Phosphorylation of neuroligin-2 by PKA regulates its cell surface abundance and synaptic stabilization.
Phosphorylation of neuroligin-2 by PKA regulates its cell surface abundance and synaptic stabilization.
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PKA 磷酸化 Neuroligin-2 可调节其细胞表面丰度和突触稳定性。
DOI：
10.1126/scisignal.abg2505
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发表时间：
2022
影响因子：
7.3
通讯作者：
Halff EF
中科院分区：
文献类型：
--
作者：
Halff EF
跨突触粘附分子神经连接素-2（NL 2）对抑制性突触的发育和功能至关重要。NL 2募集突触后支架蛋白桥蛋白，桥蛋白进而稳定突触后结构域中的γ-氨基丁酸A型受体（GABAAR）。因此，突触处NL 2的量可以控制突触GABAAR浓度以调节抑制性神经传递功效。在这里，使用生物化学，成像，单粒子跟踪和电生理学，我们发现了cAMP依赖性蛋白激酶（PKA）在NL 2突触稳定中的关键作用。我们发现PKA介导的NL 2 Ser 714磷酸化导致其从突触中分散并减少NL 2表面量，导致突触GABAAR的丢失。相反，通过消除PKA介导的磷酸化来增强NL 2在突触处的稳定性会导致抑制性信号传导增加。因此，PKA在调节NL 2功能和GABA介导的突触抑制中起关键作用。
The trans-synaptic adhesion molecule neuroligin-2 (NL2) is essential for the development and function of inhibitory synapses. NL2 recruits the postsynaptic scaffold protein gephyrin, which, in turn, stabilizes γ-aminobutyric acid type A receptors (GABAARs) in the postsynaptic domain. Thus, the amount of NL2 at the synapse can control synaptic GABAAR concentration to tune inhibitory neurotransmission efficacy. Here, using biochemistry, imaging, single-particle tracking, and electrophysiology, we uncovered a key role for cAMP-dependent protein kinase (PKA) in the synaptic stabilization of NL2. We found that PKA-mediated phosphorylation of NL2 at Ser714caused its dispersal from the synapse and reduced NL2 surface amounts, leading to a loss of synaptic GABAARs. Conversely, enhancing the stability of NL2 at synapses by abolishing PKA-mediated phosphorylation led to increased inhibitory signaling. Thus, PKA plays a key role in regulating NL2 function and GABA-mediated synaptic inhibition.