GABAB receptor trafficking and interacting proteins: Targets for the development of highly specific therapeutic strategies to treat neurological disorders?
GABAB receptor trafficking and interacting proteins: Targets for the development of highly specific therapeutic strategies to treat neurological disorders?
复制标题
DOI：
10.1016/j.bcp.2013.09.016
复制
发表时间：
2013-12-01
影响因子：
5.8
通讯作者：
Benke, Dietmar
中科院分区：
文献类型：
--
作者：
Benke, Dietmar
GABA(B)受体介导整个中枢神经系统的缓慢抑制性神经传递，从而控制神经元的兴奋性。它们与许多神经系统疾病有关，使它们成为一个有吸引力的药物靶点。然而，由于相当大的副作用，激动剂巴氯芬是迄今为止市场上唯一针对GABA(B)受体的药物，主要用于治疗痉挛。由于GABA(B)受体参与多种脑功能，因此直接针对受体配体结合位点的全身给药不太可能避免不必要的影响。为了尽量减少副作用，最好只针对那些参与特定病理状态的受体。这篇评论讨论了通过干扰受体-蛋白相互作用来恢复病变神经元中受损的GABA(B)受体功能可能是一种专门针对那些参与病理状态的受体的方法。最近发现的两种下调功能性GABA(B)受体水平的机制最有可能分别导致脑缺血和神经性疼痛。在这两种机制中，破坏蛋白质-蛋白质相互作用的小干扰肽可能提供了一种高度特异性的方法，可以选择性地在功能障碍部位恢复正常的受体功能。如果在这些疾病中恢复功能性GABA(B)受体表达具有有益作用，这可能作为开发高度特异性治疗干预措施的起点。这种方法有望将副作用降到最低，因为它保证不影响那些与功能障碍无关的GABA(B)受体。(C) 2013爱思唯尔公司版权所有。
GABA(B) receptors mediate slow inhibitory neurotransmission throughout the central nervous system thereby controlling the excitability of neurons. They have been implicated in numerous neurological disorders making them an attractive drug target. However, due to considerable side effects, the agonist baclofen is so far the only drug on the market targeting GABA(B) receptors, primarily for the treatment of spasticity. Because GABA(B) receptors are involved in a variety of brain functions it is rather unlikely to avoid unwanted effects with systemically administered drugs directly addressing ligand binding sites of the receptor. To minimize side effects, it would be desirable to target only those receptors involved in a given pathological state. This commentary discusses the idea that restoring impaired GABA(B) receptor function in diseased neurons by interfering with receptor-protein interactions may be an approach to specifically target only those receptors involved in the pathological state. Two recently discovered mechanisms that down-regulate the level of functional GABA(B) receptors most likely contribute to cerebral ischemia and neuropathic pain, respectively. In both mechanisms, small interfering peptides disrupting protein-protein interactions may offer a highly specific means to restore normal receptor function selectively at the site of malfunction. If restored functional GABA(B) receptor expression in these diseases has beneficial effects, this may serve as a starting point for the development of a highly specific therapeutic interventions. Such an approach is expected to minimize side effects because it promises to leave those GABA(B) receptors unaffected which are not involved in the dysfunction. (C) 2013 Elsevier Inc. All rights reserved.