Yale scientists decode chemical transmitter for clues to new cancer therapies

By Jon Atherton

Scientists at the Yale Cancer Biology Institute have redefined the role of a unique chemical receptor that could provide avenues for new targeted cancer therapies.   

Gamma-aminobutyric acid (or GABA) is a naturally occurring chemical that acts as a ‘neurotransmitter’, delivering electrical messages through our nervous system from one neuron to another. 

GABA receptors are inhibitory - they block other messages and reduce neural excitability – and are therefore a major target for many drugs that control nerve cell hyperactivity associated with anxiety and stress.

While GABA receptors in the brain are relatively well known, the role of a rare GABA receptor, GABA receptor Pi (GABRP), is less understood. Found outside of the nervous system and in excessive numbers in cancer, GABRP is associated with growth and metastasis – at odds with the inhibitory nature of typical neuronal GABA receptor channels.

Scientists in the lab of Daryl Klein, an associate professor of Pharmacology at Yale, have overturned the traditional view of how this receptor functions. Their work was published recently in Molecular Cell.

Building on earlier findings from collaborative partner Lajos Pusztai, professor of Medical Oncology, who revealed that GABRP is highly expressed in breast cancer, the team at the Yale Cancer Biology Institute set to develop an antibody to target these cancer cells.

Before they could do so, the scientists had to decode the physical structure of the receptor by taking high resolution molecular ‘photographs’ using Cryo-electron microscopy. 

To their surprise, they found that GABRP adopts a typical channel structure commonly used to transport “inhibitory” chloride ions (like chloride from household table salt). But in this case, the channel structure was co-opted for a new function – to drive growth promoting signals.

By understanding this structure and signaling mechanism, the team were able to develop an antibody to target GABRP, cut off signaling and stop the receptor from fueling cancer cell growth. 

Associate Research Scientist Yueyue Wang was first author of the study. The work is a collaborative effort between the Klein laboratory, the Yansheng Liu and Len Kaczmarek labs in the Department of Pharmacology, and Lajos Pusztai from Medical Oncology. Together, the teams combined their expertise in structural biology, pharmacology, proteomics and cancer research to uncover how GABRP’s mechanisms could provide new opportunities for targeted cancer therapies.