Leptin increases GABAergic synaptogenesis through the Rho guanine exchange factor β-PIX in developing hippocampal neurons.
Leptin increases GABAergic synaptogenesis through the Rho guanine exchange factor β-PIX in developing hippocampal neurons.
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DOI：
10.1126/scisignal.abe4111
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发表时间：
2021-05-18
影响因子：
7.3
通讯作者：
Wayman GA
中科院分区：
文献类型：
--
作者：
Sahin GS;Luis Rodriguez-Llamas J;Dillon C;Medina I;Appleyard SM;Gaiarsa JL;Wayman GA
发育中的海马神经元响应神经营养信号而经历快速突触发生，以形成和完善电路连接。脂肪因子瘦素是一种具有神经营养作用的饱腹感因子，可增强新生儿发育过程中海马谷氨酸能和 GABA 能突触的发生。短暂接触瘦素会增强海马神经元中 GABAA 受体依赖性突触电流。在这里，利用分子和电生理学技术，我们发现瘦素增加了雄性和雌性幼鼠海马培养物中 GABAA 受体的表面定位和功能性 GABA 能突触的数量。瘦素以依赖于激酶 CaMKK 的方式增加 GABAA 受体和 Rho 鸟嘌呤交换因子 β-PIX（GABA 突触后位点的支架蛋白）之间的相互作用。我们还发现瘦素受体和β-PIX形成复合物，其数量在瘦素受体激活后短暂增加。此外，瘦素受体中的 Tyr985 和 β-PIX 的 SH3 结构域对于这种相互作用至关重要，这是 GABA 能突触发生发育增加所必需的。我们的结果揭示了瘦素促进海马神经元 GABA 能突触发生的机制，并进一步揭示了瘦素受体信号传导及其相互作用组的复杂性。
Developing hippocampal neurons undergo rapid synaptogenesis in response to neurotrophic signals to form and refine circuit connections. The adipokine leptin is a satiety factor with neurotrophic actions which potentiates both glutamatergic and GABAergic synaptogenesis in the hippocampus during neonatal development. Brief exposure to leptin enhances GABAA receptor-dependent synaptic currents in hippocampal neurons. Here, using molecular and electrophysiological techniques, we found that leptin increased the surface localization of GABAA receptors and the number of functional GABAergic synapses in hippocampal cultures from male and female rat pups. Leptin increased the interaction between GABAA receptors and the Rho guanine exchange factor β-PIX (a scaffolding protein at GABAergic postsynaptic sites) in a manner dependent on the kinase CaMKK. We also found that the leptin receptor and β-PIX formed a complex, the amount of which transiently increased upon leptin receptor activation. Furthermore, Tyr985 in the leptin receptor and the SH3 domain of β-PIX are crucial for this interaction, which was required for the developmental increase in GABAergic synaptogenesis. Our results suggest a mechanism by which leptin promotes GABAergic synaptogenesis in hippocampal neurons and reveal further complexity in leptin receptor signaling and its interactome.
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影响因子：
13.6
作者：
Harvey, Jenni;Solovyova, Natasha;Irving, Andrew
通讯作者：
Irving, Andrew
影响因子：
3.7
作者：
Harvey J
通讯作者：
Harvey J
影响因子：
7.7
作者：
Dumon C;Diabira D;Chudotvorova I;Bader F;Sahin S;Zhang J;Porcher C;Wayman G;Medina I;Gaiarsa JL
通讯作者：
Gaiarsa JL
影响因子：
4.8
作者：
Bland, Tyler;Zhu, Mingyan;Wayman, Gary A.
通讯作者：
Wayman, Gary A.
DOI：
10.1073/pnas.95.11.6061
发表时间：
1998-05-26
影响因子：
11.1
作者：
Carpenter, LR;Farruggella, TJ;Stahl, N
通讯作者：
Stahl, N