<br>N-甲基-d-天冬氨酸受体的结构、功能和在有机磷化合物中毒中的作用,Biofactors

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N-甲基-d-天冬氨酸受体的结构、功能和在有机磷化合物中毒中的作用
Biofactors ( IF 5.0 ) Pub Date : 2024-02-28 , DOI: 10.1002/biof.2048
Dora Kolić ₁ , Zrinka Kovarik _{1,

2}

Affiliation

急性有机磷化合物（OP）中毒会诱发胆碱能危象的症状，并伴有严重的癫痫发作。癫痫发作是由胆碱能系统的过度刺激引起的，但谷氨酸能系统的过度激活会增强癫痫发作。升高的乙酰胆碱对毒蕈碱胆碱能受体的过度刺激导致谷氨酸能过度兴奋，并通过一种离子型谷氨酸受体 N-甲基-d-天冬氨酸（NMDA）受体（NMDAR）增加 Ca²⁺ 流入神经元。这些兴奋性毒性信号转导过程产生活性氧、氧化应激和神经炎症反应的激活，这可能导致反复发作的癫痫发作、神经元细胞死亡和长期的神经损伤。在这篇综述中，我们说明了 NMDAR 结构、亚基组成的复杂性以及相应变化的各种受体特性。尽管 NMDARs 在正常的生理条件下对控制突触可塑性和介导学习和记忆功能很重要，但我们详细阐述了 NMDARs 在 OPs 的神经毒性中起的不利影响，并重点介绍了 NMDAR 抑制在抑制神经毒性和调节炎症反应中的核心作用。目前药物治疗 OP 中毒在产生耐药性和减轻促炎反应方面的疗效有限，这突出了 NMDAR 抑制剂在预防神经毒性过程方面的重要性，并为探索 OP 中毒的治疗方法指明了新的途径。

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N-methyl-d-aspartate receptors: Structure, function, and role in organophosphorus compound poisoning

Acute organophosphorus compound (OP) poisoning induces symptoms of the cholinergic crises with the occurrence of severe epileptic seizures. Seizures are induced by hyperstimulation of the cholinergic system, but are enhanced by hyperactivation of the glutamatergic system. Overstimulation of muscarinic cholinergic receptors by the elevated acetylcholine causes glutamatergic hyperexcitation and an increased influx of Ca²⁺ into neurons through a type of ionotropic glutamate receptors, N-methyl-d-aspartate (NMDA) receptors (NMDAR). These excitotoxic signaling processes generate reactive oxygen species, oxidative stress, and activation of the neuroinflammatory response, which can lead to recurrent epileptic seizures, neuronal cell death, and long-term neurological damage. In this review, we illustrate the NMDAR structure, complexity of subunit composition, and the various receptor properties that change accordingly. Although NMDARs are in normal physiological conditions important for controlling synaptic plasticity and mediating learning and memory functions, we elaborate the detrimental role NMDARs play in neurotoxicity of OPs and focus on the central role NMDAR inhibition plays in suppressing neurotoxicity and modulating the inflammatory response. The limited efficacy of current medical therapies for OP poisoning concerning the development of pharmacoresistance and mitigating proinflammatory response highlights the importance of NMDAR inhibitors in preventing neurotoxic processes and points to new avenues for exploring therapeutics for OP poisoning.

更新日期：2024-02-28

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