Role of Sex Hormones in Regulation of Sodium‐Proton Exchanger NHE1: Implications for Migraine
Authors: Galloway Emily A. , Cottier Karissa E. , Kim John , Vallecillo Tissiana , Davis Thomas P. , Vanderah Todd W. , Largent‐Milnes Tally M. 
Published: June 2021

Migraine is the most common neurological disorder, affecting approximately 11% of the world population. Because women comprise over 75% of the migraineur population, female reproductive hormones, namely estrogen, are thought to play a crucial role in this debilitating disease. Preclinical studies have demonstrated that estrogen increases susceptibility to an electrical phenomenon in the brain called cortical spreading depression (CSD), which is theorized to be associated with migraine with aura; however, its mechanism is unknown. Dysregulation of pH in the brain is also known to occur in CSD and potentially aura, however it is unknown if estrogen influences brain pH. NHE1 is a ubiquitously expressed Na+/H+ exchanger involved in maintaining cellular pH. Both increases and decreases in NHE1 expression may affect neuronal excitability and meningeal nociception, which have implications in migraine. In vivo studies in Sprague‐Dawley rats were conducted to compare NHE1 expression in male and female rat whole‐brain tissue. NHE1 expression was significantly higher in male brains compared to females, approximately a four‐fold difference. Additionally, whole‐brain tissues from rats at different points in their estrous cycles, in which E2 levels fluctuate at regular intervals, were analyzed. Results indicate that NHE1 expression was highest at the cycle point that corresponds with the lowest estrogen level. Additionally, rat brain endothelial cells (GPNT), human brain endothelial cells (HBMECs), differentiated microglia, and immortalized astrocytes were incubated with physiologically‐relevant 17‐β‐estradiol (E2) concentrations in vitro. Western blotting showed a significant, inverse relationship such that increases in E2 concentration decreased NHE1 expression levels in endothelial cells; however, a similar trend was absent in microglia and astrocytes. In the same manner, a testosterone concentration response was conducted on both GPNT cells and astrocytes. There were no significant changes in NHE1 expression as testosterone concentration increased. These results indicate that hormonal changes relevant to NHE1 are likely concentrated on the female side of the sex dichotomy. To investigate how nuclear estrogen receptors mediate estrogen's effect on NHE1 expression, GPNT cells were treated with the ERβ antagonist, PHTPP, in addition to E2. NHE1 expression in the PHTPP + E2 group was equivalent to control levels, meaning that E2's method of action was blocked and could not decrease NHE1 expression. These studies clearly show that estrogen influences NHE1 expression in vitro, as well as in vivo, which in turn may contribute to the molecular mechanisms driving migraine susceptibility.

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Research supported by NIH grant R013025390

This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.