Voltage gated calcium channels – molecular targets for trigeminal neuralgia

Gambeta de Andrade, Eder

Voltage gated calcium channels – molecular targets for trigeminal neuralgia

dc.contributor.advisor	Zamponi, Gerald
dc.contributor.author	Gambeta de Andrade, Eder
dc.contributor.committeemember	Altier, Christophe
dc.contributor.committeemember	Turner, Ray
dc.contributor.committeemember	Ousman, Shalina
dc.contributor.committeemember	Hildebrand, Michael
dc.date	2023-05-29
dc.date.accessioned	2022-12-20T21:14:44Z
dc.date.available	2022-12-20T21:14:44Z
dc.date.issued	2022-12-16
dc.description.abstract	Trigeminal neuralgia (TN) is a rare debilitating disease which is characterised by excruciating facial pain and has a higher incidence in women. Recent studies demonstrated that some TN patients present mutations in genes that encode different voltage-gated calcium channels, a class of ion channel that are important players in pain pathways. Among them, mutations in the genes CACANA1A, CACNA1G, and CACNA1H, that encode CaV2.1, CaV3.1 and CaV3.2 channels, respectively, were investigated. First, we characterised the biophysical properties of these mutations using whole-cell patch-clamp recordings in tsA-201 cells. Second, we investigated the role of CaV3.2 channels in an animal model of trigeminal neuropathic pain. Finally, we explored the molecular mechanism of a selective T-type calcium channel blocker. Our data demonstrated a mix of loss- and gain-of-function in the CaV2.1 channel mutant P2455H, and a gain-of-function in a CaV3.1 channel variant (R706Q). For the CaV3.2 channel mutants, some presented a gain-of-function (G563R, P566T, P1605H), some a loss-of-function (E281K, H526Y, R1736C), and one exhibited no difference to wild type channels (D1779Y). These changes in channel function may affect pain pathways in the trigeminal system, thus potentially contributing to the pain phenotype. Considering that several studies demonstrated that CaV3.2 channels are dysregulated in models of chronic pain, we assessed the function of this channel in the constriction of the infraorbital nerve (CION) model. Both female and male CION mice developed facial thermal heat hyperalgesia. Treatment with the pan T-type blocker Z944 was able to produce an antihyperalgesic effect in CION mice, however its effect was absent in CaV3.2-/- mice. This suggests that Z944 targets CaV3.2 channels in the CION model. ELISA analysis revealed increased CaV3.2 channel expression in the spinal trigeminal subnucleus caudalis. Finally, the T-type channel blocker DX-416 was able to block CaV3.2 calcium channel current, however its effect is not altered by mutations in putative sites for A803467. Altogether, the present study demonstrates an important role of voltage-gated calcium channels in trigeminal pain.	en_US
dc.identifier.citation	Gambeta de Andrade, E. (2022). Voltage gated calcium channels – molecular targets for trigeminal neuralgia (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.	en_US
dc.identifier.uri	http://hdl.handle.net/1880/115604
dc.identifier.uri	https://dx.doi.org/10.11575/PRISM/40538
dc.publisher.faculty	Cumming School of Medicine	en_US
dc.publisher.institution	University of Calgary	en
dc.rights	University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.	en_US
dc.subject.classification	Neuroscience	en_US
dc.title	Voltage gated calcium channels – molecular targets for trigeminal neuralgia	en_US
dc.type	doctoral thesis	en_US
thesis.degree.discipline	Medicine – Neuroscience	en_US
thesis.degree.grantor	University of Calgary	en_US
thesis.degree.name	Doctor of Philosophy (PhD)	en_US
ucalgary.item.requestcopy	true	en_US