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Convergent and reciprocal modulation of a leak K⁺ current and I_h by an inhalational anaesthetic and neurotransmitters in rat brainstem motoneurones

Jay E. Sirois *, Carl Lynch III † and Douglas A. Bayliss *†

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.

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