Migraines remain poorly understood and, partly as a consequence, we have little in the way of effective treatments. Although increased activity in the brain—both increased blood flow and elevated firing by nerve cells—has been implicated, the connection between those phenomena and the symptoms remains obscure. Now, researchers have identified a new gene that is mutated in individuals that have inherited a migraine disorder, and identified yet another factor that can contribute to migraines.

The gene was isolated in patients that had both severe migraines, and a set of other disorders (glaucoma, kidney disorders) that have been associated with loss of a protein, the sodium-bicarbonate cotransporter (SLC4A4), that shuffles ions across cell membranes. Because its targets include bicarbonate, which can buffer against pH changes, some of the problems caused by its loss are associated with increased acidity of bodily fluids.

The simplest interpretation of the results would be that the problems in SLC4A4 are unrelated to the migraines, but the researchers had access to DNA from a panel of other individuals who suffer from inherited migraine disorders; they found four other individuals that also had mutations in SLC4A4, a result that is extremely unlikely to occur by chance. It appears that all of these individuals can make the sodium-bicarbonate cotransporter, but the protein never ends up on the cell surface, so it can't perform its normal function.

So, how could altered pH induce migraines? The authors note that SLC4A4 is expressed by astrocytes, brain cells that are closely associated with neurons. They propose that loss of the gene leads to locally-altered pH, which influences how the neurons release and retrieve ions when firing off nerve pulses. These changes could ultimately increase the neurons' activity, causing the onset of migraine symptoms.

PNAS, 2010. DOI: 10.1073/pnas.1008705107 (About DOIs).