title: Mechanisms of inhibition of CaV3.1 T-type calcium current by aliphatic alcohols.
abstract: 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 (alpha1G) 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 IC(50) values of 362 microM, 1063 microM and 3167 microM, respectively. Octanol similarly inhibited native thalamic Ca(V)3.1 T-currents with an IC(50) of 287 microM 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.
authors.affiliation: Department of Anesthesiology, University of Virginia Health System, School of Medicine, Charlottesville, VA 22908-0710, USA.
authors.forename: Veit-Simon
authors.initials: VS
authors.lastname: Eckle
authors.forename: Slobodan M
authors.initials: SM
authors.lastname: Todorovic
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000008:administration & dosage / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D002460:Cell Line; D002540:Cerebral Cortex / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005227:Fatty Acids / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism; D013788:Thalamus / Q000187:drug effects / Q000502:physiology
chemical_list: C121855:CACNA1G protein, human; C500994:Cacna1g protein, rat; D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D005227:Fatty Acids; D020033:Protein Isoforms; D011994:Recombinant Proteins