Bidirectional Control of Synaptic GABAAR Clustering by Glutamate and Calcium.
Bidirectional Control of Synaptic GABAAR Clustering by Glutamate and Calcium.
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DOI：
10.1016/j.celrep.2015.12.002
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发表时间：
2015-12-29
期刊：
影响因子：
8.8
通讯作者：
Mikoshiba K
中科院分区：
文献类型：
--
作者：
Bannai H;Niwa F;Sherwood MW;Shrivastava AN;Arizono M;Miyamoto A;Sugiura K;Lévi S;Triller A;Mikoshiba K
GABA能突触传递通过在神经回路中建立适当的兴奋-抑制（E/I）平衡来调节脑功能。GABA能突触的结构和功能对神经递质冲击引起的不稳定性敏感。然而，促进GABA能突触恢复性稳态稳定的信号传导机制仍然未知。在这里，通过量子点单粒子跟踪，我们表征的信号通路，促进稳定的GABAA受体（GABAAR）突触后组织。慢代谢型谷氨酸受体信号激活IP 3受体依赖性钙释放和蛋白激酶C，以促进GABAAR聚集和GABA能传递。这种GABAAR稳定途径抵消了由谷氨酸驱动的NMDA受体依赖性钙内流和钙调磷酸酶去磷酸化引起的快速簇分散，包括在病理性谷氨酸毒性的条件下。这些发现表明，谷氨酸激活不同的受体和钙信号的时空模式，以对抗GABA能突触的控制。谷氨酸和Ca 2+信号传导的双向突触控制系统通过mGluR依赖的Ca 2+通过PKC从IP 3R释放稳定GABA突触通过调节GABAAR侧向扩散稳定突触GABAAR簇与NMDAR依赖的Ca 2+通路竞争驱动突触不稳定Bannai et al.表征谷氨酸和Ca 2+对突触GABAAR稳定性的双向调节。环境谷氨酸持续稳定突触GABAAR集群通过mGluR依赖性Ca 2+释放通过IP 3Rs和PKC激活。相反，大量谷氨酸通过激活NMDA受体和钙调神经磷酸酶诱导GABAAR分散。
GABAergic synaptic transmission regulates brain function by establishing the appropriate excitation-inhibition (E/I) balance in neural circuits. The structure and function of GABAergic synapses are sensitive to destabilization by impinging neurotransmitters. However, signaling mechanisms that promote the restorative homeostatic stabilization of GABAergic synapses remain unknown. Here, by quantum dot single-particle tracking, we characterize a signaling pathway that promotes the stability of GABAA receptor (GABAAR) postsynaptic organization. Slow metabotropic glutamate receptor signaling activates IP3 receptor-dependent calcium release and protein kinase C to promote GABAAR clustering and GABAergic transmission. This GABAAR stabilization pathway counteracts the rapid cluster dispersion caused by glutamate-driven NMDA receptor-dependent calcium influx and calcineurin dephosphorylation, including in conditions of pathological glutamate toxicity. These findings show that glutamate activates distinct receptors and spatiotemporal patterns of calcium signaling for opposing control of GABAergic synapses. Bidirectional synaptic control system by glutamate and Ca2+ signaling Stabilization of GABA synapses by mGluR-dependent Ca2+ release from IP3R via PKC Synaptic GABAAR clusters stabilized through regulation of GABAAR lateral diffusion Competition with an NMDAR-dependent Ca2+ pathway driving synaptic destabilization Bannai et al. characterize bidirectional regulation of synaptic GABAAR stability by glutamate and Ca2+. Environmental glutamate continuously stabilizes synaptic GABAAR clusters through mGluR-dependent Ca2+ release through IP3Rs and PKC activation. In contrast, massive glutamate induces GABAAR dispersion through the activation of NMDA receptor and calcineurin.