Global genetic deletion of CaV3.3 channels facilitates anaesthetic induction and enhances isoflurane-sparing effects of T-type calcium channel blockers

Abstract We previously documented that the CaV3.3 isoform of T-type calcium channels (T-channels) is inhibited by clinically relevant concentrations of volatile anaesthetics, including isoflurane. However, little is understood about the functional role of CaV3.3 channels in anaesthetic-induced hypno...

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Autores principales:	Simon Feseha, Tamara Timic Stamenic, Damon Wallace, Caesare Tamag, Lingling Yang, Jen Q. Pan, Slobodan M. Todorovic
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/8216d37220d54878877abd7639662c9d
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spelling	oai:doaj.org-article:8216d37220d54878877abd7639662c9d2021-12-02T15:11:52ZGlobal genetic deletion of CaV3.3 channels facilitates anaesthetic induction and enhances isoflurane-sparing effects of T-type calcium channel blockers10.1038/s41598-020-78488-82045-2322https://doaj.org/article/8216d37220d54878877abd7639662c9d2020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-78488-8https://doaj.org/toc/2045-2322Abstract We previously documented that the CaV3.3 isoform of T-type calcium channels (T-channels) is inhibited by clinically relevant concentrations of volatile anaesthetics, including isoflurane. However, little is understood about the functional role of CaV3.3 channels in anaesthetic-induced hypnosis and underlying neuronal oscillations. To address this issue, we used CaV3.3 knock-out (KO) mice and a panselective T-channel blocker 3,5-dichloro-N-[1-(2,2-dimethyltetrahydro-pyran-4-ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide (TTA-P2). We found that mutant mice injected with the vehicle showed faster induction of hypnosis than wild-type (WT) mice, while the percent isoflurane at which hypnosis and immobility occurred was not different between two genotypes. Furthermore, we found that TTA-P2 facilitated isoflurane induction of hypnosis in the CaV3.3 KO mice more robustly than in the WT mice. Isoflurane-induced hypnosis following injections of TTA-P2 was accompanied with more prominent delta and theta EEG oscillations in the mutant mice, and reached burst-suppression pattern earlier when compared to the WT mice. Our findings point to a relatively specific value of CaV3.3 channels in anaesthetic induced hypnosis. Furthermore, we propose that T-channel blockers may be further explored as a valuable adjunct to reducing the usage of potent volatile anaesthetics, thereby improving their safety.Simon FesehaTamara Timic StamenicDamon WallaceCaesare TamagLingling YangJen Q. PanSlobodan M. TodorovicNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-10 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Simon Feseha Tamara Timic Stamenic Damon Wallace Caesare Tamag Lingling Yang Jen Q. Pan Slobodan M. Todorovic Global genetic deletion of CaV3.3 channels facilitates anaesthetic induction and enhances isoflurane-sparing effects of T-type calcium channel blockers
description	Abstract We previously documented that the CaV3.3 isoform of T-type calcium channels (T-channels) is inhibited by clinically relevant concentrations of volatile anaesthetics, including isoflurane. However, little is understood about the functional role of CaV3.3 channels in anaesthetic-induced hypnosis and underlying neuronal oscillations. To address this issue, we used CaV3.3 knock-out (KO) mice and a panselective T-channel blocker 3,5-dichloro-N-[1-(2,2-dimethyltetrahydro-pyran-4-ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide (TTA-P2). We found that mutant mice injected with the vehicle showed faster induction of hypnosis than wild-type (WT) mice, while the percent isoflurane at which hypnosis and immobility occurred was not different between two genotypes. Furthermore, we found that TTA-P2 facilitated isoflurane induction of hypnosis in the CaV3.3 KO mice more robustly than in the WT mice. Isoflurane-induced hypnosis following injections of TTA-P2 was accompanied with more prominent delta and theta EEG oscillations in the mutant mice, and reached burst-suppression pattern earlier when compared to the WT mice. Our findings point to a relatively specific value of CaV3.3 channels in anaesthetic induced hypnosis. Furthermore, we propose that T-channel blockers may be further explored as a valuable adjunct to reducing the usage of potent volatile anaesthetics, thereby improving their safety.
format	article
author	Simon Feseha Tamara Timic Stamenic Damon Wallace Caesare Tamag Lingling Yang Jen Q. Pan Slobodan M. Todorovic
author_facet	Simon Feseha Tamara Timic Stamenic Damon Wallace Caesare Tamag Lingling Yang Jen Q. Pan Slobodan M. Todorovic
author_sort	Simon Feseha
title	Global genetic deletion of CaV3.3 channels facilitates anaesthetic induction and enhances isoflurane-sparing effects of T-type calcium channel blockers
title_short	Global genetic deletion of CaV3.3 channels facilitates anaesthetic induction and enhances isoflurane-sparing effects of T-type calcium channel blockers
title_full	Global genetic deletion of CaV3.3 channels facilitates anaesthetic induction and enhances isoflurane-sparing effects of T-type calcium channel blockers
title_fullStr	Global genetic deletion of CaV3.3 channels facilitates anaesthetic induction and enhances isoflurane-sparing effects of T-type calcium channel blockers
title_full_unstemmed	Global genetic deletion of CaV3.3 channels facilitates anaesthetic induction and enhances isoflurane-sparing effects of T-type calcium channel blockers
title_sort	global genetic deletion of cav3.3 channels facilitates anaesthetic induction and enhances isoflurane-sparing effects of t-type calcium channel blockers
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/8216d37220d54878877abd7639662c9d
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Global genetic deletion of CaV3.3 channels facilitates anaesthetic induction and enhances isoflurane-sparing effects of T-type calcium channel blockers

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