LAUSR

ABSTRACT Trigeminal neuralgia (TN) is a rare but debilitating disorder characterized by excruciating facial pain, with a higher incidence in women. Recent studies demonstrated that TN patients present mutations in the gene encoding the CaV3.2 T-type calcium channel, an important player in peripheral pain pathways. Here we characterize the role of CaV3.2 channels in TN at two levels. First, we examined the biophysical properties of CACNA1H variants found in TN patients. Second, we investigated the role of CaV3.2 in an animal model of trigeminal neuropathic pain. Whole cell patch clamp recordings from four different mutants expressed in tsA-201 cells (E286K in the pore loop of domain I, H526Y, G563R and P566T in the domain I-II linker) identified a loss-of-function in activation in the E286K mutation and gain-of-function in the G563R and P566T mutations. Moreover, a loss-of-function in inactivation was observed with the E286K and H526Y mutations. Cell surface biotinylation revealed no difference in channel trafficking among the variants. The G563R mutant also caused a gain-of-function in the firing properties of transfected trigeminal ganglion neurons. In female and male mice, constriction of the infraorbital nerve (CION) induced facial thermal heat hyperalgesia. Block of T-type channels with Z944 resulted in antihyperalgesia. The effect of Z944 was absent in CaV3.2-/- mice, indicating that CaV3.2 is the molecular target of the antihyperalgesic Z944 effect. Finally, ELISA analysis revealed increased CaV3.2 channel expression in the spinal trigeminal subnucleus caudalis. Altogether, the present study demonstrates an important role of CaV3.2 channels in trigeminal pain.