Char Palfrey was awarded a PhD studentship in March 2020 to pursue research to help understand the causes of migraine.
Char had previously completed an MBiol in Neuroscience at the University of Leeds in 2020 and, as part of this, undertook an extended laboratory research project under the supervision of Professor Nikita Gamper, a leading expert in the cellular, molecular and genetic mechanisms of pain. This honed Char’s interest in this area of research, laid an excellent foundation from which to embark upon this PhD project, under the joint supervision of Professor Nikita Gamper and Dr Viktor Lukacs.
Char’s PhD project focused on understanding what goes on in the nerve cells of migraine patients to give rise to such intense headache, to gain insight into what might be the most effective type of medicines.
Char submitted her PhD thesis in December 2024, and is now a Postdoctoral Research Associate at the University of Sheffield.
Migraine is one of the most common neurological conditions, affecting more than 10 million people in the UK. It is a complex and disabling disorder with a variety of symptoms, usually featuring a severe headache. Other symptoms include disturbed vision, nausea, and increased sensitivity to light and sound.
Whilst migraine can be treated effectively in some people - with drugs that reduce the severity of attacks, or drugs that can prevent attacks - these drugs do not work for everyone and do not cure migraine. New, more effective treatments are desperately needed.
During a migraine, activated nerve fibres in the head send pain signals to the brain and release an inflammatory substance (called CGRP), which sensitises nerves, increasing pain signalling. In groups of nerve cells further down the spine, research has suggested that a particular protein, ANO1, has a role in increasing activity of pain nerves, increasing the perception of pain.
Char’s research applied that hypothesis to groups of nerve fibres in the head that are activated during migraine – to investigate whether ANO1 plays a role in migraine, and whether it could be targeted by drugs to reduce pain signalling and migraine pain.
Char’s project explored how ANO1 interacts with other important pain signalling proteins. What Char discovered was that ANO1 forms dynamic molecular complexes in response to pain-inducing stimuli, such as capsaicin, the compound that is responsible for the ‘spicy’ component of chilli peppers. This discovery suggests that ANO1 may play a critical role in amplifying pain signals in the nerve cells that specifically detect painful stimuli in the head, face, and neck. In particular, novel evidence from Char’s PhD suggested that ANO1 function could significantly increase release of CGRP, which is found in larger concentrations in patients experiencing migraine. This finding highlights ANO1 signalling mechanisms as an important novel therapeutic target for the development of new anti-migraine medications.
In addition, Char’s project discovered that a protein called Esyt1 helps regulate the contact between different membranes within the neurons that are responsible for detecting and transmitting pain signals in the body and in the head, face, and neck, and that Esyt1 also plays a role in modulating the ANO1 pain signalling processes, suggesting that it too could be a useful therapeutic target to disrupt pain signalling mechanisms.
There is huge unmet need for effective migraine treatments – to alleviate the debilitating effects and reduce the impact on patients’ lives.
The findings from Char’s research are significant because they provide new insights into how pain signals are amplified in the head, face, and neck, which could lead to more effective treatments for conditions such as migraine. Specifically, targeting the molecular interactions between ANO1 and other important pain signalling proteins could offer a novel way to interfere with pain pathways. Moreover, understanding how proteins like Esyt1 regulate the formation of dynamic molecular complexes opens up new possibilities for therapeutic interventions aimed at reducing both chronic and acute pain.
Palfrey, C., Shapiro, M., Gamper, N. and Shah, S. 2025. Esyt1 underlies ER-PM junctions for ANO1 activity and store-operated Ca2+ entry in sensory neurons. Biophysical Journal, 124(3): 133a. https://doi.org/10.1016/j.bpj.2024.11.746
Palfrey, C., Gamper, N. and Shah, S. 2024. Super-resolution insights into the role of Esyt1 in ER-PM junction dynamics in sensory neurons. Biophysical Journal, 123(3): 172a. https://doi.org/10.1016/j.bpj.2023.11.1139
Palfrey, C., Gamper, N. and Shah, S. 2024. Identifying scaffolding proteins supporting inflammatory receptor complexes in sensory neurons. Biophysical Journal, 123: 518a-519a. https://doi.org/10.1016/j.bpj.2023.11.3141
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