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Suppression of ih contributes to propofol-induced inhibition of mouse cortical pyramidal neurons.
J Neurophysiol. 2005 Dec; 94(6):3872-83.JN

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+Show Affiliations

Chen X
Department of Pharmacology, University of Virginia, Charlottesville, 22908-0735, USA. xc9b@virginia.edu
Shu S
No affiliation info available
Bayliss DA
No affiliation info available

MeSH

AnimalsAnimals, NewbornAnticonvulsantsBicucullineCerebral CortexCyclic Nucleotide-Gated Cation ChannelsDose-Response Relationship, DrugDose-Response Relationship, RadiationDrug InteractionsElectric StimulationFemaleGABA AntagonistsGlycine AgentsHyperpolarization-Activated Cyclic Nucleotide-Gated ChannelsIn Vitro TechniquesIon Channel GatingIon ChannelsLysineMaleMembrane PotentialsMiceNeural InhibitionNeural PathwaysOocytesPatch-Clamp TechniquesPotassium ChannelsPropofolPyramidal CellsPyrimidinesRatsStrychnineThalamusTime FactorsXenopus

Pub Type(s)

Comparative Study
Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16093340

Citation

Chen, Xiangdong, et al. "Suppression of Ih Contributes to Propofol-induced Inhibition of Mouse Cortical Pyramidal Neurons." Journal of Neurophysiology, vol. 94, no. 6, 2005, pp. 3872-83.
Chen X, Shu S, Bayliss DA. Suppression of ih contributes to propofol-induced inhibition of mouse cortical pyramidal neurons. J Neurophysiol. 2005;94(6):3872-83.
Chen, X., Shu, S., & Bayliss, D. A. (2005). Suppression of ih contributes to propofol-induced inhibition of mouse cortical pyramidal neurons. Journal of Neurophysiology, 94(6), 3872-83.
Chen X, Shu S, Bayliss DA. Suppression of Ih Contributes to Propofol-induced Inhibition of Mouse Cortical Pyramidal Neurons. J Neurophysiol. 2005;94(6):3872-83. PubMed PMID: 16093340.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Suppression of ih contributes to propofol-induced inhibition of mouse cortical pyramidal neurons. AU - Chen,Xiangdong, AU - Shu,Shaofang, AU - Bayliss,Douglas A, Y1 - 2005/08/10/ PY - 2005/8/12/pubmed PY - 2006/1/26/medline PY - 2005/8/12/entrez SP - 3872 EP - 83 JF - Journal of neurophysiology JO - J Neurophysiol VL - 94 IS - 6 N2 - 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. SN - 0022-3077 UR - https://www.unboundmedicine.com/medline/citation/16093340/Suppression_of_ih_contributes_to_propofol_induced_inhibition_of_mouse_cortical_pyramidal_neurons_ DB - PRIME DP - Unbound Medicine ER -