title: Inhibition of T-type calcium current in rat thalamocortical neurons by isoflurane.
abstract: Thalamocortical (TC) neurons provide the major sensory input to the mammalian somatosensory cortex. Decreased activity of these cells may be pivotal in the ability of general anesthetics to induce loss of consciousness and promote sleep (hypnosis). T-type voltage-gated calcium currents (T-currents) have a key function regulating the cellular excitability of TC neurons and previous studies have indicated that volatile general anesthetics may alter the excitability of these neurons. Using a patch-clamp technique, we investigated the mechanisms whereby isoflurane, a common volatile anesthetic, modulates isolated T-currents and T-current-dependent excitability of native TC neurons in acute brain slices of the rat. In voltage-clamp experiments, we found that isoflurane strongly inhibited peak amplitude of T-current, yielding an IC(50) of 1.1 vol-% at physiological membrane potentials. Ensuing biophysical studies demonstrated that inhibition was more prominent at depolarized membrane potentials as evidenced by hyperpolarizing shifts in channel availability curves. In current-clamp experiments we found that isoflurane decreased the rate of depolarization of low-threshold-calcium spikes (LTCSs) and consequently increased the latency of rebound spike firing at the same concentrations that inhibited isolated T-currents. This effect was mimicked by a novel selective T-channel blocker 3,5-dichloro-N-[1-(2,2-dimethyl-tetrahydro-pyran-4-ylmethyl)-4-fluoro-piperidin-4-ylmethyl]-benzamide (TTA-P2). In contrast, isoflurane and TTA-P2 had minimal effect on resting membrane potential and cell input resistance. We propose that the clinical properties of isoflurane may at least partly be provided by depression of thalamic T-currents.
authors.affiliation: Department of Anesthesiology, University of Virginia Health System, School of Medicine, Charlottesville, VA, USA.
authors.forename: Veit-Simon
authors.initials: VS
authors.lastname: Eckle
authors.forename: Michael R
authors.initials: MR
authors.lastname: Digruccio
authors.forename: Victor N
authors.initials: VN
authors.lastname: Uebele
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.forename: Slobodan M
authors.initials: SM
authors.lastname: Todorovic
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020747:Calcium Channels, T-Type / Q000502:physiology*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D007530:Isoflurane / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013788:Thalamus / Q000187:drug effects* / Q000502:physiology
chemical_list: D002121:Calcium Channel Blockers; D020747:Calcium Channels, T-Type; D007530:Isoflurane; D002118:Calcium