GABAB receptors in the hippocampus: allosteric modulation and receptor isoforms.

GABAB受体属于一个特殊的大脑信号分子家族，感知抑制性神经递质GABA。GABAB受体已被证明参与神经系统的基本功能，如痛觉、奖励、学习和记忆，因此是各种疾病的重要治疗靶点，包括痉挛、癫痫、疼痛和成瘾。巴氯芬（lioreal）是一种可以激活GABAB受体的分子，是一种肌肉松弛剂，目前临床上用于治疗痉挛。最近，也发现了一些分子通过变构调节的替代方式增强GABAB受体的功能，这些分子在动物模型中被发现有效治疗成瘾和焦虑。因此，这些GABAB受体增强剂可能成为治疗精神和神经疾病的一类新药物。然而，这些新的GABAB增强剂作用的详细机制仍然知之甚少。在这个基础科学项目中，我们设计了一系列旨在阐明GABAB增强剂在神经元信号传导中的作用机制的实验。详细的电生理和药理学表征结合GABAB受体表达的遗传操作将在脑组织神经元信号传导的背景下进行。对GABAB受体功能调节的进一步了解将有助于开发出更有效、副作用更小的精神和神经疾病药物。大型制药公司对这种新药靶标表现出了浓厚的兴趣。

The GABAB receptors belong to a family of specialised brain signalling molecules sensing the inhibitory neurotransmitter GABA. The GABAB receptors have been shown to participate in essential functions of the nervous system, like pain sensation, reward and learning and memory, and are hence important therapeutic targets for various diseases, including spasticity, epilepsy, pain and addiction. Baclofen (Lioresal), a molecule that can activate the GABAB receptors, is a muscle relaxant and currently used clinically to treat spasticity. Recently, molecules were also identified to enhance the function of the GABAB receptors by an alternative way of allosteric modulation, and these molecules were found effective in treating addiction and anxiety in animal models. These GABAB receptor potentiators may, thus, become a new class of therapeutics for psychiatric and neurological disorders. However, the detailed mechanisms underlying the actions of these new GABAB potentiators are still poorly understood. In this basic scientific project, we designed a series of experiments aiming to elucidate the mechanisms of the GABAB potentiators in neuronal signalling. Detailed electrophysiological and pharmacological characterization combined with genetic manipulations on GABAB receptor expression will be carried out in the context of neuronal signalling in brain tissues. The further understanding of the GABAB receptor functional modulations will aid the development of newer and more effective drugs for psychiatric and neurological disorders with reduced side effects. Major pharmaceutical companies have shown keen interests in this new drug target.