Further evidence that inhibition of neuronal voltage-gated calcium channels contributes to the hypnotic effect of neurosteroid analogue, 3β-OH

We recently reported that a neurosteroid analogue with T-channel-blocking properties (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile (3β-OH), induced hypnosis in rat pups without triggering neuronal apoptosis. Furthermore, we found that the inhibition of the C

The T-type calcium channel isoform Ca v 3.1 is a target for the hypnotic effect of the anaesthetic neurosteroid (3β,5β,17β)-3-hydroxyandrostane-17-carbonitrile

BACKGROUND: The mechanisms underlying the role of T-type calcium channels (T-channels) in thalamocortical excitability and oscillations in vivo during neurosteroid-induced hypnosis are largely unknown. METHODS: We used patch-clamp electrophysiological recordings from acute brain slices ex vivo, recordings of local field potentials (LFPs) from the central medial thalamic nucleus in vivo, and wild-type (WT) and Ca RESULTS: Patch-clamp recordings showed that 3β-OH inhibited isolated T-currents but had no effect on phasic or tonic γ-aminobutyric acid A currents. Also in acute brain slices, 3β-OH inhibited the spike firing mode more profoundly in WT than in Ca CONCLUSIONS: The C

Thalamic T-Type Calcium Channels as Targets for Hypnotics and General Anesthetics

General anesthetics mainly act by modulating synaptic inhibition on the one hand (the potentiation of GABA transmission) or synaptic excitation on the other (the inhibition of NMDA receptors), but they can also have effects on numerous other proteins, receptors, and channels. The effects of general anesthetics on ion channels have been the subject of research since the publication of reports of direct actions of these drugs on ion channel proteins. In particular, there is considerable interest in T-type voltage-gated calcium channels that are abundantly expressed in the thalamus, where they control patterns of cellular excitability and thalamocortical oscillations during awake and sleep states. Here, we summarized and discussed our recent studies focused on the CaV3.1 isoform of T-channels in the nonspecific thalamus (intralaminar and midline nuclei), which acts as a key hub through which natural sleep and general anesthesia are initiated. We used mouse genetics and in vivo and ex vivo electrophysiology to study the role of thalamic T-channels in hypnosis induced by a standard general anesthetic, isoflurane, as well as novel neuroactive steroids. From the results of this study, we conclude that CaV3.1 channels contribute to thalamocortical oscillations during anesthetic-induced hypnosis, particularly the slow-frequency range of δ oscillations (0.5–4 Hz), by generating “window current” that contributes to the resting membrane potential. We posit that the role of the thalamic CaV3.1 isoform of T-channels in the effects of various classes of general anesthetics warrants consideration

A novel phospho-modulatory mechanism contributes to the calcium-dependent regulation of T-type Ca2+ channels

International audienceca v 3 / T-type Ca 2+ channels are dynamically regulated by intracellular ca 2+ ions, which inhibit Ca v 3 availability. Here, we demonstrate that this inhibition becomes irreversible in the presence of non-hydrolysable ATP analogs, resulting in a strong hyperpolarizing shift in the steady-state inactivation of the residual ca v 3 current. Importantly, the effect of these ATP analogs was prevented in the presence of intracellular BAPTA. Additional findings obtained using intracellular dialysis of inorganic phosphate and alkaline phosphatase or nan 3 treatment further support the involvement of a phosphorylation mechanism. Contrasting with Ca v 1 and Ca v 2 Ca 2+ channels, the Ca 2+-dependent modulation of ca v 3 channels appears to be independent of calmodulin, calcineurin and endocytic pathways. Similar findings were obtained for the native T-type Ca 2+ current recorded in rat thalamic neurons of the central medial nucleus. Overall, our data reveal a new Ca 2+ sensitive phosphorylation-dependent mechanism regulating ca v 3 channels, with potentially important physiological implications for the multiple cell functions controlled by t-type ca 2+ channels