How a Small Variation in a Brain Receptor May Improve Future Migraine Treatments

What is it about?

The PAC1 receptor is a receptor present in the brain that helps control migraine pain response, stress responses and other nervous system functions. The receptor exists in different forms due to alternative splicing, creating two of the more common forms called PAC1nR and PAC1sR. We found that a peptide hormone called VIP works more strongly on the PAC1sR form compared to the PAC1nR, while a different peptide, PACAP, activates both receptor forms to a similar level. To understand why, we used cryo-electron microscopy, cell-based functional assays and computer simulations to visualise how these hormones interact with the receptors, and what effects these have on signalling responses inside the cell. Structural differences created by alternative splicing change how VIP can interact with the receptors and tune how PAC1nR and PAC1sR couple to signalling effectors within the cell. These small structural changes can explain the differences in signalling by the VIP peptide.

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Why is it important?

PAC1R is a promising target for migraine treatment, but it is difficult to design drugs that work well because the receptor functions differently depending on which splice variant is present in the brain. Revealing how PAC1nR and PAC1sR respond to the VIP peptide provides structural insights that can assist in designing more effective medicines that have fewer side effects. It also extends our understanding of how small receptor variations can fine-tune signalling in the brain, which may guide therapies for other neurological conditions.