Arancibia-Cárcamo I Lorena, Yuen Eunice Y, Muir James, Lumb Michael J, Michels Guido, Saliba Richard S, Smart Trevor G, Yan Zhen, Kittler Josef T, Moss Stephen J
Department of Neuroscience, Physiology, and Pharmacology, University College London, Gower Street, London, WC1E 6BT, United Kingdom.
Proc Natl Acad Sci U S A. 2009 Oct 13;106(41):17552-7. doi: 10.1073/pnas.0905502106. Epub 2009 Oct 6.
The strength of synaptic inhibition depends partly on the number of GABA(A) receptors (GABA(A)Rs) found at synaptic sites. The trafficking of GABA(A)Rs within the endocytic pathway is a key determinant of surface GABA(A)R number and is altered in neuropathologies, such as cerebral ischemia. However, the molecular mechanisms and signaling pathways that regulate this trafficking are poorly understood. Here, we report the subunit specific lysosomal targeting of synaptic GABA(A)Rs. We demonstrate that the targeting of synaptic GABA(A)Rs into the degradation pathway is facilitated by ubiquitination of a motif within the intracellular domain of the gamma2 subunit. Blockade of lysosomal activity or disruption of the trafficking of ubiquitinated cargo to lysosomes specifically increases the efficacy of synaptic inhibition without altering excitatory currents. Moreover, mutation of the ubiquitination site within the gamma2 subunit retards the lysosomal targeting of GABA(A)Rs and is sufficient to block the loss of synaptic GABA(A)Rs after anoxic insult. Together, our results establish a previously unknown mechanism for influencing inhibitory transmission under normal and pathological conditions.
突触抑制的强度部分取决于突触部位GABA(A)受体（GABA(A)Rs）的数量。GABA(A)Rs在内吞途径中的运输是表面GABA(A)R数量的关键决定因素，并且在诸如脑缺血等神经病理学中会发生改变。然而，调节这种运输的分子机制和信号通路却知之甚少。在这里，我们报告了突触GABA(A)Rs的亚基特异性溶酶体靶向。我们证明，γ2亚基细胞内结构域内一个基序的泛素化促进了突触GABA(A)Rs进入降解途径。溶酶体活性的阻断或泛素化货物向溶酶体运输的破坏会特异性增加突触抑制的效力，而不会改变兴奋性电流。此外，γ2亚基内泛素化位点的突变会延迟GABA(A)Rs的溶酶体靶向，并且足以阻止缺氧损伤后突触GABA(A)Rs的丢失。总之，我们的结果建立了一种在正常和病理条件下影响抑制性传递的前所未知的机制。
