Neuronal gamma-aminobutyric acid (GABA) type A receptors undergo cognate ligand chaperoning in the endoplasmic reticulum by endogenous GABA.
Neuronal gamma-aminobutyric acid (GABA) type A receptors undergo cognate ligand chaperoning in the endoplasmic reticulum by endogenous GABA.
复制标题
DOI：
10.3389/fncel.2015.00188
复制
发表时间：
2015
影响因子：
5.3
通讯作者：
Leidenheimer NJ
中科院分区：
文献类型：
--
作者：
Wang P;Eshaq RS;Meshul CK;Moore C;Hood RL;Leidenheimer NJ
GABAA受体介导大脑中的快速抑制性神经传递。这些受体的功能障碍与各种精神/神经障碍相关，靶向该受体的药物是广泛使用的治疗剂。GABAA受体介导的神经传递的有效性和可塑性取决于表面GABAA受体的数量。受体细胞表面表达的一个未充分研究的方面是内质网（ER）内受体生物发生的翻译后调节。我们以前已经表明，外源性GABA可以作为重组GABAA受体在早期分泌途径的配体伴侣，导致我们现在调查内源性GABA是否有利于GABAA受体在原代大脑皮层文化的生物合成。在免疫荧光标记实验中，我们已经确定，表达表面GABAA受体的神经元含有GABA及其降解酶GABA转氨酶（GABA-T）。用GABA-T抑制剂处理神经元（已知增加细胞内GABA水平的处理）降低受体与ER质量控制蛋白钙连接蛋白的相互作用，伴随增加受体正向运输和质膜插入。GABA-T抑制对受体/钙连接蛋白相互作用的影响不是由于表面GABAA或GABAB受体的激活。与我们的假设，GABA作为一个同源配体伴侣在ER，啮齿动物脑切片的免疫金标记揭示了GABA的存在下，粗糙的ER。这种标记的密度与线粒体中存在的密度相似，线粒体是GABA降解的细胞器。最后，GABA-T抑制对受体/钙连接蛋白相互作用的影响通过用GABA转运蛋白抑制剂预处理来防止。总之，这些数据表明，内源性GABA作为同源配体伴侣在粗糙ER中起作用，以促进神经元GABAA受体的生物发生。
GABAA receptors mediate fast inhibitory neurotransmission in the brain. Dysfunction of these receptors is associated with various psychiatric/neurological disorders and drugs targeting this receptor are widely used therapeutic agents. Both the efficacy and plasticity of GABAA receptor-mediated neurotransmission depends on the number of surface GABAA receptors. An understudied aspect of receptor cell surface expression is the post-translational regulation of receptor biogenesis within the endoplasmic reticulum (ER). We have previously shown that exogenous GABA can act as a ligand chaperone of recombinant GABAA receptors in the early secretory pathway leading us to now investigate whether endogenous GABA facilitates the biogenesis of GABAA receptors in primary cerebral cortical cultures. In immunofluorescence labeling experiments, we have determined that neurons expressing surface GABAA receptors contain both GABA and its degradative enzyme GABA transaminase (GABA-T). Treatment of neurons with GABA-T inhibitors, a treatment known to increase intracellular GABA levels, decreases the interaction of the receptor with the ER quality control protein calnexin, concomittantly increasing receptor forward-trafficking and plasma membrane insertion. The effect of GABA-T inhibition on the receptor/calnexin interaction is not due to the activation of surface GABAA or GABAB receptors. Consistent with our hypothesis that GABA acts as a cognate ligand chaperone in the ER, immunogold-labeling of rodent brain slices reveals the presence of GABA within the rough ER. The density of this labeling is similar to that present in mitochondria, the organelle in which GABA is degraded. Lastly, the effect of GABA-T inhibition on the receptor/calnexin interaction was prevented by pretreatment with a GABA transporter inhibitor. Together, these data indicate that endogenous GABA acts in the rough ER as a cognate ligand chaperone to facilitate the biogenesis of neuronal GABAA receptors.
登录
查看更多内容
影响因子：
7.8
作者：
Bass, J;Chiu, G;Argon, Y;Steiner, DF
通讯作者：
Steiner, DF
影响因子：
3.3
作者：
Belenky, MA;Sagiv, N;Yarom, Y
通讯作者：
Yarom, Y
影响因子：
4.8
作者：
Connolly, CN;Krishek, BJ;Moss, SJ
通讯作者：
Moss, SJ
影响因子：
4.7
作者：
Charych, Erik I.;Liu, Feng;Moss, Stephen J.;Brandon, Nicholas J.
通讯作者：
Brandon, Nicholas J.
DOI：
10.1074/mcp.m111.011445
发表时间：
2012-01
期刊：
Molecular & cellular proteomics : MCP
影响因子：
--
作者：
Chen ZW;Fuchs K;Sieghart W;Townsend RR;Evers AS
通讯作者：
Evers AS