Discovery over receptors could change our understanding of molecular neuroscience, says MRC Laboratory of Molecular Biology
They play a critical role in mediating signals in our brains, ensuring the proper function of the central nervous system.
They are also involved in many other tissues, assisting hormonal release in the pancreas, for example, and dampening the inflammatory response of the immune system.
But despite the fact that GABAA receptors are important drug targets, we have had limited understanding of their molecular make-up – until now.
The MRC Laboratory of Molecular Biology in Cambridge has carried out structural analysis of these receptors and uncovered a much larger diversity of arrangements than had been anticipated.
This could have significant implications for the development of drugs to treat a wide range of conditions.
GABAA receptors – or type A gamma-aminobutyric acid receptors, to give them their full name – are targeted already by drugs that treat neurological and neuropsychiatric disorders, including anxiety, depression, insomnia, epilepsy and schizophrenia.
That is because they are principal mediators of inhibitory neurotransmission in vertebrates, which means they reduce the likelihood that a neuron will fire an electrical impulse or ‘action potential’. These impulses are caused when there is a temporary shift from negative to positive in the neuron’s membrane potential, caused by ions flowing in and out.
Radu Aricescu’s group, in the LMB’s Neurobiology Division, investigates the structure, physiology and pharmacology of GABAA receptors.
Using cryogenic electron microscopy, Andrija Sente, a PhD student in Radu’s group, aimed to solve the structure of a representative GABAA receptor, and learned that the arrangement of its subunits differed from what was expected.
Further analysis found that cells expressing some of these subunits assemble multiple receptor populations in a differential, context-dependent but non-random manner.
Andrija and Jonas Miehling, another PhD student in Radu’s group, worked with Tomas Malinauskas, from the Wellcome Centre for Human Genetics at University of Oxford, then solved the structures of receptors bound to two drug-like molecules – a candidate for the treatment of insomnia and an intriguing antidote of alcohol inebriation.
Their findings altered our understanding of where and how these molecules bind to the subunits.
The research highlights the potential to adapt clinical treatments so that they can have increased specificity and fewer side effects.
In addition to being implicated in these neurological and neuropsychiatric disorders when they malfunction, these receptors are also the major targets of volatile and intravenous general anaesthetics, used in modern medicine and surgery.
And since they are also involved in signalling outside the central nervous system, the LMB’s research could also have an impact on treating other conditions, such as diabetes and cancer immunotherapy.
The researchers could only use cryo-EM to solve the structures of receptors that could be purified and classified, so Andrija also mined single-cell RNA sequencing results from the human cortex.
There was further surprise here, when he discovered most neuron types express sufficiently large subsets of these genes to assemble potentially tens or even hundreds of thousands of receptors, with different subunit arrangements.
Working with Katerina Naydenova, a PhD student in Chris Russo’s group in the LMB’s Structural Studies Division, a computational strategy was devised to simulate the distribution of the receptor subtypes. It repeatedly predicted the existence of additional subtypes, with distinct signalling properties.
The LMB believes the study, published in Nature, represents a “new way of looking at the field of molecular neuroscience in general”.
Other receptors, encoded by multiple genes like GABAA receptors, could also be more diverse than we realised.
Better understanding of this could enable us to develop drugs that work better and have fewer side effects.
The work was funded by UKRI MRC, National Institute for General Medical Sciences, Massachusetts General Hospital, Cambridge Trust, University of Cambridge, Boehringer Ingelheim Fonds and the Wellcome Trust.