Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), Barry and Judy Silverman College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL 33328, USA.
Int J Mol Sci. 2024 May 11;25(10):5227. doi: 10.3390/ijms25105227.
Sympathetic nervous system (SNS) hyperactivity is mediated by elevated catecholamine (CA) secretion from the adrenal medulla, as well as enhanced norepinephrine (NE) release from peripheral sympathetic nerve terminals. Adrenal CA production from chromaffin cells is tightly regulated by sympatho-inhibitory α-adrenergic (auto)receptors (ARs), which inhibit both epinephrine (Epi) and NE secretion via coupling to Gi/o proteins. α-AR function is, in turn, regulated by G protein-coupled receptor (GPCR)-kinases (GRKs), especially GRK2, which phosphorylate and desensitize them, i.e., uncouple them from G proteins. On the other hand, the short-chain free fatty acid (SCFA) receptor (FFAR)-3, also known as GPR41, promotes NE release from sympathetic neurons via the Gi/o-derived free Gβγ-activated phospholipase C (PLC)-β/Ca signaling pathway. However, whether it exerts a similar effect in adrenal chromaffin cells is not known at present. In the present study, we examined the interplay of the sympatho-inhibitory α-AR and the sympatho-stimulatory FFAR3 in the regulation of CA secretion from rat adrenal chromaffin (pheochromocytoma) PC12 cells. We show that FFAR3 promotes CA secretion, similarly to what GRK2-dependent α-AR desensitization does. In addition, FFAR3 activation enhances the effect of the physiologic stimulus (acetylcholine) on CA secretion. Importantly, GRK2 blockade to restore α-AR function or the ketone body beta-hydroxybutyrate (BHB or 3-hydroxybutyrate), via FFAR3 antagonism, partially suppress CA production, when applied individually. When combined, however, CA secretion from PC12 cells is profoundly suppressed. Finally, propionate-activated FFAR3 induces leptin and adiponectin secretion from PC12 cells, two important adipokines known to be involved in tissue inflammation, and this effect of FFAR3 is fully blocked by the ketone BHB. In conclusion, SCFAs can promote CA and adipokine secretion from adrenal chromaffin cells via FFAR3 activation, but the metabolite/ketone body BHB can effectively inhibit this action.
交感神经系统（SNS）的活性亢进是由肾上腺髓质中儿茶酚胺（CA）分泌增加以及外周交感神经末梢去甲肾上腺素（NE）释放增强介导的。来自嗜铬细胞的肾上腺 CA 产生受交感抑制性 α-肾上腺素能（自）受体（ARs）的紧密调节，该受体通过与 Gi/o 蛋白偶联，抑制肾上腺素（Epi）和 NE 的分泌。α-AR 的功能又受 G 蛋白偶联受体（GPCR）-激酶（GRK）调节，特别是 GRK2，其通过磷酸化和脱敏（即与 G 蛋白解偶联）来调节它们。另一方面，短链游离脂肪酸（SCFA）受体（FFAR）-3，也称为 GPR41，通过 Gi/o 衍生的游离 Gβγ 激活的磷脂酶 C（PLC）-β/Ca 信号通路促进来自交感神经元的 NE 释放。然而，目前尚不清楚它是否在肾上腺嗜铬细胞中产生类似的作用。在本研究中，我们研究了交感抑制性 α-AR 和交感刺激性 FFAR3 在调节大鼠肾上腺嗜铬细胞瘤（嗜铬细胞瘤）PC12 细胞 CA 分泌中的相互作用。我们表明，FFAR3 促进 CA 分泌，类似于 GRK2 依赖性 α-AR 脱敏作用。此外，FFAR3 激活增强了生理刺激（乙酰胆碱）对 CA 分泌的影响。重要的是，GRK2 阻断以恢复 α-AR 功能或酮体β-羟丁酸（BHB 或 3-羟丁酸），通过 FFAR3 拮抗，可部分抑制 CA 生成，当单独应用时。然而，当联合应用时，PC12 细胞的 CA 分泌被显著抑制。最后，丙酸盐激活的 FFAR3 诱导 PC12 细胞分泌瘦素和脂联素，这两种重要的脂肪因子已知参与组织炎症，而 FFAR3 的这种作用被酮体 BHB 完全阻断。总之，SCFAs 可以通过 FFAR3 激活促进肾上腺嗜铬细胞中 CA 和脂肪因子的分泌，但代谢物/酮体 BHB 可以有效抑制这种作用。
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