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.
Highlights
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
We found that mutant mice had moderately faster time to LORR (TTLORR) by about 15% when compared to the WT mice (Fig. 1A)
Our results reveal for the first time the potential utility of TTA-P2 as an adjuvant to isoflurane in the context of induction, as this is a critical aspect of clinical anaesthesia
Summary
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. Little is understood about the functional role of CaV3.3 channels in anaesthetic-induced hypnosis and underlying neuronal oscillations. Molecular studies have shown that the pore forming α1 subunit of T-channels consist of three isoforms such as CaV3.1, CaV3.2, and C aV3.3 with distinct pharmacological and kinetic p roperties[4] These isoforms are differentially expressed in the thalamocortical circuits, which play an essential role in natural sleep and anaestheticinduced hypnosis. We have previously established that both native thalamic and recombinant CaV3.3 currents are inhibited by clinically relevant concentrations of volatile GAs including isoflurane[12,13], but studies to date have not evaluated the role of CaV3.3 channels in anaesthetic mechanisms in vivo. Antagonist to investigate the role of C aV3.3 channels in isoflurane-induced hypnosis and underlying thalamocortical oscillations
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