Mutations May Initiate Pain

The team investigated the physiological basis of a severe, inherited form of migraine called “familial hemiplegic migraine type-3” (FHM3). The aura associated with FHM3 often includes a transient weakness or paralysis of one side of the body.

According to the scientists, FHM3 is caused by mutations in a sodium channel gene, SCN1A. The researchers genetically inserted the mutant sodium channels into cultured human cells and recorded the cells’ electrical properties – the key function modulated by sodium channels.

They found that one mutant, called L1649Q, failed to generate any measurable current, indicating that this mutant caused a complete loss of function of the sodium channel and that the two other mutants – L263V and Q1489K – work as sodium channels but are dysfunctional.

The mutations affected the opening and closing of the channel, known as “gating”. Under normal situations, sodium channels are closed and open only briefly to allow sodium to flow into the cell, which helps generate the electrical current conducted by the cell. The dysfunctional channels tend to stay open too long, as if the gating mechanism is stuck, so the scientists, and, thus, may predispose neurons to fire more frequently.

The enhanced predisposition to nerve cell firing may be the spark that initiates the aura. “The aura has been linked to a brain phenomenon known as ‘cortical spreading depression’ which is essentially a wave of inexcitability that travels across the surface of the cortex”, Alfred George Junior, Medical Doctor, explained. “The dysfunctional channels probably aren’t directly causing the headache. They’re likely involved in causing cortical spreading depression, which then triggers other events ultimately culminating in the severe headache.”; Source: Vanderbilt University