Abstract
G protein-coupled receptors (GPCRs) are historically the most successful family of drug targets. In recent times it has become clear that the pharmacology of these receptors is far more complex than previously imagined. Understanding of the pharmacological regulation of GPCRs now extends beyond simple competitive agonism or antagonism by ligands interacting with the orthosteric binding site of the receptor to incorporate concepts of allosteric agonism, allosteric modulation, signaling bias, constitutive activity, and inverse agonism. Herein, we consider how evolving concepts of GPCR pharmacology have shaped understanding of the complex pharmacology of receptors that recognize and are activated by nonesterified or "free" fatty acids (FFAs). The FFA family of receptors is a recently deorphanized set of GPCRs, the members of which are now receiving substantial interest as novel targets for the treatment of metabolic and inflammatory diseases. Further understanding of the complex pharmacology of these receptors will be critical to unlocking their ultimate therapeutic potential.
Highlights
Alongside the multitude of hormones, neurotransmitters, and other regulatory factors that are generated by cells and tissues of multicellular organisms to allow integration of communication, recent years have seen an explosion of information about the capacity of molecules contained within or derived from food sources to regulate and control cellular function and maintain homeostasis
The current review centers on a family of G protein-coupled receptors (GPCRs) activated by free fatty acids and in particular will examine the complex pharmacology of both the fatty acid and the synthetic molecules that regulate the function of these receptors, in particular as this relates to the ability of these receptors to regulate metabolism and inflammation
A recent study demonstrated that effects of rosiglitazone to upregulate gene targets through peroxisome proliferator−activated receptor-γ (PPARγ) involved an initial activation of FFA1, suggesting a complex, dual-receptor signaling pathway between PPARγ and FFA1.160 While these findings suggest a complex pharmacology of the thiazolidinediones, it must be noted that the potency of these ligands at FFA1 is rather modest and potentially at the limits of clinically relevant concentrations.[154]
Summary
Alongside the multitude of hormones, neurotransmitters, and other regulatory factors that are generated by cells and tissues of multicellular organisms to allow integration of communication, recent years have seen an explosion of information about the capacity of molecules contained within or derived from food sources to regulate and control cellular function and maintain homeostasis. Key among these are the nonesterified or “free” fatty acids, which have long been known to have diverse effects on many biological processes, including those related to cardiovascular health, metabolism, and inflammation. Consideration will be given to key areas of both biological knowledge and pharmacological tools that are still lacking that would further expand our understanding of this important family of receptors
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