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- W4308139715 abstract "Abstract Background Free fatty acids (FFAs) are essential cell nutrients but also important signaling molecules regulating various cellular processes. Short-chain fatty acids (SCFAs), like propionate and butyrate, activate two different types of G protein-coupled receptors (GPCRs), FFAR2 and FFAR3. FFAR3 (also known as GPR41) couples to Gi/o proteins lowering cyclic 3', 5'-adenosine monophosphate (cAMP) levels and activating mitogen-activated protein kinases (MAPKs). In addition to adipose tissue, FFAR3 is highly expressed in peripheral sympathetic ganglia augmenting sympathetic nervous system (SNS) outflow. Regulator of G protein Signaling (RGS)-4 belongs to the RGS superfamily of proteins and inactivates (terminates) both Gi/o- and Gq-protein signaling. Cardiac RGS4 has been implicated in atrial fibrillation (AFib) prevention via calcium signaling attenuation. Finally, β-adrenergic receptors (ARs), the major mediators of catecholaminergic and SNS actions in cardiac myocytes, stimulate cAMP synthesis and activate protein kinase A (PKA), which is known to activate RGS4 via phosphorylation. Objective We examined whether RGS4 regulates cardiac FFAR3 signaling. Methods We used H9c2 cardiomyocytes transfected to express the human FFAR3. After treatment with catecholaminergic agonists and/or propionic acid plus various pharmacological inhibitors and siRNA to deplete RGS4, we performed signaling assays (western blotting, cAMP accumulation, GTP binding, ELISA) to delineate the precise involvement of RGS4 in the cardiac βAR-FFAR3 signaling crosstalk. Results RGS4 is essential for the dampening of propionate/FFAR3-dependent signaling in H9c2 cardiomyocytes since siRNA-mediated RGS4 depletion significantly enhances the effect of propionic acid on cAMP lowering, Gi/o activation, and p38 MAPK activation. Notably, concomitant isoproterenol or salbutamol treatment blocks propionic acid-induced signaling via the FFAR3 in H9c2 cardiomyocytes, indicating negative regulation of FFAR3 by catecholamines via the β2AR. Mechanistically, this is mediated by RGS4, since neither isoproterenol, nor salbutamol can inhibit propionate signaling upon siRNA-mediated RGS4 depletion. Finally, β2AR inhibition of FFAR3 signaling via RGS4 is dependent on β2AR-activated PKA, because pre-treatment with the PKA inhibitor H89 abrogates the catecholaminergic inhibition of FFAR3 signaling in H9c2 cardiomyocytes, as measured by cAMP lowering, downstream p38 MAPK activation, and interleukin (IL)-6 production. Conclusion Catecholamine-activated RGS4 abrogates SCFA/FFAR3 signaling and function in cardiac myocytes. This may represent part of the mechanism via which RGS4 protects against both AFib pathogenesis and FFAR3-promoted SNS hyperactivity and inflammation in the myocardium. Presentation: Monday, June 13, 2022 12:30 p.m. - 2:30 p.m." @default.
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- W4308139715 date "2022-11-01" @default.
- W4308139715 modified "2023-09-26" @default.
- W4308139715 title "PMON181 RGS4 Is Essential For The Sympathetic Regulation of The Short-chain Fatty Acid Receptor FFAR3 In The Heart" @default.
- W4308139715 doi "https://doi.org/10.1210/jendso/bvac150.1220" @default.
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