Section of Neurobiology, University of Texas, A4800, 2500 Speedway, MBB 1.148, Austin, TX 78712, USA.
J Biol Chem. 2010 Jul 23;285(30):22840-5. doi: 10.1074/jbc.M110.130815. Epub 2010 May 25.
The glycine receptor (GlyR) is a member of the Cys-loop superfamily of ligand-gated ion channels and the major mediator of inhibitory neurotransmission in the spinal cord and brainstem. Many allosteric modulators affect the functioning of members of this superfamily, with some such as benzodiazepines showing great specificity and others such as zinc, alcohols, and volatile anesthetics acting on multiple members. To date, no potent and efficacious allosteric modulator acting specifically at the GlyR has been identified, hindering both experimental characterization of the receptor and development of GlyR-related therapeutics. We used phage display to identify novel peptides that specifically modulate GlyR function. Peptide D12-116 markedly enhanced GlyR currents at low micromolar concentrations but had no effects on the closely related gamma-aminobutyric acid type A receptors. This approach can readily be adapted for use with other channels that currently lack specific allosteric modulators.
甘氨酸受体（GlyR）是配体门控离子通道 Cys 环超家族的成员，也是脊髓和脑干中抑制性神经递质传递的主要介质。许多变构调节剂会影响该超家族成员的功能，其中一些如苯二氮䓬类具有很高的特异性，而另一些如锌、醇和挥发性麻醉剂则作用于多个成员。迄今为止，尚未发现能够特异性作用于 GlyR 的有效且强效的变构调节剂，这既阻碍了对受体的实验表征，也阻碍了与 GlyR 相关的治疗药物的开发。我们使用噬菌体展示技术来鉴定能够特异性调节 GlyR 功能的新型肽。肽 D12-116 在低微摩尔浓度下显著增强 GlyR 电流，但对密切相关的γ-氨基丁酸 A 型受体没有影响。这种方法可以很容易地适应于目前缺乏特异性变构调节剂的其他通道。
