World first: Researchers from Monash University have harnessed cutting-edge technology to discover the progression of molecular events that lead to migraine – something that, until now, has remained a mystery.

The discovery has filled one of the most important gaps in our understanding of how migraines are activated.

Published today in the prestigious journal Science, the breakthrough study was led by a team of researchers from the Monash Institute of Pharmaceutical Sciences (MIPS) and the recently established ARC Centre for Cryo-EM of Membrane Proteins (CCeMMP).

One of the most common causes for migraine is abnormal levels of activation of the target for an extremely potent vascular regulator, calcitonin gene-related peptide (CGRP).

The newest and most exciting treatments for migraine act by blocking this activity, but how CGRP activates its receptor at the molecular level has been poorly understood.

In this study, the researchers tapped into significant recent advancements in the field of cryo-electron microscopy (cryo-EM) to, for the first time, show how the binding of CGRP to the receptor leads to receptor activation that, in turn, leads to the onset of migraine.

Until now this simply wasn’t possible as proteins such as the CGRP receptor were too small and too mobile to be captured and studied by any method.

Lead author of the study, Dr Tracy Josephs from MIPS said: “To really understand what triggers migraines, we need to be able to study structure and dynamics using unmodified forms of the receptor - this has been a major technical hurdle in understanding the progression of molecular events that link CGRP binding to activation of the cellular signalling pathways that govern migraine pain, and one the team have now overcome.”

“Based on the structures and data from complementary biophysical techniques, we showed that initial binding of CGRP to the receptor caused unexpectedly small conformational changes in the most prevalent form of the receptor.

It was the coordinated change in dynamics of the external (CGRP binding) face of the receptor and the intracellular face that was the key, and visualising this would not have been possible by other methods.”

Migraines affect approximately five million Australians. It is a neurological condition that can cause multiple, debilitating symptoms including intense headaches, nausea, vomiting, difficulty speaking, numbness or tingling and sensitivity to light and sound.

“The team has filled in one of the most important gaps in our molecular understanding of how cells work - moving the field from atomic level ‘snapshots’ towards atomic-level ‘movies’,” said Dr Josephs.

Professor Patrick Sexton, co-lead on the study and Director of the ARC CCeMMP said: “This is an example of the enormous benefits of fundamental basic research in addressing major unmet medical needs.”

The team from MIPS and ARC CCeMMP worked with collaborators from the University of Tokyo, the University of Otago and the Hudson Institute of Medical Research.

This work was supported by funding from the Australian Research Council and the National Health and Medical Research Council. High performance computing was provided by the Monash MASSIVE program.