title: Acid-sensitive TASK-like K+ conductances contribute to resting membrane potential and to orexin-induced membrane depolarization in rat thalamic paraventricular nucleus neurons.
abstract: Orexin (hypocretin) peptides are known to depolarize rat thalamic paraventricular nucleus (PVT) neurons by suppression of one or more undefined potassium conductances. Here, we investigated a contribution of TWIK-related acid-sensitive K(+) (TASK) channels to the resting membrane potential and orexin-induced depolarization of PVT neurons, using patch clamp recording techniques in brain slice preparations. Upon exposure to an acidic (pH 6.3) extracellular solution, PVT neurons displayed membrane depolarization. Under voltage-clamp and in the presence of tetrodotoxin (TTX, 0.5 microM), low pH solutions induced an inward shift in baseline membrane current, accompanied by a net decrease in membrane conductance, reversing close to the potassium equilibrium potential. By contrast, exposure to alkaline (pH 8.3) solutions resulted in membrane hyperpolarization, induced an outward shift in baseline membrane current and an increase in net conductance that reversed close to the potassium equilibrium potential. A local anesthetic bupivacaine (20-40 microM) and the endocannabinoid anandamide (5-10 microM) mimicked the effects of the acidic solution. Exposure to the volatile anesthetic isoflurane (0.2-0.5 mM) induced changes in resting membrane potential, baseline current and membrane conductance similar to those caused by the alkaline solution. Although responsiveness to orexins was preserved under each of the above conditions, the amplitude of the orexin B (0.5 microM)-induced inward current was depressed in the acidic solution and in the presence of anandamide, remained largely unchanged in the alkaline solution, and was enhanced by isoflurane when compared with that in normal artificial cerebrospinal solution. We conclude that pH-sensitive potassium channels, TASK-1 and TASK-3 channels, contribute substantially to the resting membrane conductance(s) and excitability in PVT neurons. The observations that orexin-induced currents were affected by putative TASK-specific drugs in a manner predictable from their effects on TASK channels also suggest that the orexin-induced excitation in PVT neurons is mediated by closure of TASK channels.
authors.affiliation: University of Ottawa, Ottawa, Ontario, Canada K1Y 4E9. pdoroshenko@ohri.ca
authors.forename: P
authors.initials: P
authors.lastname: Doroshenko
authors.forename: L P
authors.initials: LP
authors.lastname: Renaud
mesh_terms: D000143:Acids / Q000494:pharmacology; D000468:Alkalies / Q000494:pharmacology; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D001095:Arachidonic Acids / Q000494:pharmacology; D002045:Bupivacaine / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004558:Electric Stimulation / Q000379:methods; D063388:Endocannabinoids; D005110:Extracellular Space / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D007530:Isoflurane / Q000494:pharmacology; D008564:Membrane Potentials / Q000187:drug effects* / Q000502:physiology; D020644:Midline Thalamic Nuclei / Q000166:cytology*; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009479:Neuropeptides / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D000068797:Orexins; D018408:Patch-Clamp Techniques; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D024683:Potassium Channels, Tandem Pore Domain / Q000037:antagonists & inhibitors / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D000143:Acids; D000468:Alkalies; D000779:Anesthetics, Local; D001095:Arachidonic Acids; D002121:Calcium Channel Blockers; D063388:Endocannabinoids; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D018377:Neurotransmitter Agents; D000068797:Orexins; D053284:Polyunsaturated Alkamides; D024683:Potassium Channels, Tandem Pore Domain; C420132:potassium channel subfamily K member 3; D013779:Tetrodotoxin; D007530:Isoflurane; D011188:Potassium; C078814:anandamide; D002045:Bupivacaine