title: Suppression of ih contributes to propofol-induced inhibition of mouse cortical pyramidal neurons.
abstract: The contributions of the hyperpolarization-activated current, I(h), to generation of rhythmic activities are well described for various central neurons, particularly in thalamocortical circuits. In the present study, we investigated effects of a general anesthetic, propofol, on native I(h) in neurons of thalamus and cortex and on the corresponding cloned HCN channel subunits. Whole cell voltage-clamp recordings from mouse brain slices identified neuronal I(h) currents with fast activation kinetics in neocortical pyramidal neurons and with slower kinetics in thalamocortical relay cells. Propofol inhibited the fast-activating I(h) in cortical neurons at a clinically relevant concentration (5 microM); inhibition of I(h) involved a hyperpolarizing shift in half-activation voltage (DeltaV1/2 approximately -9 mV) and a decrease in maximal available current (approximately 36% inhibition, measured at -120 mV). With the slower form of I(h) expressed in thalamocortical neurons, propofol had no effect on current activation or amplitude. In heterologous expression systems, 5 muM propofol caused a large shift in V1/2 and decrease in current amplitude in homomeric HCN1 and linked heteromeric HCN1-HCN2 channels, both of which activate with fast kinetics but did not affect V1/2 or current amplitude of slowly activating homomeric HCN2 channels. With GABA(A) and glycine receptor channels blocked, propofol caused membrane hyperpolarization and suppressed action potential discharge in cortical neurons; these effects were occluded by the I(h) blocker, ZD-7288. In summary, these data indicate that propofol selectively inhibits HCN channels containing HCN1 subunits, such as those that mediate I(h) in cortical pyramidal neurons-and they suggest that anesthetic actions of propofol may involve inhibition of cortical neurons and perhaps other HCN1-expressing cells.
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, 22908-0735, USA. xc9b@virginia.edu
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Chen
authors.forename: Shaofang
authors.initials: S
authors.lastname: Shu
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Bayliss
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D000927:Anticonvulsants / Q000494:pharmacology*; D001640:Bicuculline / Q000494:pharmacology; D002540:Cerebral Cortex / Q000166:cytology*; D054815:Cyclic Nucleotide-Gated Cation Channels; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D004558:Electric Stimulation / Q000379:methods; D005260:Female; D018756:GABA Antagonists / Q000494:pharmacology; D018684:Glycine Agents / Q000494:pharmacology; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D066298:In Vitro Techniques; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D007473:Ion Channels / Q000145:classification / Q000187:drug effects* / Q000502:physiology / Q000528:radiation effects; D008239:Lysine / Q000031:analogs & derivatives / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D051379:Mice; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D009434:Neural Pathways / Q000166:cytology; D009865:Oocytes; D018408:Patch-Clamp Techniques / Q000379:methods; D015221:Potassium Channels; D015742:Propofol / Q000494:pharmacology*; D017966:Pyramidal Cells / Q000187:drug effects*; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D013331:Strychnine / Q000494:pharmacology; D013788:Thalamus / Q000166:cytology; D013997:Time Factors; D014981:Xenopus
chemical_list: D000927:Anticonvulsants; D054815:Cyclic Nucleotide-Gated Cation Channels; D018756:GABA Antagonists; D018684:Glycine Agents; C578666:Hcn1 protein, mouse; C578667:Hcn1 protein, rat; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D015221:Potassium Channels; D011743:Pyrimidines; C082246:ICI D2788; C013411:biocytin; D013331:Strychnine; D008239:Lysine; D001640:Bicuculline; D015742:Propofol