Effects of familial hemiplegic migraine type 1 mutation T666M on voltage-gated calcium channel activities in trigeminal ganglion neurons

Abstract

Cao YQ. Effects of familial hemiplegic migraine type 1 mutation T666M on voltagegated calcium channel activities in trigeminal ganglion neurons. J Neurophysiol 107: 1666 -1680, 2012. First published December 21, 2011 doi:10.1152/jn.00551.2011.-Familial hemiplegic migraine type 1 (FHM-1), a rare hereditary form of migraine with aura and hemiparesis, serves as a good model for exploring migraine pathophysiology. The FHM-1 gene encodes the pore-forming Ca V 2.1 subunit of human P/Q-type voltage-gated Ca 2ϩ channels (VGCCs). Some FHM-1 mutations result in a decrease of whole cell P/Q-type current density in transfected cells/neurons. Questions remain as to whether and how these mutations may increase the gain of the trigeminal nociceptive pathway underlying migraine headache. Here, we investigated the effects of T666M, the most frequently occurring FHM-1 mutation, on VGCC currents and neuronal excitability in trigeminal ganglion (TG) neurons. We expressed human wild-type and T666M Ca V 2.1 subunits in cultured TG neurons from Ca V 2.1 knockout mice and recorded whole cell VGCC currents in transfected neurons. Currents mediated by individual VGCC subtypes were dissected according to their pharmacological and biophysical properties. TG neurons were sorted into three subpopulations based on their soma size and their affinity to isolectin B4 (IB4). We found that the T666M mutation did not affect total or surface expression of Ca V 2.1 proteins but caused a profound reduction of P/Q-type current in all subtypes of TG neurons. Interestingly, a compensatory increase in Ca V 3.2-mediated low-voltageactivated T-type currents only occurred in small IB4-negative (IB4 Ϫ ) TG neurons expressing T666M subunits. Current-clamp recordings showed that the T666M mutation resulted in hyperexcitability of the small IB4 Ϫ TG population. Taken together, our results suggest a possible scenario through which FHM-1 mutations might increase the gain of the trigeminal nociceptive pathway.

Impact of A118G Polymorphism on the Mu Opioid Receptor Function in Pain

“…This study found that Ca V currents from trigeminal ganglion neurons are inhibited at lower morphine doses when the neurons are injected with human MOR-D mRNA as compared with the inhibition observed in neurons injected with MOR-N mRNA [11]. The discrepancy between this report and the previously mentioned studies could be due to the fact that trigeminal ganglia have several Ca V types contributing to the voltage gated calcium currents [28,29] while Lopez Soto et al [8] analyzed Ca V 2.2 transfected in HEK293 cells and Margas et al [7] studied SGC neurons where the Ca V 2.2 are the predominant voltage gated channels.…”

Nonmigraine-associated TRESK K+ channel variant C110R does not increase the excitability of trigeminal ganglion neurons

“…This calls into question a direct causal relationship between TRESK dysfunction and migraine phenotype (Andres-Enguix et al 2012;Eising et al 2013;Lafreniere et al 2010). On the other hand, previous works have illustrated the importance of studying migraine-associated gene mutations in neurons involved in migraine pathophysiology (Fioretti et al 2011;Hullugundi et al 2014;Liu et al 2013;Tao et al 2012;Tottene et al 2009;van Den Maagdenberg et al 2004). While the Xenopus oocyte system is a powerful tool for ion channel research, it may have limitations in predicting the genotype-phenotype correlation between TRESK mutations/variants and migraine susceptibility.…”

Pearls and pitfalls in genetic studies of migraine

“…Most cellular studies showed that FHM1 mutations exert gain-of-function effects by shifting neuronal Ca V 2.1 channels' voltagedependence toward more negative membrane potentials while enhancing channel open probability (34), although loss-of-function effects have been reported as well (35,36). Loss of glial Na…”