Science: New study identifies the structure and dynamics of key receptors for migraines, paving the way for better treatments!

March 6, 2021 //--In a study, a research team from Monash University in Australia, the ARC Membrane Protein Cryogenic Electron Microscopy Center, the University of Tokyo in Japan, and the University of Otago in New Zealand have identified an important cell surface The shape and dynamics of the (membrane) receptor, which is called calcitonin gene-related peptide (CGRP), has long been thought to be associated with migraine.
The relevant research results have been published in the recent Science journal under the title Structure and dynamics of the CGRP receptor in apo and peptide-bound forms.

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Image source: Patrick M.
Sexton, PhD.

Migraine is a headache that is not simple.
More than 3 million migraine sufferers have at least once a year, and more than 60% of them are women.
A small percentage of patients experience chronic migraine, that is, migraine attacks that occur for 15 days or more every month for 3 months or more.
Although patients experience many different symptoms of different intensities, usually nausea, dizziness, sensitivity to light and sound, severe pain on one or both sides of the head, the physiological process of migraine attack and pain is different from other types of headaches, such as Muscle tension or sinus pain.
Although migraine has long been considered a neurovascular disease that involves vasodilation of the skull, face, and meninges, studies have ruled out vasodilation as a factor in this type of pain.
Recent studies have confirmed that an increase in CGRP in the pain pathway of the trigeminal nerve sensory nerve leads to headaches.

Dr.
Radostin Danev from the University of Tokyo said: “We have determined the atomic structure of an important cell surface (membrane) receptor related to migraine.
In this preliminary study, we determined the individual structure of the receptor and its relationship with The structure of the natural target molecule binding.
This gives us a clear understanding of how the normal function of the receptor in the body works.
"

Future research will expand the screening of potential drug targets.
Dr.
Danev said that there are currently several migraine drugs targeting this receptor, but knowledge about protein structure is essential for understanding pharmacology and future treatment development, which will help us understand the pathological mechanism of chronic diseases and Helps develop more effective and more accessible treatments.

Dr.
Patrick M.
Sexton, a professor of pharmacology at Monash University and the corresponding author of the paper, explained that identifying the structure of CGRP is the first molecular revelation of the initiation event related to migraine.
"The method we used to do this work (low temperature electron microscopy) is similar to the method used to support the development of new coronavirus vaccines and drugs," he said.

The trigeminal nerve is the fifth cranial nerve, which is responsible for transmitting the sensations of the face, endometrial lining, eyes, sinuses, temporomandibular joint, ears, salivary glands, oral cavity, nasal cavity and teeth to the brain.
It consists of three branches; eyes, upper jaw and lower jaw.
It is also the nerve that controls the chewing muscle.
Source: orofacialpain.
org.
uk

Although this research and all research on COVID-19 are recent, cryo-electron microscopy (cryo-EM) has been in use since the 1970s.
Advances in the past decade have improved detection techniques and computational imaging, enabling cryo-electron microscopy to reveal the structure of biomolecules with near-atomic resolution.
Dr.
Danev is excited about the future of cryo-electron microscopy research: “This is the first high-resolution cryo-electron microscopy of the successful inactive and pre-activated state of isolated G protein-coupled receptors without the presence of G protein.
Research.
It demonstrates the expanding capabilities of cryo-electron microscopy in determining the structure of small membrane proteins.
” Dr.
Danev said that the team is excited about the results of their work, and the real benefits are about to be revealed.
"This work paves the way for further research on inactive GPCRs, and so far this has only been the prerogative of X-ray crystallography.
"

Now that they have such an understanding of the structure of CGRP and have the ability to study it, what are the future plans and directions? Dr.
Sexton explained: "The new structure and understanding of receptor movement can be used to design better receptor activation methods.
This work reveals a key event in migraine, so we have recently obtained research for our research.
Approval of effective therapies for receptors.
Anyway, we also want to treat other diseases by increasing receptor activation.
” ()

Original source: Tracy M.
Josephs et al.
sciencemag.
org/content/early/2021/02/17/science.
abf7258">Structure and dynamics of the CGRP receptor in apo and peptide-bound forms, Science (2021).
DOI: 10.
1126/science.
abf7258