Abstract
A novel missense mutation in the CACNA1A gene that encodes the pore forming α1 subunit of the CaV2.1 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 CaV2.1 channels. Whole-cell patch clamp recordings of wild type and mutant CaV2.1 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 CaV2.1 missense mutation alters the gating properties of the channel, suggesting that associated changes in CaV2.1-dependent synaptic communication in the trigeminal system may contribute to the development of trigeminal neuralgia.
Highlights
Trigeminal neuralgia (TN) is one of the most common forms of craniofacial pain
The etiology of TN can be classified into (1) classical TN, which is related to neurovascular compression in the root entry zone at the trigeminal ganglia, (2) secondary TN which is associated with neurological diseases such as multiple sclerosis, and (3) idiopathic TN with unknown etiology [2]
A recent study reported that patients with familial TN exhibit rare variants in ion channels, including the C aV2.1 voltage gated calcium channel [4]. CaV2.1 encodes native P-and Q-type calcium channels [5]
Summary
Trigeminal neuralgia (TN) is one of the most common forms of craniofacial pain. CaV2.1 encodes native P-and Q-type calcium channels [5]. These channels are expressed at high levels in trigeminal neurons, the trigeminal sensory nuclear complex, the brain stem, cerebral cortex and cerebellum, where their main function is to control the release of neurotransmitters [6, 7]. Cytoplasmic regions connecting the various domains are involved in channel regulation, as are the N- and C-termini (Fig. 1a). The latter is a key site for calcium regulation of C aV2.1 channel activity [8]. The CaV2.1 α1 subunit associates with ancillary α2δ and β subunits to form a functional
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