G-protein coupled receptors (GPCR) and environmental exposure. Consequences for cell metabolism using the β-adrenoceptors as example

Abstract

International audienceThe impact of endocrine disruptors (EDs), compounds disturbing the normal action of hormones, represents a major field of toxicological research, in particular through the interference with steroid hormones and their nuclear receptors. By contrast, G-protein coupled receptors (GPCRs) have been a major focus of pharmacological research and drug-development, but have received limited attention in toxicology as potential targets of EDs. In this review we discuss the potential importance of GPCRs in the mode of action of EDs, using the recently observed interaction between polycyclic aromatic hydrocarbons (PAHs) and β-adrenergic receptors as an example. This ability to disturb adrenoceptor function represent a novel mode of action (MOA) for hormone disruption by EDs which may affect both metabolic processes and immune responses. The outcome may be of relevance to development or exacerbation of multifactorial non-communicable diseases (NCDs). © 2017 Elsevier B.V

Molecular mechanisms linking environmental toxicants to cancer development: Significance for protective interventions with polyphenols

“…Non-coplanar PCBs, PBDEs, bisphenol A, phthalates, DDT and other organochlorine pesticides, can act as estrogen receptor agonists or antagonists, exert antiandrogenic activity and/or target the thyroid system [49,[89][90][91]. In addition to nuclear receptors-mediated actions, rapid effects of some endocrine disruptors on intracellular calcium or cAMP levels implicate membrane receptors such as G protein-coupled receptors (GPCRs) in the toxicity mechanisms [92].…”

“…Various studies have been pointing GPCRs, such as adrenergic and dopaminergic receptors, as targets of environmental toxicants mediating their immune and metabolic effects, and B[a]P was demonstrated to bind to the beta2-adrenergic receptor [92,150]. Orai1 and STIM1 expression are increased in cancer cells, namely in malignant esophageal squamous cell carcinoma [151], in multiple myeloma cells [152] and in cervical cancer [153].…”

Molecular characterization of G-protein-coupled receptor (GPCR) and protein kinase A (PKA) cDNA in Perinereis aibuhitensis and expression during benzo(a)pyrene exposure

“…However, no AhR homologues have been identified in other invertebrates, including marine polychaetes (Jorgensen et al, 2008). Le Ferrec & Øvrevik (2018) reported that a number of GPCR ligands contain aromatic structures, and that B(a)P modulates the concentration of intracytosolic cAMP through the GPCR pathway without the involvement of conventional nuclear receptors. In this study, we demonstrated the induction of GPCR and PKA expression during B(a)P exposure, so we hypothesized that the GPCR pathway is also involved in the biotransformation of PAHs in P. aibuhitensis .…”

“…Because the aromatic structures present a number of GPCR ligands, GPCRs are potential targets of aromatic pollutants such as B(a)P (Le Ferrec & Øvrevik, 2018). Mayati et al (2012) reported the interaction between B(a)P and the β 2 -adrenergic receptor (β 2 ADR) in endothelial HMEC-1 cells and the consequent increase in intracellular Ca 2+ , which influenced the expression of cytochrome P450 B1.…”

Rafting on the Evidence for Lipid Raft-like Domains as Hubs Triggering Environmental Toxicants’ Cellular Effects

“…In addition to the luteinizing hormone receptor and TSHR already mentioned, there are GPCRs for a variety of peptide hormones, lipid mediators of inflammation, and biogenic amines (e.g., adrenaline), among other ligands, and GPCRs are commonly palmitoylated and located at cholesterol-rich domains of the plasma membrane [ 174 , 175 ]. In this regard, the β-adrenoceptor has been implicated in the PAH-induced increase of intracellular calcium concentration [ 176 ], and the beta-blocker carvedilol attenuates B[a]P toxicity [ 177 ]. GPCRs transduce the signal primarily by the cAMP/protein kinase A and the phosphatidylinositol/PLC/PKC pathways, incorporating calcium/calmodulin, ROS, and nitric oxide signaling, so their possible modulation by environmental toxicants warrants more extensive studies.…”