Specificities of Gβγ subunits for the SNARE complex before and after stimulation of α2a-adrenergic receptors.
Specificities of Gβγ subunits for the SNARE complex before and after stimulation of α2a-adrenergic receptors.
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刺激 α2a 肾上腺素能受体之前和之后 SNARE 复合体的 Gβγ 亚基的特异性。
DOI：
10.1126/scisignal.abc4970
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发表时间：
2021
影响因子：
7.3
通讯作者：
Hamm,HeidiE
中科院分区：
文献类型：
--
作者：
Yim,YunYoung;McDonald,WHayes;Betke,KatherineM;Kaya,Ali;Hyde,Karren;Erreger,Kevin;Gilsbach,Ralf;Hein,Lutz;Hamm,HeidiE
配体与 G 蛋白偶联受体 (GPCR)（例如 α2a 肾上腺素受体 (α2aAR)）结合，导致异三聚体 G 蛋白激活，该蛋白由功能不同的 Gα 亚基和 Gβγ 二聚体组成。 α2aAR 依赖性突触传递抑制可调节自发运动活动、麻醉节省和工作记忆增强等功能，并且需要可溶性 NSF 附着蛋白受体 (SNARE) 复合物（一种 Gβγ 效应器）。为了了解 Gβγ-SNARE 复合物如何成为 α2aAR 依赖性突触传递抑制的基础，我们检查了肾上腺素能神经元中 Gβγ 亚基对 SNARE 复合物的特异性，在肾上腺素能神经元中，自身 α2aAR 对这些神经元释放的肾上腺素做出反应，而在非肾上腺素能神经元中，异质 α2aAR 对其他神经元释放的肾上腺素作出反应。我们对小鼠大脑突触体中与 SNARE 复合体结合的 Gβ 和 Gγ 亚基进行了定量、有针对性的多反应监测蛋白质组学分析。在没有自身 α2aAR 刺激的情况下，Gβ1 和 Gγ3 与 SNARE 复合体相互作用。然而，当肾上腺素激活自动α2aAR时，在复合物中发现了Gβ1、Gβ2和Gγ3。进一步了解不同 Gβγ 亚基在体内的具体用途可能有助于深入了解突触传递的稳态调节以及神经系统疾病中发生的功能障碍的机制。
Ligand binding to G protein–coupled receptors (GPCRs), such as the α2a-adrenergic receptor (α2aAR), results in the activation of heterotrimeric G proteins, which consist of functionally distinct Gα subunits and Gβγ dimers. α2aAR-dependent inhibition of synaptic transmission regulates functions such as spontaneous locomotor activity, anesthetic sparing, and working memory enhancement and requires the solubleNSFattachment protein receptor (SNARE) complex, a Gβγ effector. To understand how the Gβγ-SNARE complex underlies the α2aAR-dependent inhibition of synaptic transmission, we examined the specificity of Gβγ subunits for the SNARE complex in adrenergic neurons, in which auto-α2aARs respond to epinephrine released from these neurons, and nonadrenergic neurons, in which hetero-α2aARs respond to epinephrine released from other neurons. We performed a quantitative, targeted multiple reaction monitoring proteomic analysis of Gβ and Gγ subunits bound to the SNARE complex in synaptosomes from mouse brains. In the absence of stimulation of auto-α2aARs, Gβ1and Gγ3interacted with the SNARE complex. However, Gβ1, Gβ2, and Gγ3were found in the complex when auto-α2aARs were activated by epinephrine. Further understanding of the specific usage of distinct Gβγ subunits in vivo may provide insights into the homeostatic regulation of synaptic transmission and the mechanisms of dysfunction that occur in neurological diseases.