title: Effects of familial hemiplegic migraine type 1 mutation T666M on voltage-gated calcium channel activities in trigeminal ganglion neurons.
abstract: 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(2+) 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-voltage-activated T-type currents only occurred in small IB4-negative (IB4(-)) TG neurons expressing T666M subunits. Current-clamp recordings showed that the T666M mutation resulted in hyperexcitability of the small IB4(-) TG population. Taken together, our results suggest a possible scenario through which FHM-1 mutations might increase the gain of the trigeminal nociceptive pathway.
authors.affiliation: Washington University Pain Center and Department of Anesthesiology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Tao
authors.forename: Ping
authors.initials: P
authors.lastname: Liu
authors.forename: Zheman
authors.initials: Z
authors.lastname: Xiao
authors.forename: Hucheng
authors.initials: H
authors.lastname: Zhao
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Gerber
authors.forename: Yu-Qing
authors.initials: YQ
authors.lastname: Cao
mesh_terms: D000818:Animals; D020864:Calcium Channels, N-Type / Q000235:genetics* / Q000378:metabolism; D020013:Calcium Signaling / Q000235:genetics*; D002478:Cells, Cultured; D006801:Humans; D015640:Ion Channel Gating / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation; D009474:Neurons / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D012668:Trigeminal Ganglion / Q000378:metabolism* / Q000503:physiopathology
chemical_list: D020864:Calcium Channels, N-Type