Department of Pharmacy, Section of Pharmacology and Toxicology, University of Genova, Italy.
Department of Experimental Medicine, Section of Biochemistry and Italian Institute of Biostructures and Biosystems, University of Genova, Italy.
Biofactors. 2018 Mar;44(2):148-157. doi: 10.1002/biof.1406. Epub 2017 Dec 19.
Glucagon-like peptide-1 receptors (GLP-1Rs) have been shown to mediate cognitive-enhancing and neuroprotective effects in the central nervous system. However, little is known about their physiological roles on central neurotransmission, especially at the presynaptic level. Using purified synaptosomal preparations and immunofluorescence techniques, here we show for the first time that GLP-1Rs are localized on mouse cortical and hippocampal synaptic boutons, in particular on glutamatergic and GABAergic nerve terminals. Their activation by the selective agonist exendin-4 (1-100 nM) was able to increase the release of either [ H]d-aspartate or [ H]GABA. These effects were abolished by 10 nM of the selective GLP1-R antagonist exendin-3 (9-39) and were prevented by the selective adenylyl cyclase inhibitor 2',5'-dideoxyadenosine (10 µM), indicating the involvement of classic GLP-1Rs coupled to G protein stimulating cAMP synthesis. Our data demonstrate the existence and activity of presynaptic receptors for GLP-1 that could represent additional mechanisms by which this neurohormone exerts its effects in the CNS. © 2017 BioFactors, 44(2):148-157, 2018.
胰高血糖素样肽-1 受体 (GLP-1Rs) 已被证明在中枢神经系统中具有增强认知和神经保护作用。然而，关于它们在中枢神经传递中的生理作用，特别是在突触前水平上的作用，知之甚少。本研究使用纯化的突触小体制剂和免疫荧光技术，首次表明 GLP-1Rs 定位于小鼠皮质和海马突触小体上，特别是在谷氨酸能和 GABA 能神经末梢上。选择性激动剂 exendin-4（1-100 nM）的激活能够增加 [ H]d-天冬氨酸或 [ H]GABA 的释放。这些作用被 10 nM 的选择性 GLP1-R 拮抗剂 exendin-3（9-39）所阻断，并且被选择性腺苷酸环化酶抑制剂 2'，5'-双脱氧腺苷（10 µM）所预防，表明存在经典的 GLP-1R 与 G 蛋白偶联，刺激 cAMP 的合成。我们的数据表明存在和活性的 GLP-1 突触前受体，这可能是这种神经激素在中枢神经系统中发挥作用的额外机制。
