Möykkynen Tommi, Liebkind Ron, Sjöberg Jari, Korpi Esa R, Liesi Päivi
Institute of Biomedicine (Pharmacology), Biomedicum Helsinki, University of Helsinki, Helsinki, Finland.
J Neurosci Res. 2005 Sep 15;81(6):797-804. doi: 10.1002/jnr.20523.
Previous work from this laboratory indicates that the KDI (Lys-Asp-Ile) domain of gamma 1-laminin promotes functional regeneration of adult rat spinal cord injuries and protects adult rat hippocampal neurons against massive neuronal death induced by intracerebral injection of the glutamate analogue kainic acid. In the present study, we used patch clamp recordings on cultured human embryonic neocortical neurons and HEK 293 cells expressing recombinant glutamate receptor subunits to study a putative interaction of the KDI with the glutamate system. We show that the KDI domain of gamma 1-laminin is a universal and potent inhibitor of AMPA, kainate, and NMDA subclasses of glutamate receptors, with a noncompetitive action on the AMPA receptor channel activity. Glutamate neurotoxicity plays a key role in both CNS trauma and neurodegenerative disorders, so this unexpected, novel function of the gamma 1-laminin-derived tripeptide may prove clinically valuable in treatment of CNS trauma and/or disease.
该实验室先前的研究表明，γ1-层粘连蛋白的KDI（赖氨酸-天冬氨酸-异亮氨酸）结构域可促进成年大鼠脊髓损伤的功能再生，并保护成年大鼠海马神经元免受脑内注射谷氨酸类似物海藻酸诱导的大量神经元死亡。在本研究中，我们对培养的人胚胎新皮质神经元和表达重组谷氨酸受体亚基的HEK 293细胞进行膜片钳记录，以研究KDI与谷氨酸系统之间的假定相互作用。我们发现，γ1-层粘连蛋白的KDI结构域是AMPA、海人藻酸和NMDA亚型谷氨酸受体的通用强效抑制剂，对AMPA受体通道活性具有非竞争性作用。谷氨酸神经毒性在中枢神经系统创伤和神经退行性疾病中均起关键作用，因此，γ1-层粘连蛋白衍生的三肽这一意外的新功能可能在中枢神经系统创伤和/或疾病的治疗中具有临床价值。
