| Cholesterol |
Plays a role in signal transduction and receptor oligomerization Stabilizes dimerization interface for various class A GPCRs Can affect GPCR oligomerization directly or indirectly through membrane organization Associates into lipid rafts, affecting signal transduction and regulating GPCR oligomers Directly involved in the dimerization of A2A adenosine receptors, β2-adrenergic receptors, 5-HT1A receptors, and μ-opioid receptors D1 dopamine receptor is sensitive to cholesterol, affecting localization, and homodimerization, while the D2 receptor remains unaffected
|
[73,74,75,76,77,78,79,80,81,82,83,84,85,86,87,88,89,90,91,92,93,94,95,96] |
| Polyunsaturated Fatty Acids |
Modulators of membrane physical properties, influencing GPCR activity Affect ligand binding and modulate oligomerization Facilitate partitioning of receptor molecules into ordered membrane domains Influence homo-oligomerization and hetero-oligomerization of receptors like A2AR and D2R Enhance D2 receptor ligand binding affinity and conformational dynamics Can weaken oligomerization by impeding the formation of compact dimers, as observed in the neurotensin receptor NTS1
|
[97,98,99,100,101,102,103,104] |
| Anionic Lipids |
GPCRs show a preference for anionic lipids over zwitterionic ones Impact membrane partitioning of receptor molecules and play a role in ternary interactions Enhance stability of the receptor’s active state and prolong its lifetime Unique interactions observed between G proteins and the dopamine D2 receptor involving specific lipid headgroups
|
[105,106,107,108,109,110] |
| G Proteins |
Lipid–protein interactions prevalent in G proteins, G protein-coupled effectors, and receptor kinases Post-translational fatty acid modifications crucial for accurate membrane localization Lipidations anchor proteins to the cytoplasmic side of the cell membrane G protein signaling through GPCRs is dependent on membrane localization Distinct membrane localizations of Gαi1-3; subunits influence signal transduction
|
[111,112,113,114,115,116,117,118,119,120,121,122,123,124] |
| Lipidation of GPCRs |
Lipidation affects signal transduction through dimers GPCRs can undergo palmitoylation, impacting various aspects of signaling and interactions with G proteins Palmitoylation facilitates receptor compartmentalization in lipid rafts and dimerization, as seen in opioid receptors
|
[125,126,127] |
| Active Role of Lipids in GPCR–Ligand Interaction |
Lipids and membrane surfaces influence the diffusion and dynamics of neurotransmitters and drugs targeting membrane proteins Membrane sorting may augment the binding rate of ligands designed to reach cell membrane-embedded or extracellular ligand-binding sites
|
[128,129] |
