Chemical Tools for Studying Lipid-Binding Class A G Protein–Coupled Receptors

Abstract

Cannabinoid, free fatty acid, lysophosphatidic acid, sphingosine 1-phosphate, prostanoid, leukotriene, bile acid, and platelet-activating factor receptor families are class A G protein-coupled receptors with endogenous lipid ligands. Pharmacological tools are crucial for studying these receptors and addressing the many unanswered questions surrounding expression of these receptors in normal and diseased tissues. An inherent challenge for developing tools for these lipid receptors is balancing the often lipophilic requirements of the receptor-binding pharmacophore with favorable physicochemical properties to optimize highly specific binding. In this study, we review the radioligands, fluorescent ligands, covalent ligands, and antibodies that have been used to study these lipid-binding receptors. For each tool type, the characteristics and design rationale along with in vitro and in vivo applications are detailed.

Correlations Between Intestinal Microbial Community and Hematological Profile in Native Tibetans and Han Immigrants

“…Parabacteroides species modulate the host metabolism by the produce of succinate and secondary bile acids (Wang et al, 2019). Bile acid receptors and platelet-activating factor receptors are numbers of the G-protein-coupled receptors family, which Frontiers in Microbiology | www.frontiersin.org are activated by lipid-derived endogenous ligands (Cooper et al, 2017). Cholesterol, cholic acid, ursodeoxycholic acid, deoxycholic acid, and tauroursodeoxycholic acid affect platelet activation through adenosine diphosphate (ADP; Baele et al, 1980;McGregor et al, 1980;Tan et al, 2012).…”

GPCR Modulation in Breast Cancer

“…Following computational studies, electrostatic contacts occurring between the two basic amino acids Arg-120 and Arg-292 and the phosphate group of S1P, as well as between the ammonium group and the residue Glu-121, have indeed been observed [77]. S1P analogues issued from rational modifications of the lipidic chain have also been synthesized (e.g., [78,79]). The functional S1P receptor antagonist FTY720 (Gilenya ® , fingolimod, 2-amino-2-[2-(4-octylphenyl)ethyl]propan-1,3-diol) becomes active after its phosphorylation by the intracellular type 2 sphingosine kinase, an enzyme that is in charge of the conversion of sphingosine into S1P [80].…”

Selective Photoaffinity Probe That Enables Assessment of Cannabinoid CB2 Receptor Expression and Ligand Engagement in Human Cells

“… 17 This provides a challenge for the study of GPCRs, because they are usually expressed at very low levels in native cells and tissues. 18 In addition, GPCRs are known for their inducible nature, which includes the adaptation from inactive to active conformations and internalization and desensitization upon durable activation. These factors may lead to variable surface expression of the GPCRs.…”