A CACNA1A variant associated with trigeminal neuralgia alters the gating of Cav2.1 channels

A novel missense mutation in the CACNA1A gene that encodes the pore forming α₁ subunit of the Ca_V2.1 voltage-gated calcium channel was identified in a patient with trigeminal neuralgia. This mutation leads to a substitution of proline 2455 by histidine (P2455H) in the distal C-terminus region of the channel. Due to the well characterized role of this channel in neurotransmitter release, our aim was to characterize the biophysical properties of the P2455H variant in heterologously expressed Ca_V2.1 channels. Whole-cell patch clamp recordings of wild type and mutant Ca_V2.1 channels expressed in tsA-201 cells reveal that the mutation mediates a depolarizing shift in the voltage-dependence of activation and inactivation. Moreover, the P2455H mutant strongly reduced calcium-dependent inactivation of the channel that is consistent with an overall gain of function. Hence, the P2455H Ca_V2.1 missense mutation alters the gating properties of the channel, suggesting that associated changes in Ca_V2.1-dependent synaptic communication in the trigeminal system may contribute to the development of trigeminal neuralgia.