The thalamocortical system is characterized by synchronized oscillatory burst activity during states of slow wave sleep and tonic generation of action potentials during wakefulness. Neurons of the arousing brainstem system release a number of neurotransmitters including acetylcholine (ACh) into the thalamus and mediate the switch between activity modes. A common action of these transmitters is a depolarizing shift of the membrane potential of thalamocortical relay (TC) neurons, leading to cessation of rhythmic bursts and occurrence of tonic activity. One crucial step of membrane depolarization is the decrease in a leak K⁺ conductance, the molecular nature of which has recently been attributed to TWIK-related acid-sensitive potassium (TASK)-1 and TASK-3 channels. The expression of these channels was correlated with the presence of an outwardly rectifying acid-sensitive K⁺ current which was inhibited by activation of muscarinic ACh receptors (mAChR). Whether TASK channels are directly modulated by G protein a subunits or indirectly via phospholipase C (PLC) activation and depletion of phosphatidyl-4,5-inositolbisphosphate (PIP₂) is currently a matter of discussion.

Using electrophysiological and molecular biological techniques in rodent brain slices in combination with a genetic strategy, we aimed to unravel the modulation pathway of TASK channels in TC neurons. Whole-cell voltage-clamp recordings at a constant holding potential of -30 mV revealed a standing outward current (I_SO) which was substantially carried by TASK channels. Application of muscarine significantly reduced I_SO an effect which was nearly completely abolished in a Ga₁₁/Ga_q^-/- double-deficient mouse line and after adding GDPßS to the internal recording solution during recordings in rats. The use of blockers with preferred affinity to mAChR subtypes and specific antibodies revealed the involvement of mAChR₁ and mAChR₃. While I_SO was stable over rather long recording periods under control conditions, exchange of ATP by ADPßS in the internal recording solution resulted in a fast run down of I_SO amplitude and the affected current component resembled a current through TASK channels. In contrast to the significant reduction of the muscarine effect by inhibitors (U72122, Et-18-OCH3) of phosphatidylinositol-specific PLC, the phosphatidylcholine-specific PLC inhibitor D609 had no effect. Extracellular application of PIP₂ activated an acid-sensitive outward rectifying K⁺ current and partially reversed the action of muscarine. However it is currently not clear whether these effects resulted from PIP₂ entering the cell interior. Taken together our findings indicate that TASK channels are modulated by both, direct interaction with Ga_q as well as breakdown of PIP₂. Therefore TASK channels in the thalamus represent a pool of highly modulated ion channels and contribute to the arousing effects of the ascending brainstem system.