Mechanisms of inhibition of Cav3.1 T-type calcium current by aliphatic alcohols

NEUROPHARMACOLOGY

卷:59

Article

Eckle, Veit-Simon^1,4  Todorovic, Slobodan M.^1,2,3 

[1] Univ Virginia Hlth Syst, Dept Anesthesiol, Sch Med, Charlottesville, VA 22908 USA

[2] Univ Virginia Hlth Syst, Sch Med, Dept Neurosci, Charlottesville, VA 22908 USA

[3] Univ Virginia Hlth Syst, Sch Med, Grad Program Neurosci, Charlottesville, VA 22908 USA

[4] Tech Univ Munich, Klinikum Rechts Isar, Dept Anesthesiol, D-8000 Munich, Germany

关键词: Anesthetics;    T-type channels;    Low-threshold-activated;    Calcium;    Ca2+;    Alcohols;    Thalamus;   

DOI  :  10.1016/j.neuropharm.2010.03.016

来源: Elsevier

【 摘 要 】

Many aliphatic alcohols modulate activity of various ion channels involved in sensory processing and also exhibit anesthetic capacity in vivo. Although the interaction of one such compound, 1-octanol (octanol) with different T-type calcium channels (T-channels) has been described, the mechanisms of current modulation and its functional significance are not well studied. Using patch-clamp technique, we investigated the mechanisms of inhibition of T-currents by a series of aliphatic alcohols in recombinant human Ca(V)3.1 (alpha 1G) T-channel isoform expressed in human embryonic kidney (HEK) 293 cells and thalamocortical (TC) relay neurons in brain slices of young rats. Octanol, 1-heptanol (heptanol) and 1-hexanol (hexanol) inhibited the recombinant Ca(V)3.1 currents in concentration-dependent manner yielding IC50 values of 362 mu M, 1063 mu M and 3167 mu M, respectively. Octanol similarly inhibited native thalamic Ca(V)3.1 T-currents with an IC50 of 287 mu M and diminished burst firing without significant effect on passive membrane properties of these neurons. Inhibitory effect of octanol on T-currents in both native and recombinant cells was accompanied with accelerated macroscopic inactivation kinetics and hyperpolarizing shift in the steady-state inactivation curve. Additionally, octanol induced a depolarizing shift in steady-state activation curves of T-current in TC neurons. Surprisingly, the recovery from fast inactivation at hyperpolarized membrane potentials was accelerated by octanol up 3-fold in native but not recombinant channels. Given the importance of thalamocortical pathways in providing sleep, arousal, and anesthetic states, modulation of thalamic T-currents may at least contribute to the pharmacological effects of aliphatic alcohols. (C) 2010 Elsevier Ltd. All rights reserved.

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