Convergent and reciprocal modulation of a leak K+ current and I(h) by an inhalational anaesthetic and neurotransmitters in rat brainstem motoneurones.
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.
Sirois
Jay E
JE
Department of Pharmacology, University of Virginia, Charlottesville 22908, USA. jes8q@virginia.edu
Lynch
Carl
C
Bayliss
Douglas A
DA
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
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