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4-Hydroxynonenal-induced GPR109A (HCA2 receptor) activation elicits bipolar responses, Gαi -mediated anti-inflammatory effects and Gβγ -mediated cell death.
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ABSTRACT: Background and purpose
In this study, we examined the possibility that 4-hydroxynonenal (4-HNE) acting as a ligand for the HCA2 receptor (GPR109A) elicits both anti-inflammatory and cell death responses.Experimental approach
Agonistic activity of 4-HNE was determined by observing the inhibition of cAMP generation in CHO-K1-GPR109A-Gi cell line, using surface plasmon resonance (SPR) binding and competition binding assays with [3 H]-niacin. 4-HNE-mediated signalling pathways and cellular responses were investigated in cells expressing GPR109A and those not expressing these receptors.Key results
Agonistic activity of 4-HNE was stronger than that of niacin or 3-OHBA at inhibiting forskolin-induced cAMP production and SPR binding affinity. In ARPE-19 and CCD-841 cells, activation of GPR109A by high concentrations of the agonists 4-HNE (≥10 μM), niacin (≥1000 μM) and 3-OHBA (≥1000 μM) induced apoptosis accompanied by elevated Ca2+ and superoxide levels. This 4-HNE-induced cell death was blocked by knockdown of GPR109A or NOX4 genes, or treatment with chemical inhibitors of Gβγ (gallein), intracellular Ca2+ (BAPTA-AM), NOX4 (VAS2870) and JNK (SP600125), but not by the cAMP analogue 8-CPT-cAMP. By contrast, low concentrations of 4-HNE, niacin and 3-OHBA down-regulated the expression of pro-inflammatory cytokines IL-6 and IL-8. These 4-HNE-induced inhibitory effects were blocked by a cAMP analogue but not by inhibitors of Gβγ -downstream signalling molecules.Conclusions and implications
These results revealed that 4-HNE is a strong agonist for GPR109A that induces Gαi -dependent anti-inflammatory and Gβγ -dependent cell death responses. Moreover, the findings indicate that specific intracellular signalling molecules, but not GPR109A, can serve as therapeutic targets to block 4-HNE-induced cell death.
SUBMITTER: Gautam J
PROVIDER: S-EPMC6003634 | biostudies-literature | 2018 Jul
REPOSITORIES: biostudies-literature
Publications
4-Hydroxynonenal-induced GPR109A (HCA<sub>2</sub> receptor) activation elicits bipolar responses, G<sub>αi</sub> -mediated anti-inflammatory effects and G<sub>βγ</sub> -mediated cell death.
British journal of pharmacology 20180522 13
<h4>Background and purpose</h4>In this study, we examined the possibility that 4-hydroxynonenal (4-HNE) acting as a ligand for the HCA<sub>2</sub> receptor (GPR109A) elicits both anti-inflammatory and cell death responses.<h4>Experimental approach</h4>Agonistic activity of 4-HNE was determined by observing the inhibition of cAMP generation in CHO-K1-GPR109A-G<sub>i</sub> cell line, using surface plasmon resonance (SPR) binding and competition binding assays with [<sup>3</sup> H]-niacin. 4-HNE-me ...[more]