Oligomerization and cooperativity in GPCRs from the perspective of the angiotensin AT1 and dopamine D2 receptors

• Published in: Neuroscience letters 2019-05, Vol.700, p.30-37
• Main Authors: Durdagi, Serdar, Erol, Ismail, Salmas, Ramin Ekhteiari, Aksoydan, Busecan, Kantarcioglu, Isik
• Format: Article
• Language: English
• Subjects: Allosteric effects; Allosteric Regulation; Angiotensin AT1 receptor; Angiotensin II Type 1 Receptor Blockers - pharmacology; Animals; Brain - metabolism; Cell Membrane - chemistry; Cell Membrane - metabolism; Cholesterol - chemistry; Dopamine D2 receptor; GPCRs; Humans; Hypertension - metabolism; Ligands; MD simulations; Models, Molecular; Molecular modeling; Oligomerization; Protein Binding; Protein Conformation; Protein Multimerization; Protein-protein docking; Receptor, Angiotensin, Type 1 - chemistry; Receptor, Angiotensin, Type 1 - metabolism; Receptors, Dopamine D2 - chemistry; Receptors, Dopamine D2 - metabolism; Receptors, G-Protein-Coupled - chemistry; Receptors, G-Protein-Coupled - metabolism; Renin-Angiotensin System
• ISSN: 0304-3940; 1872-7972
• DOI: 10.1016/j.neulet.2018.04.028

•Oligomerization studies of GPCRs (focusing on D2R and AT1R) using molecular modeling approaches and experimental techniques are reviewed.•The interaction of GPCRs with various small molecules and the effects of these interactions on protein are discussed.•The effect of oligomerization to the conformational changes that affects signal transduction into the cell is discussed. G Protein-Coupled Receptors (GPCRs) can form homo- and heterodimers or constitute higher oligomeric clusters with other heptahelical GPCRs. In this article, multiscale molecular modeling approaches as well as experimental techniques which are used to study oligomerization of GPCRs are reviewed. In particular, the effect of dimerization/oligomerization to the ligand binding affinity of individual protomers and also on the efficacy of the oligomer are discussed by including diverse examples from the literature. In addition, possible allosteric effects that may emerge upon interaction of GPCRs with membrane components, like cholesterol, is also discussed. Investigation of these above-mentioned interactions may greatly contribute to the candidate molecule screening studies and development of novel therapeutics with fewer adverse effects.