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1 Department of Anaesthetics, Pain Medicine and Intensive Care, Division of Surgery, Oncology, Reproductive Biology
2 Biophysics Section, Blackett Laboratory, Imperial College, London, UK
Dorsal vagal neurones (DVN) receive serotonergic projections from the medullary raphé 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 µM) elicited a depolarization by 5.1 ± 1.5 mV and an increase in firing rate. In voltage clamp, 5-HT reduced the standing outward current (ISO) 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 (pHo), we next investigated the pH sensitivity of ISO in Hepes-buffered ACSF. At pHo 7.3, DVN exhibited an ISO of 147 ± 15 pA at –20 mV. Acidification to pHo 6.3 reduced ISO to 85 ± 13 pA, whereas raising pHo to 8.5 increased ISO to 216 ± 26 pA. At pHo 7.3, ISO was inhibited by BaCl2 (IC50 465 µM), but unaffected by ZnCl2 (100 µM). 5-HT (10 µM) reduced ISO by 114 ± 17 pA at pHo 7.3, but at pHo 6.3 the 5-HT-induced inhibition of ISO 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.
(Received 20 June 2005;
accepted after revision 13 July 2005;
first published online 14 July 2005)
Corresponding author S. Trapp: Biophysics Section, Blackett Laboratory, South Kensington Campus, Imperial College London, London SW7 2AZ, UK. Email: s.trapp{at}imperial.ac.uk
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