Delivering next-generation pharmacological tools against GABAA receptors

人脑是地球上最强大的生物处理器。它也是极其复杂的。它包含大约1000亿个脑细胞，以及这些脑细胞之间超过1万亿个连接，这些连接引导着大量信息的流动。显然，如此复杂的制度要想顺利运作，就需要规则。这需要一个监管体系。我们研究的靶点，γ-氨基丁酸A型受体，称为GABA-A-Rs，是这个调节系统中最重要的部分。GABA-A-R是在神经细胞表面表达的蛋白质。它们存在于整个大脑中，允许神经细胞对神经递质γ-氨基丁酸（称为GABA）做出反应。神经递质GABA作用于GABA-A-Rs，向神经细胞发送停止信号。这意味着GABA-A-R是大脑的刹车。他们传播平静。它们调节兴奋。因此，毫不奇怪，当这些调节器失灵时，结果是大脑活动加剧，导致一系列使人衰弱的疾病，如失眠、焦虑症和癫痫，这些疾病影响着全世界数千万人。幸运的是，有治疗方法。例如，苯二氮卓类药物如安定和Xanax加强了GABA-A-R的镇静作用，以治疗焦虑。所谓的Z药物，如安必恩，治疗失眠。不幸的是，由于GABA-A-R对大脑中的许多不同过程至关重要，这些药物具有副作用。此外，GABA-A-R在大脑功能中发挥的许多作用还远未完全解决。例如，GABA-A-R也是全身麻醉剂和大脑自身产生的抗应激分子神经类固醇的靶点。它们也是产后抑郁症和慢性疼痛的目标，并正在研究作为精神分裂症，中风和酒精成瘾的治疗方法。一般来说，可以说GABA-A-Rs调节许多不同的过程，包括镇静、焦虑、认知、成瘾、癫痫发作、肌肉松弛、共济失调、兴奋性毒性、疼痛、食欲等。尽管存在并发症和挑战，但GABA-A-Rs基础研究和改进治疗方法的一条希望之路是开发具有改进药理学的工具。这是因为实际上有许多不同类型的GABA-A-R，它们位于不同大脑区域的不同神经元，并有助于不同的功能过程。开发针对一种或另一种GABA-A-R的选择性工具将增强我们剖析每种GABA-A-R类型的作用的能力，并自然导致下一代生物技术疗法的创建，以针对仅涉及该受体类型的特定神经系统疾病。最近，我们的实验室参与了一系列抗体的开发，这些抗体能够像药物一样调节GABA-A-R。不仅如此，我们还表明它们在不同类型的GABA-A-R之间具有高水平的选择性。最后，我们已经解决了这些抗体结合的GABA-A-R的高分辨率结构，以了解它们是如何工作的。这项研究表明，通过将这些抗体融合在一起形成新的合成组合工具，将产生令人兴奋的新药理学，这在以前是不可能的。这些将为研究特定类型的GABA-A-R在中枢神经系统功能中的作用提供实质性优势。

The human brain is the most powerful biological processor on the planet. It is also extremely complicated. It contains around one-hundred billion brain cells and over a trillion connections between those brain cells which channel the flow of vast quantities of information. Clearly such a complicated system requires rules if it is to operate smoothly. It requires a regulatory system. And the targets of our research, gamma-aminobutyric acid Type-A receptors, termed GABA-A-Rs, are a most important part of this regulatory system. GABA-A-Rs are proteins expressed at the surface of nerve cells. They exist throughout the brain to allow nerve cells to respond to the neurotransmitter gamma-aminobutyric acid, called GABA. The neurotransmitter GABA acts upon GABA-A-Rs to send a stop signal to nerve cells. This means GABA-A-Rs are the brakes on the brain. They spread calm. They regulate excitement. And so it is no surprise that when these regulators fail the result is heightened brain activity, which leads to a range of debilitating illnesses such as insomnia, anxiety-disorders and epilepsy, disorders that affect tens of millions of people worldwide.Fortunately, there are treatments available. For example, benzodiazepines such as Valium and Xanax reinforce the calming influence of GABA-A-Rs to treat anxiety. And so-called Z-drugs, such as Ambien, treat insomnia. Unfortunately, because GABA-A-Rs are vital to so many different processes in the brain these drugs have side-effects. Furthermore, the many roles that GABA-A-Rs play in brain function are far from fully resolved. For example, GABA-A-Rs are also targets for general anaesthetics and for the brain's home-grown anti-stress molecules, the neurosteroids. They are also targets in postpartum depression and chronic pain, and are being investigated as therapeutics in schizophrenia, stroke and alcohol addiction. In general, it can be said that GABA-A-Rs modulate many different processes, including sedation, anxiety, cognition, addiction, seizure, muscle relaxation, ataxia, excitotoxicity, pain, appetite, and more.Despite the complications and challenges, one avenue of hope for basic research on GABA-A-Rs and for the development of improved therapeutics is the development of tools with improved pharmacology. This is because there are actually many different types of GABA-A-Rs and they are localised to different neurones in different brain regions and contribute to different functional processes. Development of selective tools against one type or other of GABA-A-R would enhance our ability to dissect out the roles of each type of GABA-A-R and naturally lead to the creation of next generation biotechnological therapeutics to target specific neurological disorders involving only that receptor type.Recently our lab has been involved in the development of a catalogue of antibodies that are capable of acting like drugs to modulate GABA-A-Rs. Not only this but we have shown that they possess a high level of selectivity between different types of GABA-A-Rs. Finally, we have solved high resolution structures of GABA-A-Rs bound by these antibodies to understand how they work. This research shows that combining these antibodies by fusing them together into new synthetic combinatorial tools will generate exciting new pharmacologies that have not been possible before. These will offer substantial advantage in studying the roles of specific types of GABA-A-Rs in central nervous system function.