TASK-like K+ channels mediate effects of 5-HT and extracellular pH in rat dorsal vagal neurones in vitro

Dorsal vagal neurones (DVN) receive serotonergic projections from the medullary raphe nuclei, suggesting that 5-HT modulates vagal activity. A previous study has shown that 5-HT excites DVN in part by inhibition of a K+ current via postsynaptic 5-HT2A receptors. As mRNA for the two-pore-domain K+ channels TASK-1 (KCNK3) and TASK-3 (KCNK9) has been found in DVN, we investigated the possibility that 5-HT exerts its effects via inhibition of these K+ channels using whole-cell patch-clamp techniques. In current clamp, 5-HT (20 mu m) elicited a depolarization by 5.1 +/- 1.5 mV and an increase in firing rate. In voltage damp, 5-HT reduced the standing outward current (I-SO) at -20 mV by 106 +/- 17 pA, inhibiting a conductance (reversal, -95 +/- 4 mV) which displayed Goldman-Hodgkin-Katz outward rectification, supportive of a TASK-like K' current. Since TASK channels are modulated by extracellular PH (pH(o)), we next investigated the PH sensitivity of ISO in Hepes-buffered ACSF. At pH(o) 7.3, DVN exhibited an I-SO of 147 15 pA at -20 mV. Acidification to pH(o), 6.3 reduced ISO to 85 13 pA, whereas raising pH(o) to 8.5 increased I-SO to 216 +/- 26 PA. At pH(o) 7.3, I-SO was inhibited by BaCl2 (IC50 465 mu m), but unaffected by ZnCl2 (100 mu m). 5-HT (10 mu m) reduced I-SO by 114 +/- 17 pA at pH(o) 7.3, but at PH. 6.3 the 5-HT-induced inhibition of I-SO was significantly smaller. The present data suggest that the excitatory effects of 5-HT on DVN are mediated in part by inhibition of a TASK-like, pH-sensitive K+ conductance. The pharmacological profile of this conductance excludes TASK-3 homomers, but rather implicates TASK-1-containing channels.