Delivering next-generation pharmacological tools against GABAA receptors

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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.