Finding the Molecular Mechanism of Casein Kinase 1δ Mediated Migraine

Published in Science Translational Medicine, Volume 5, Issue 183, May 2013

Summary

Migraine can include aura, head pain, dilation of blood vessels, and hypersensitivity to heat, touch, light, and sound. Migraines can be inherited. We found that mutations in a gene called casein kinase 1 delta (CK1δ) are associated with migraines. We showed that in mice, this mutation causes sensitivity to a chemical migraine trigger, increased blood vessel dilation in the brain. A mutant form of CKIδ also makes the mice more susceptible to aura. One of the targets of CK1δ is an estrogen receptor (ER). Decreased CKIδ function causes less estrogen receptor to be made in cells.

Converging evidence led us to think that estrogen may be part of the mechanism of migraine. Migraines affect three times more post-pubescent women than men. For women, migraine increases in frequency and severity during puberty and often subsides after menopause. For some female patients, migraine is triggered monthly at the same point of the menstrual cycle. Estrogen regulates inflammation and pain and can sensitize pain-sensing neurons. In addition, estrogen can regulate neuronal activity. Estrogen signals through estrogen receptors dilate veins/arteries in response to a common chemical migraine trigger. Thus, it could be that in response to a migraine trigger, the mutant CKIδ could modify estrogen receptors to increase pain responses. Similarly, estrogen could be causing abnormal dilation of cranial blood vessels. These correlations led us to test the hypothesis that estrogen signaling is important for susceptibility to migraine.

Hypothesis vs. Findings:

We hypothesized that an estrogen receptor is downstream of CK1δ in the molecular mechanism of migraine. To this end, we generated mice that lack estrogen receptor beta (ERβ) and carry the mutant CKIδ. We tested whether ERβ changes migraine pain behavior. We found that female mice were more sensitive to the chemical migraine trigger than male mice. We found that female mice that lack ERβ are less sensitive to thermal stimuli at baseline than are normal mice. After a chemical migraine trigger, mice that lack ERβ were more sensitive to pain than normal mice.  CKIδ mutant mice were more sensitive than normal mice and ERβ knock out mice.  When mice lack ERβ and have mutant CKIδ, they are not significantly different from loss of ERβ alone.

Conclusion:

The Migraine Research Foundation grant allowed us to demonstrate that, as in humans, female mice were more susceptible to migraine triggers than male mice. Loss of an estrogen receptor, ERβ made female mice more susceptible to the migraine trigger, and the addition of mutant CKIδ did not significantly change that. We conclude that estrogen signaling is likely to be a component of a migraine progression.

Unanswered questions:

Because mutant CKIδ affects migraine susceptibility in the same way as loss of ERβ, we are unable to conclude if CKIδ and ERβ function in the same pathway.  Further studies will include loss of two estrogen receptors.

What this research means to you:

Funding by the Migraine Research Foundation allowed us to demonstrate that estrogen plays a role in migraine. This research may have implications about the use of estrogen-based birth control or hormone replacement therapy for women with migraines.