KCC2: unlocking the secrets of ‘over excited’ nerves

Combining rigorous neuroscience with drug discovery expertise is helping IMED Biotech Unit scientists at AstraZeneca to identify novel treatment opportunities for patients with epilepsy and other neurological diseases, focused on a neuronal potassium-chloride transporter protein called KCC2.

In the latest high impact publication in Nature Medicine our team of researchers at the AstraZeneca-Tufts Laboratory in Boston, and their collaborators in the US, UK and France have provided increasingly detailed insights into KCC2’s essential role in controlling nerve excitation in the brain, and the potential of small molecules to modulate its activity.

Down-regulation of KCC2 has been seen in a number of neurological diseases, and the protein is considered a key target in the search for new treatments for epilepsy, especially some forms of childhood epilepsy that respond poorly to current therapies. 

“Epilepsy is today’s main interest but the ubiquitous role of KCC2 in nerve excitation in the brain means that it has potential as a target for innovative therapeutic interventions for other conditions, such as pain,” explains Dr Nick Brandon, Co-Director of the AstraZeneca-Tufts Neuroscience Laboratory and Chief Scientist in Neuroscience, IMED Biotech Unit.

“KCC2 has been implicated as a critical underlying cause of cognitive disorders such as schizophrenia and autism, as well as epilepsy and neuropathic pain, so enhancing KCC2 function is a much sought-after goal. Our research published in Nature Medicine advances understanding of how drug discovery can target KCC2 more effectively,” says Stephen Moss, professor of neuroscience at Tufts University School of Medicine and corresponding author on the Nature Medicine paper.

KCC2 and Gamma-Aminobutyric acid (GABA) type A receptors work as the neuronal ‘double act’ for controlling chloride transport in and out of cells – deficits of which can cause excessive nerve excitation in the brain and lead to seizures and other neurological abnormalities.

By bringing together an exceptional battery of complex, cutting edge techniques, the transatlantic KCC2 partners were able to get ‘up close’ to what happens to chloride ‘flux’.

As one of a small number of laboratories that use gramicidin perforated patch electrophysiology, the AstraZeneca-Tufts researchers were able to measure chloride entry into cells in a highly controlled way. Alongside this very labour intensive but accurate form of electrophysiology, the research group had access to the world-leading chloride imaging expertise of Dr Igor Medina in Marseille through an Open Innovation collaboration with AstraZeneca.  Completing the picture were high quality biochemical techniques to quantify KCC2 function, including thallium influx assays.

“Being able to look at KCC2 function and chloride transport in so many different but complementary ways, using the right cell systems, was critical for enabling us to validate our results and reduce the risk of generating false leads for future drug discovery and development focused on KCC2,” says Nick.

The AstraZeneca-Tufts partnership, which recently celebrated its fourth anniversary, is proving a highly successful model for collaboration between academia and industry. This publication builds on a number of recent papers [TINS Review, Jawhari et al structure, NEM potentiation] from the group together with IMED Biotech Unit scientists in this field to understand the complexities of this mechanistic pathway in the brain. There are currently 12 AstraZeneca funded scientists working alongside researchers in the neuroscience department at Tufts, with a rapidly growing portfolio of high impact publications to their name.

“It’s a true academia-industry hybrid. With their high-quality research, our scientists support our early discovery neuroscience portfolio, while Tufts provides outstanding biochemistry and electrophysiology expertise,” says Nick. “Thanks to the technological achievements of all our collaborators in the KCC2 research, we are poised to identify compounds that could take targeted treatment of epilepsy and other neurological disorders to a new level.”

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