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 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 microM) 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 microM), but unaffected by ZnCl2 (100 microM). 5-HT (10 microM) 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.
Hopwood
Sarah E
SE
Department of Anaesthetics, Pain Medicine and Intensive Care, Division of Surgery, Oncology, Reproductive Biology, Blackett Laboratory, South Kensington Campus, Imperial College London, London SW7 2AZ, UK.
Trapp
Stefan
S
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D017609:Barium Compounds / Q000494:pharmacology; D002712:Chlorides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D011188:Potassium / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects* / Q000378:metabolism; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044348:Receptors, Serotonin, 5-HT2 / Q000187:drug effects* / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology*; D013997:Time Factors; D014630:Vagus Nerve / Q000187:drug effects* / Q000502:physiology
D017609:Barium Compounds; D002712:Chlorides; D009419:Nerve Tissue Proteins; D024661:Potassium Channels, Inwardly Rectifying; D024683:Potassium Channels, Tandem Pore Domain; D044348:Receptors, Serotonin, 5-HT2; C024986:barium chloride; C420132:potassium channel subfamily K member 3; D012701:Serotonin; D011188:Potassium