent studies Żuk et al [100] investigated the role of lipids for allosteric modulation of D 2 receptor. They found that there is a significant interplay between the membrane, G proteins, receptor and modulators.…”

Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

“…In addition to direct interaction with GPCR allosteric sites, lipids, affecting the physicochemical properties of the plasma membrane (fluidity, tension, and mechanical stability), are able to change the conformational characteristics of GPCRs and the kinetics of its activated states, as shown for photosensitive rhodopsin [ 134 ]. Lipids can affect subcellular compartmentalization and stability of complexes between GPCRs and different regulatory and adapter proteins, as well as the formation of caveolae and lipid rafts, which make a significant contribution to the functional activity of GPCRs [ 135 , 136 ]. This is especially relevant in connection with the concept of “spatial bias” in signaling from the plasma membrane to intracellular compartments, such as endosomes, the Golgi apparatus, and nuclear membranes [ 47 , 137 , 138 ].…”