CaV3.2 calcium channels contribute to trigeminal neuralgia

Abstract

Supplemental Digital Content is Available in the Text.Cav3.2 T-type calcium channels are identified as potential therapeutic targets for facial pain.

Central and peripheral contributions of T-type calcium channels in pain

“…Although comparatively less is known about T-type channels within the TG, it does appear to express Ca v 3.1, Ca v 3.2, and Ca v 3.3, with activity of Ca v 3.2 being increased in TG neurons in a facial inflammatory pain model [ 82 ]. Moreover, intra-TG injection of the T-type antagonist TTA-P2, systemic administration of Z944, or silencing of Ca v 3.2 was shown to produce significant analgesia in rodent models of trigeminal neuralgia [ 82 , 83 ]. Mutations in Ca v 3.2 have also been associated with the development of trigeminal neuralgia [ 84 ], some of which produce potent gain of function [ 83 ].…”

“…Moreover, intra-TG injection of the T-type antagonist TTA-P2, systemic administration of Z944, or silencing of Ca v 3.2 was shown to produce significant analgesia in rodent models of trigeminal neuralgia [ 82 , 83 ]. Mutations in Ca v 3.2 have also been associated with the development of trigeminal neuralgia [ 84 ], some of which produce potent gain of function [ 83 ]. However, there is also evidence that within the TG, Ca v 3.1 and Ca v 3.3 may have significant contributions to chronic pain.…”

Electrophysiological and computational analysis of Cav3.2 channel variants associated with familial trigeminal neuralgia

“…Hence, an alteration of neuronal excitability resulting from abnormal functioning of ion channels has emerged as a potential underlying mechanism [ 4 – 7 ] and consistent with this notion, the sodium channel blockers carbamazepine and oxcarbazepine represent the first line therapy in TN [ 8 ]. Moreover, alterations of the expression of several ion channels including sodium, calcium, and potassium channels have been reported in TN patients [ 9 ] as well as in preclinical rodent models [ 10 – 17 ]. In addition, rare polymorphisms in ion channel genes were identified in TN patients [ 18 – 20 ] suggesting the existence of predisposing genetic factors and gain-of-function mutations (GoF) were reported for Na v 1.6 [ 18 ], Ca v 2.1 [ 21 ], TRPM7 [ 22 , 23 ], and TRPM8 channels [ 24 ].…”

“…Ca v 3.2 channels belong to the subfamily of low-voltage-activated T-type channels and are widely expressed throughout the nervous system where they play an essential role in the control of neuronal excitability [ 26 ]. Importantly, Ca v 3.2 is expressed in all structures of the trigeminal pathway including trigeminal ganglion sensory neurons [ 27 , 28 ], the spinal trigeminal nucleus (SpV) [ 17 ] as well as several thalamic nuclei such as the ventroposterior nucleus (VPM) [ 29 ] that receives projections from the SpV. Hence, Ca v 3.2 channels may be of direct relevance for the transmission of trigeminal sensory information and a role for Ca v 3.2 in TN-like syndrome was reported in a preclinical rodent model [ 17 ].…”

“…In this study, we aimed to provide a comprehension analysis of TN-associated CACNA1H variants with regard to their impact on the functioning of Ca v 3.2 channels. Of the 19 variants reported [ 25 ], four had already been assessed for their impact on the biophysical properties of Ca v 3.2 channels and revealed a variant-dependent effect such that G563R and P566T produced a GoF of the channel, E286K caused a mild loss-of-function (LoF), and H526Y did not cause any alteration [ 17 , 30 ]. We now report the functional characterization of 13 additional variants.…”