Saliba Richard S, Michels Guido, Jacob Tija C, Pangalos Menelas N, Moss Stephen J
Department of Neuroscience, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
J Neurosci. 2007 Nov 28;27(48):13341-51. doi: 10.1523/JNEUROSCI.3277-07.2007.
GABA(A) receptors (GABA(A)Rs) are the major mediators of fast synaptic inhibition in the brain. In neurons, these receptors undergo significant rates of endocytosis and exocytosis, processes that regulate both their accumulation at synaptic sites and the efficacy of synaptic inhibition. Here we have evaluated the role that neuronal activity plays in regulating the residence time of GABA(A)Rs on the plasma membrane and their targeting to synapses. Chronic blockade of neuronal activity dramatically increases the level of the GABA(A)R ubiquitination, decreasing their cell surface stability via a mechanism dependent on the activity of the proteasome. Coincident with this loss of cell surface expression levels, TTX treatment reduced both the amplitude and frequency of miniature inhibitory synaptic currents. Conversely, increasing the level of neuronal activity decreases GABA(A)R ubiquitination enhancing their stability on the plasma membrane. Activity-dependent ubiquitination primarily acts to reduce GABA(A)R stability within the endoplasmic reticulum and, thereby, their insertion into the plasma membrane and subsequent accumulation at synaptic sites. Thus, activity-dependent ubiquitination of GABA(A)Rs and their subsequent proteasomal degradation may represent a potent mechanism to regulate the efficacy of synaptic inhibition and may also contribute to homeostatic synaptic plasticity.
γ-氨基丁酸A型受体（GABA(A)Rs）是大脑中快速突触抑制的主要介质。在神经元中，这些受体经历显著的内吞和外排速率，这些过程调节它们在突触部位的积累以及突触抑制的效力。在这里，我们评估了神经元活动在调节GABA(A)Rs在质膜上的驻留时间及其靶向突触方面所起的作用。长期阻断神经元活动会显著增加GABA(A)R泛素化水平，通过一种依赖蛋白酶体活性的机制降低其细胞表面稳定性。与细胞表面表达水平的这种丧失相一致，河豚毒素（TTX）处理降低了微小抑制性突触电流的幅度和频率。相反，增加神经元活动水平会降低GABA(A)R泛素化，增强其在质膜上的稳定性。活性依赖性泛素化主要作用是降低内质网内GABA(A)R的稳定性，从而减少其插入质膜以及随后在突触部位的积累。因此，GABA(A)Rs的活性依赖性泛素化及其随后的蛋白酶体降解可能是调节突触抑制效力的一种有效机制，也可能有助于稳态突触可塑性。
