Lack of positive allosteric modulation of mutated α1S267I glycine receptors by cannabinoids
Lack of positive allosteric modulation of mutated α1S267I glycine receptors by cannabinoids
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DOI：
10.1007/s00210-010-0506-9
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发表时间：
2010-05-01
影响因子：
3.6
通讯作者：
Ahrens, Joerg
中科院分区：
文献类型：
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作者：
Foadi, Nilufar;Leuwer, Martin;Ahrens, Joerg
脊髓背角内抑制性突触传递的丧失在炎症或神经损伤后慢性疼痛的发展中起关键作用。成年脊髓中抑制性突触后传递主要涉及甘氨酸。Ajulemic acid和HU210是非精神性的合成大麻素。大麻二酚是大麻的一种非精神药物成分。有迹象表明，这些大麻素的非大麻素受体机制可能通过甘氨酸受体介导。在这项研究中，我们研究了267位氨基酸残基丝氨酸对阿佳酸、大麻二酚和HU210的甘氨酸调节作用的影响。利用全细胞钳夹技术研究了突变的α（1）S267 I甘氨酸受体在HEK293细胞中的瞬时表达。α（1）亚基TM2丝氨酸残基突变为异亮氨酸消除了共激活和直接激活甘氨酸受体的研究大麻素。甘氨酸α（1）亚基的TM2（267）残基的性质对于阿佳酸、大麻二酚和HU210的甘氨酸调节作用至关重要。这种突变的影响，在体内的相互作用，大麻素与甘氨酸受体的调查应允许更好地了解大麻素的行动的分子决定因素。
Loss of inhibitory synaptic transmission within the dorsal horn of the spinal cord plays a key role in the development of chronic pain following inflammation or nerve injury. Inhibitory postsynaptic transmission in the adult spinal cord involves mainly glycine. Ajulemic acid and HU210 are non-psychotropic, synthetic cannabinoids. Cannabidiol is a non-psychotropic plant constituent of cannabis sativa. There are hints that non-cannabinoid receptor mechanisms of these cannabinoids might be mediated via glycine receptors. In this study, we investigated the impact of the amino acid residue serine at position 267 on the glycine-modulatory effects of ajulemic acid, cannabidiol and HU210. Mutated alpha(1)S267I glycine receptors transiently expressed in HEK293 cells were studied by utilising the whole-cell clamp technique. The mutation of the alpha(1) subunit TM2 serine residue to isoleucine abolished the co-activation and the direct activation of the glycine receptor by the investigated cannabinoids. The nature of the TM2 (267) residue of the glycine alpha(1) subunit is crucial for the glycine-modulatory effect of ajulemic acid, cannabidiol and HU210. An investigation of the impact of such mutations on the in vivo interaction of cannabinoids with glycine receptors should permit a better understanding of the molecular determinants of action of cannabinoids.