Revealing the Association of TRPA1 and ERK in the Pathogenesis of Migraine: Breakthrough Research on Cortical Spreading Depolarization Mechanisms

April 09, 2024

A study titled "The contribution of transient receptor potential protein Ankyrin 1-dependent extracellular signal-regulated kinase 2 activation in cerebral cortex to cortical spreading depolarization" was recently published in the journal Neuroscience. The results of the study, led by Professor Minyan Wang from the School of Science at Xi 'an Jiaotong-Liverpool University, reveal that ERK2 is a downstream molecule of TRPA1, serving as a noval target for preventive and therapeutic drugs for migraine. By understanding how TRPA1 regulates the activity of ERK2 to modulate central sensitization and its impact on neuroinflammatory responses, a better understanding of the pathogenesis of migraine can be achieved.

The research direction of Professor Minyan Wang's group in the School of Science is on the molecular pathogenesis of migraine and potential new drug targets. According to Professor Wang, migraine is a disabling disease of the neurovascular system, characterized by recurrent severe headache, nausea, vomiting, photophobia, and phonophobia. Migraine is known to be associated with abnormal activity of genes, the environment, neurons and blood vessels. In fact, it involves a complex interplay of multiple neurotransmitters, neuroregulatory pathways, and vascular responses and is a systemic disorder. According to the World Health Organization (WHO), migraine is a chronic disease that affects more than one billion people worldwide. However, current migraine treatment is less effective and has certain safety concerns. Therefore, there is still a huge demand for the understanding of migraine pathophysiology for the development of novel drugs.

"In the current research progress on migraine, the transient receptor potential ankyrin 1 (TRPA1) ion channel is a very promising therapeutic target."

In the early stage, Professor Wang's research group has previously pioneered the discovery and reporting of how TRPA1 may sensitize the central nervous system and trigger migraine, placing them at the forefront of international migraine pathogenesis research. Recently, they have further established an acute migraine-like behavior model induced by TRPA1 activators in mice and revealed its molecular pathways promoting trigeminal ganglion inflammatory reactions.

"Although the exact cause of migraine and how TRPA1 signal is transmitted to downstream molecules are not fully understood, the role of the molecular extracellular signal-regulated kinase (ERK), including the ERK1 and ERK2 subtypes, has aroused our great interest. This serine/threonine selective protein can be phosphorylated in both peripheral and central brain regions after cortical spreading depression (CSD), which is a phenomenon of transient cortical excitation followed by inhibition." Professor Wang says.

Based on this, the study specifically focused on the regulation of ERK activity within the cerebral cortex and the expression of neuroinflammatory factors in an animal migraine model, and explored whether this involves the transmission of TRPA1 channel signals. Through the study of CSD and neuroinflammation, the research team found a close association between TRPA1-mediated headache signaling and the activity of ERK2 in the cerebral cortex.

"In migraine models, TRPA1 transmits signals by activating the extracellular signal-regulated kinase ERK2 subtype (rather than ERK1), thereby increasing central nervous system sensitivity, in association with neuroinflammation, promoting migraine occurrence. The results of this study show that ERK activity plays a crucial role in regulating the sensitivity of the male rodent cerebral cortex to migraine-like stimuli. Through experiments in rat in vivo models and mouse in vitro models, the inhibition of ERK activity significantly prolonged the latency of CSD and reduced its propagation rate."

Additionally, the research team found that after CSD induction, the level of cytoplasmic ERK phosphorylation (pERK) in the cerebral cortex increased and was correlated with the mRNA levels of interleukin-1β (IL-1β). This finding suggests that neuroinflammation is simultaneously mediated during the process of increased pERK induced by CSD. The team further revealed the potential crucial role of transport receptors: TRPA1 antibodies reduced the level of cytoplasmic pERK2 in the rat cortex without affecting pERK1 levels, and were positively correlated with cortical IL-1β protein levels. Conversely, ERK activators reversed the prolonged latency of CSD induced by TRPA1 inhibitors.

It's worth mentioning that this research project lasted for three years, with significant involvement from undergraduate students in the School of Science, who achieved remarkable success. The first author, Li Haoyang, from the Class of 2023, received a direct Ph.D. offer from Westlake University; Gong Ziyang, from the Class of 2022, obtained a direct Ph.D. offer from our university. Other undergraduate authors, Wang Chenyi from the Class of 2021, and Xu Jiaxin from the Class of 2023, also respectively secured Master's offers from UCL to further pursue their interests in neurobiology topics.

About the Researcher

Professor Minyan Wang

Professor Minyan Wang joined the Department of Biological Sciences at XJTLU in 2011; At the same time, she holds an honorary faculty position at the University of Liverpool and a doctoral supervisor at the Institute of Systems, Molecular % Integrative Biology, University of Liverpool, UK. Prior to his appointment at XJTLU, she was a lecturer in the School of Pharmacy and the School of Biomedical Sciences at the University of Central Lancashire, UK.

From 2004 to 2008, she worked as a postdoctoral fellow at the Institute of Neurobiology, Newcastle University and the School of Life Sciences, University of Bradford, UK. She received her PhD in neuropharmacology from the University of Bradford in 2004, her master's degree in pharmacology from Hebei Medical University in 1997, and her Bachelor's degree in pharmacy in 1988. She has extensive experience in curriculum design and development in higher education and holds a Master's degree in Teaching in Higher Education in the United Kingdom.

Professor Wang has 35 years of experience in research and new drug evaluation in multiple fields including migraine, cancer, diabetes, cerebral ischemia and epilepsy. Since 2000, she has focused on migraine pathogenesis and molecular drug target development and neuropharmacological research; In 2003, she founded the Neuroscience Research Center of Xi 'an Jiaotong-Liverpool University (jointly established by XJTLU and Wenli Wang Charitable Foundation). The center has a comprehensive migraine research platform and technology, multi-angle migraine preclinical research model, and innovative international new molecular targets for new drug development. Its research is at the forefront of the field.

For more details on her publications, please visit:

Materials and proofreading: Professor Minyan Wang
Translation and Editing: Luyao Wang

April 09, 2024