Synaptic inhibition by volatile ansethetics

挥发性麻醉剂的突触抑制

• 批准号: 6623321
• 负责人: LING-GANG WU
• 金额: $ 22.49万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2003-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6623321
• 关键词: action potentials; anesthetics; auditory pathways; biophysics; brain stem; calcium channel; calcium flux; calcium indicator; evoked potentials; general anesthesia; glutamates; halothane; inhalation anesthesia; isoflurane; laboratory rat; neural transmission; neurotransmitter transport; photolysis; potassium channel; preoptic areas; sectioning; sodium channel; synapses; tissue /cell preparation; voltage /patch clamp

Volatile anesthetics achieve their anesthetic effects partly by depressing excitatory glutamatergic synaptic transmission. Evidence suggests that depression of glutamatergic synaptic transmission is caused by inhibition of transmitter release. However, the cellular and molecular mechanisms underlying inhibition of transmitter release remain unclear. Based on our preliminary results, I hypothesize that volatile anesthetics depress glutamatergic synaptic transmission by reducing the presynaptic Ca2+ influx by two mechanisms: 1) inhibition of presynaptic Na+ channels, which decreases the action potential amplitude and thus the action potential-evoked Ca2+ influx, and 2) inhibition of presynaptic Ca2+ channels. We will test this hypothesis at a glutamatergic synapse in the medial nucleus of the trapezoid body in rat brainstem slices. This synapse offers a significant advantage over other synapses, because it has a large nerve terminal that allows for direct recordings of presynaptic action potentials, Na+, K+ and Ca2+ currents and fluorescence recordings of Ca2+ influx. These presynaptic recordings can be performed simultaneously with recordings of the postsynaptic excitatory current (EPSC) at the same synapse, which allows us to quantitatively evaluate the involvement of each presynaptic ion channel type in controlling action potential-evoked transmitter release. With these techniques, we will study the action of three commonly used volatile anesthetics, isoflurane, halothane and sevoflurane at clinically relevant concentrations. We will characterize the effects of these anesthetics on presynaptic Na+, K+ and Ca2+ channels and the contribution of each of these effects to depression of the EPSC. In addition, we will investigate whether these anesthetics also inhibit the EPSC by a mechanism independent of modulation of ion channels, i.e., direct inhibition of the release machinery. By revealing mechanisms underlying volatile anesthetic-induced depression of glutamate release, the proposed work will significantly contribute to our understanding of the cellular and molecular mechanisms of general anesthesia, and may ultimately help to design better general anesthetics.

挥发性麻醉剂部分通过抑制兴奋性谷氨酸突触传递来实现其麻醉效果。 有证据表明，谷氨酸能突触传递的抑制是由递质释放的抑制引起的。 然而，抑制递质释放的细胞和分子机制仍不清楚。根据我们的初步结果，我假设挥发性麻醉剂通过两种机制减少突触前 Ca2+ 流入，从而抑制谷氨酸突触传递：1) 抑制突触前 Na+ 通道，从而降低动作电位幅度，从而降低动作电位诱发的 Ca2+ 流入，2) 抑制突触前 Ca2+ 通道。 我们将在大鼠脑干切片梯形体内侧核的谷氨酸突触上检验这一假设。该突触比其他突触具有显着优势，因为它具有较大的神经末梢，可以直接记录突触前动作电位、Na+、K+ 和 Ca2+ 电流以及 Ca2+ 流入的荧光记录。 这些突触前记录可以与同一突触的突触后兴奋电流（EPSC）记录同时进行，这使我们能够定量评估每种突触前离子通道类型在控制动作电位诱发的递质释放中的参与。 通过这些技术，我们将研究临床相关浓度下三种常用挥发性麻醉剂异氟烷、氟烷和七氟烷的作用。 我们将描述这些麻醉剂对突触前 Na+、K+ 和 Ca2+ 通道的影响，以及每种影响对 EPSC 抑制的贡献。 此外，我们将研究这些麻醉剂是否也通过独立于离子通道调节的机制（即直接抑制释放机制）抑制 EPSC。 通过揭示挥发性麻醉剂引起的谷氨酸释放抑制的机制，所提出的工作将极大地促进我们对全身麻醉的细胞和分子机制的理解，并可能最终有助于设计更好的全身麻醉剂。

项目成果

Conversion of fibroblasts to neural cells by p53 depletion.

通过p53耗竭将成纤维细胞转化为神经细胞。

• DOI: 10.1016/j.celrep.2014.11.040
• 发表时间: 2014-12-24
• 期刊: Cell reports
• 影响因子: 8.8
• 作者: Zhou D;Zhang Z;He LM;Du J;Zhang F;Sun CK;Zhou Y;Wang XW;Lin G;Song KM;Wu LG;Yang Q
• 通讯作者: Yang Q