毛喉素逆转了海马突触GABAAR电流幅度的O-GlcNA酰化依赖性降低，可能是在GABAAR的神经甾体部位-动脉网

Forskolin reverses the O-GlcNAcylation dependent decrease in GABAAR current amplitude at hippocampal synapses possibly at a neurosteroid site on GABAARs

Nature 等信源发布 2024-07-29 04:58

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AbstractGABAergic transmission is influenced by post-translational modifications, like phosphorylation, impacting channel conductance, allosteric modulator sensitivity, and membrane trafficking. O-GlcNAcylation is a post-translational modification involving the O-linked attachment of β-N-acetylglucosamine on serine/threonine residues.

摘要GABA能传递受翻译后修饰的影响，如磷酸化，影响通道电导，变构调节剂敏感性和膜运输。O-GlcNAcylation是一种翻译后修饰，涉及β-N-乙酰葡糖胺在丝氨酸/苏氨酸残基上的O-连接。

Previously we reported an acute increase in O-GlcNAcylation elicits a long-term depression of evoked GABAAR inhibitory postsynaptic currents (eIPSCs) onto hippocampal principal cells. Importantly, O-GlcNAcylation and phosphorylation can co-occur or compete for the same residue; whether they interact in modulating GABAergic IPSCs is unknown.

以前，我们报道了O-GlcNAcylation的急剧增加会引起海马主细胞上诱发的GABAAR抑制性突触后电流（eIPSC）的长期抑制。重要的是，O-GlcNAcylation和磷酸化可以共同发生或竞争相同的残基；它们是否在调节GABA能iPSC中相互作用尚不清楚。

We tested this by recording IPSCs from hippocampal principal cells and pharmacologically increased O-GlcNAcylation, before or after increasing serine phosphorylation using the adenylate cyclase activator, forskolin. Although forskolin had no significant effect on baseline eIPSC amplitude, we found that a prior increase in O-GlcNAcylation unmasks a forskolin-dependent increase in eIPSC amplitude, reversing the O-GlcNAc-induced eIPSC depression.

我们通过记录海马主细胞的iPSC和药理学上增加的O-GlcNAcylation来测试这一点，在使用腺苷酸环化酶激活剂福司柯林增加丝氨酸磷酸化之前或之后。。

Inhibition of adenylate cyclase or protein kinase A did not prevent the potentiating effect of forskolin, indicating serine phosphorylation is not the mechanism. Surprisingly, increasing O-GlcNAcylation also unmasked a potentiating effect of the neurosteroids 5α-pregnane-3α,21-diol-20-one (THDOC) and progesterone on eIPSC amplitude in about half of the recorded cells, mimicking forskolin.

抑制腺苷酸环化酶或蛋白激酶A并不能阻止福司柯林的增强作用，表明丝氨酸磷酸化不是其机制。令人惊讶的是，在大约一半的记录细胞中，增加O-GlcNAcylation也揭示了神经甾体5α-孕烷-3α，21-二醇-20-酮（THDOC）和孕酮对eIPSC振幅的增强作用，类似于福司柯林。

Our findings show that under conditions of heightened O-GlcNAcylation, the neurosteroid site on synaptic GABAARs is possibly accessible to agonists, permitting strengthening of synaptic inhibition..

我们的研究结果表明，在O-GlcNAcylation升高的条件下，突触GABAAR上的神经甾体位点可能被激动剂接近，从而可以加强突触抑制。。

IntroductionGamma-aminobutyric acid type A receptors (GABAARs) are heteropentameric ligand-gated chloride channels composed of α, β, γ, and sometimes δ subunits that mediate both fast synaptic and tonic inhibition, depending on their synaptic vs extrasynaptic location, respectively1. Mutations in specific subunits are linked to epilepsy syndromes2, and gene polymorphisms in specific GABAAR subunits associate with neuropsychiatric disorders, including alcohol use disorder3, anxiety4, schizophrenia5, bipolar disorder5, and even major depressive disorder6, including postpartum depression7.For decades it has been appreciated that neurosteroids mediate their sedative hypnotic and anxiolytic effects via positive allosteric binding to specific GABAAR subunits, particularly extrasynaptic GABAARs containing α4, α5 or δ subunits8,9.

引言γ-氨基丁酸A型受体（GABAAR）是由α，β，γ和有时δ亚基组成的异五聚体配体门控氯通道，分别介导快速突触和强直抑制，具体取决于它们的突触与突触外位置1。特定亚基的突变与癫痫综合征有关，特定GABAAR亚基的基因多态性与神经精神疾病有关，包括酒精使用障碍3，焦虑症4，精神分裂症5，双相情感障碍5，甚至包括产后抑郁症7。几十年来，人们已经认识到神经甾体通过与特定GABAAR亚基的正变构结合来介导其镇静催眠和抗焦虑作用，特别是含有α4，α5或δ亚基的突触外GABAAR 8,9。

GABAAR function is also potently modulated by serine phosphorylation10. For example, protein kinase A (PKA) mediated phosphorylation of specific serines on synaptic GABAARs induced by application of the adenylate cyclase activator, forskolin, bidirectionally modulates GABA-gated current amplitude and induces endocytosis depending on the neuron type and phosphorylated residue8,11,12,13,14.

GABAAR功能也受到丝氨酸磷酸化的有效调节10。例如，通过应用腺苷酸环化酶激活剂福司柯林诱导的蛋白激酶A（PKA）介导的突触GABAAR上特定丝氨酸的磷酸化双向调节GABA门控电流幅度并根据神经元类型和磷酸化残基诱导内吞作用8,11,12,13,14。

Importantly, the phosphorylation state has direct consequences on potency of allosteric modulation of GABAARs by neurosteriods, barbiturates, and benzodiazepines in a subunit-specific manner10.The post-translational modification of proteins by β-N-acetylglucosamine via an O-linkage on serine and threonine residues (O-GlcNAcylation), can modulate protein phosphorylation by competing directly with phosphorylation for the same residues, or indirectly via modification of other sites thereby changing protein structure and protein–protein interactions.

重要的是，磷酸化状态对神经甾体，巴比妥类和苯二氮卓类以亚基特异性方式变构调节GABAARs的效力有直接影响10。β-N-乙酰葡糖胺通过丝氨酸和苏氨酸残基上的O-键对蛋白质进行翻译后修饰（O-GlcNAcylation），可以通过直接与相同残基的磷酸化竞争来调节蛋白质磷酸化，或者通过修饰其他位点间接调节蛋白质结构和蛋白质-蛋白质相互作用。

In addition, many ki.

此外，许多ki。

Data availability

数据可用性

The datasets generated and analyzed during the current study are available from the corresponding author on reasonable request.

在当前研究期间生成和分析的数据集可根据合理的要求从通讯作者处获得。

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Download referencesAcknowledgementsThis research was supported by MUSC Institutional funds to L.L.M. and S.P.; NIA R01AG066489 to LLM and 1F99NS134163-01 and NINDS R25 NS089463 to F. Lubin at UAB.Author informationAuthors and AffiliationsDepartment of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, 35294, USAShekinah Phillips & Lori L.

下载参考文献致谢本研究得到了MUSC机构基金对L.L.M.和S.P.的支持。；LLM的NIA R01AG066489和UAB的F.Lubin的1F99NS134163-01和NINDS R25 NS089463。作者信息作者和附属机构阿拉巴马大学伯明翰分校细胞，发育和整合生物学系，伯明翰，AL，35294，USAShekinah PHILIPS＆Lori L。

McMahonDivision of Molecular and Cellular Pathology, Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35294, USAJohn C. ChathamDepartment of Neuroscience, Medical University of South Carolina, 173 Ashley Ave, Charleston, SC, 29403, USAShekinah Phillips & Lori L. McMahonAuthorsShekinah PhillipsView author publicationsYou can also search for this author in.

McMahonDivision of Molecular and Cellular Pathology，Department of Pathology，阿拉巴马大学伯明翰分校，伯明翰，阿拉巴马州，35294，美国约翰·C·查塔姆南卡罗莱纳医科大学神经科学系，173 Ashley Ave，Charleston，SC，29403，USAShekinah PHILIPS＆Lori L.McMahonAuthorsShekinah PHILIPVIEW author Publications你也可以在中搜索这位作者。

PubMed Google ScholarJohn C. ChathamView author publicationsYou can also search for this author in

PubMed谷歌学者John C.ChathamView作者出版物您也可以在

PubMed Google ScholarLori L. McMahonView author publicationsYou can also search for this author in

PubMed谷歌学术评论L.McMahonView作者出版物您也可以在中搜索这位作者。的信息。的研究报告中找到他。的作者。的研究报告。的研究报告。的研究报告中，该报告的作者是一位来自美国的学者，他是一位研究人员，他是一位研究人员，他

PubMed Google ScholarContributionsS.P. and L.L.M. designed the experiments; S.P. conducted experiments; S.P. and L.L.M. analyzed data; S.P., J.C.C., and L.L.M. wrote and revised the manuscript.Corresponding authorCorrespondence to

PubMed谷歌学术贡献。P、和L.L.M.设计了实验；S、 P.进行实验；S、 P.和L.L.M.分析数据；S、 P.，J.C.C。和L.L.M.撰写并修订了手稿。对应作者对应

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Reprints and permissionsAbout this articleCite this articlePhillips, S., Chatham, J.C. & McMahon, L.L. Forskolin reverses the O-GlcNAcylation dependent decrease in GABAAR current amplitude at hippocampal synapses possibly at a neurosteroid site on GABAARs.

转载和许可本文引用本文Phillips，S.，Chatham，J.C。＆McMahon，L.L。Forskolin逆转了海马突触中GABAAR电流幅度的O-GlcNAcylation依赖性降低，可能是在GABAAR的神经甾体部位。

Sci Rep 14, 17461 (2024). https://doi.org/10.1038/s41598-024-66025-wDownload citationReceived: 21 March 2024Accepted: 26 June 2024Published: 29 July 2024DOI: https://doi.org/10.1038/s41598-024-66025-wShare this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

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神经系统中的离子通道神经回路神经科学突触可塑性突触传递

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