title: Convergent and reciprocal modulation of a leak K+ current and I(h) by an inhalational anaesthetic and neurotransmitters in rat brainstem motoneurones.
abstract: Neurotransmitters and volatile anaesthetics have opposing effects on motoneuronal excitability which appear to reflect contrasting modulation of two types of subthreshold currents. Neurotransmitters increase motoneuronal excitability by inhibiting TWIK-related acid-sensitive K+ channels (TASK) and shifting activation of a hyperpolarization-activated cationic current (I(h)) to more depolarized potentials; on the other hand, anaesthetics decrease excitability by activating a TASK-like current and inducing a hyperpolarizing shift in I(h) activation. Here, we used whole-cell recording from motoneurones in brainstem slices to test if neurotransmitters (serotonin (5-HT) and noradrenaline (NA)) and an anaesthetic (halothane) indeed compete for modulation of the same ion channels - and we determined which prevails. When applied together under current clamp conditions, 5-HT reversed anaesthetic-induced membrane hyperpolarization and increased motoneuronal excitability. Under voltage clamp conditions, 5-HT and NA overcame most, but not all, of the halothane-induced current. When I(h) was blocked with ZD 7288, the neurotransmitters completely inhibited the K+ current activated by halothane; the halothane-sensitive neurotransmitter current reversed at the equilibrium potential for potassium (E(K)) and displayed properties expected of acid-sensitive, open-rectifier TASK channels. To characterize modulation of I(h) in relative isolation, effects of 5-HT and halothane were examined in acidified bath solutions that blocked TASK channels. Under these conditions, 5-HT and halothane each caused their characteristic shift in voltage-dependent gating of I(h). When tested concurrently, however, halothane decreased the neurotransmitter-induced depolarizing shift in I(h) activation. Thus, halothane and neurotransmitters converge on TASK and I(h) channels with opposite effects; transmitter action prevailed over anaesthetic effects on TASK channels, but not over effects on I(h). These data suggest that anaesthetic actions resulting from effects on either TASK or hyperpolarization-activated cyclic nucleotide-gated (HCN) channels in motoneurones, and perhaps at other CNS sites, can be modulated by prevailing neurotransmitter tone.
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville 22908, USA. jes8q@virginia.edu
authors.forename: Jay E
authors.initials: JE
authors.lastname: Sirois
authors.forename: Carl
authors.initials: C
authors.lastname: Lynch
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Bayliss
mesh_terms: D018685:Anesthetics, Inhalation / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001933:Brain Stem / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D054815:Cyclic Nucleotide-Gated Cation Channels; D004558:Electric Stimulation; D004594:Electrophysiology; D006221:Halothane / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007002:Hypoglossal Nerve / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D007473:Ion Channels / Q000378:metabolism*; D008564:Membrane Potentials / Q000502:physiology; D009046:Motor Neurons / Q000187:drug effects* / Q000378:metabolism; D018377:Neurotransmitter Agents / Q000378:metabolism / Q000494:pharmacology*; D009638:Norepinephrine / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D015221:Potassium Channels / Q000187:drug effects*; D051381:Rats; D012701:Serotonin / Q000494:pharmacology
chemical_list: D018685:Anesthetics, Inhalation; D054815:Cyclic Nucleotide-Gated Cation Channels; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D007473:Ion Channels; D018377:Neurotransmitter Agents; D015221:Potassium Channels; D012701:Serotonin; D006221:Halothane; D009638:Norepinephrine