胍基乙酸酯 (GAA) 是一种有效的 GABAA 受体 GABA 模拟物：对神经疾病病理学的影响,Journal of Neurochemistry

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胍基乙酸酯 (GAA) 是一种有效的 GABAA 受体 GABA 模拟物：对神经疾病病理学的影响
Journal of Neurochemistry ( IF 4.2 ) Pub Date : 2023-02-01 , DOI: 10.1111/jnc.15774
Pratap Meera ₁ , Mikko Uusi-Oukari ₂ , Martin Wallner ₃ , Gerald S Lipshutz _{3,

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Affiliation

例如，由于肝或肾衰竭，或尿素循环和肌酸合成酶缺陷，氮的排泄和酶促加工受损令人惊讶地导致主要的神经系统症状，但确切的机制在很大程度上仍然是个谜。在胍基乙酸 N-甲基转移酶 (GAMT) 缺乏症中，胍基化合物胍基乙酸 (GAA) 显着增加，包括在脑脊液 (CSF) 中，并且与介导 GAMT 缺陷患者的神经系统症状有关。GAA 由精氨酸-甘氨酸脒基转移酶 (AGAT) 合成，这是一种混杂的酶，不仅可以将脒基从精氨酸转移到甘氨酸，还可以转移到伯胺，例如 GABA 和牛磺酸，以生成 γ-胍基丁酸 (γ-GBA) ) 和胍基乙磺酸 (GES)，分别。_A受体 (GABA _A R) 在小鼠脑切片的小脑颗粒细胞中介导电流（而肌酸 [甲基化 GAA] 和精氨酸未能引起可辨别的电流）并取代全脑中的高亲和力 GABA 位点放射性配体 [ 3 H] 蕈^醇匀浆 GABA _A Rs。虽然 γ-GBA 和 GES 是 GABA 激动剂并取代 [ ³ H] 蕈醇（EC ₅₀ /IC ₅₀在 10 和 40 μM 之间），但 GAA 在激活 GABA _A Rs (EC ₅₀ ~6 μM) 和取代 GABA _A R 配体 [ ³ H] muscimol (IC ₅₀~3 μM) 在病理生理相关浓度。这些发现强调了显着升高的 GAA 作为 GAMT 缺乏症的主要神经毒剂的作用，我们讨论了 GAA 在精氨酸酶（和肌酸转运蛋白）缺乏症中的潜在作用，这表明 GAA 浓度的增加更为适度，但具有独特的过度兴奋性神经病理学GAMT 缺陷。我们得出结论，GAA 和潜在的其他 GABA A R 模拟胍基化合物 (GC)（如 γ-GBA 和 GES）对 GABA A Rs 的_正构激活会干扰正常的抑制性 GABA 能神经传递，后者可能介导并导致神经毒性_。

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Guanidinoacetate (GAA) is a potent GABAA receptor GABA mimetic: Implications for neurological disease pathology

Impairment of excretion and enzymatic processing of nitrogen, for example, because of liver or kidney failure, or with urea cycle and creatine synthesis enzyme defects, surprisingly leads to primarily neurologic symptoms, yet the exact mechanisms remain largely mysterious. In guanidinoacetate N-methyltransferase (GAMT) deficiency, the guanidino compound guanidinoacetate (GAA) increases dramatically, including in the cerebrospinal fluid (CSF), and has been implicated in mediating the neurological symptoms in GAMT-deficient patients. GAA is synthesized by arginine–glycine amidinotransferase (AGAT), a promiscuous enzyme that not only transfers the amidino group from arginine to glycine, but also to primary amines in, for example, GABA and taurine to generate γ-guanidinobutyric acid (γ-GBA) and guanidinoethanesulfonic acid (GES), respectively. We show that GAA, γ-GBA, and GES share structural similarities with GABA, evoke GABA_A receptor (GABA_AR) mediated currents (whereas creatine [methylated GAA] and arginine failed to evoke discernible currents) in cerebellar granule cells in mouse brain slices and displace the high-affinity GABA-site radioligand [³H]muscimol in total brain homogenate GABA_ARs. While γ-GBA and GES are GABA agonists and displace [³H]muscimol (EC₅₀/IC₅₀ between 10 and 40 μM), GAA stands out as particularly potent in both activating GABA_ARs (EC₅₀ ~6 μM) and also displacing the GABA_AR ligand [³H]muscimol (IC₅₀ ~3 μM) at pathophysiologically relevant concentrations. These findings stress the role of substantially elevated GAA as a primary neurotoxic agent in GAMT deficiency and we discuss the potential role of GAA in arginase (and creatine transporter) deficiency which show a much more modest increase in GAA concentrations yet share the unique hyperexcitability neuropathology with GAMT deficiency. We conclude that orthosteric activation of GABA_ARs by GAA, and potentially other GABA_AR mimetic guanidino compounds (GCs) like γ-GBA and GES, interferes with normal inhibitory GABAergic neurotransmission which could mediate, and contribute to, neurotoxicity.

更新日期：2023-02-01

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