title: GIRK-like and TRPC-like conductances mediate thyrotropin-releasing hormone-induced increases in excitability in thalamic paraventricular nucleus neurons.
abstract: The thalamic paraventricular nucleus (PVT), reported to participate in arousal and motivated behaviors, contains abundant receptors for thyrotropin-releasing hormone (TRH), a neuropeptide also known to modulate arousal and mood. To test the hypothesis that TRH could influence the excitability of PVT neurons, whole cell patch-clamp recordings obtained in rat brain slice preparations were evaluated during bath applied TRH. In the majority of neurons tested, TRH induced reversible TTX-resistant membrane depolarization. Under voltage-clamp, TRH induced a concentration-dependent G protein- mediated inward current. The mean net TRH-induced current exhibited a decrease in membrane conductance. Further analyses identified two concurrent conductances contributing to the TRH-induced response. One conductance featured a Na(+)-independent and K(+)-dependent net current that displayed rectification and was suppressed by micromolar concentrations of Ba(2+) and two GIRK antagonists, tertiapin Q and SCH 23390. The second conductance featured a Na(+)-dependent net inward current with an I-V relationship that exhibited double rectification with a negative slope conductance below -40 mV. This conductance was suppressed by nonselective TRPC channel blockers 2-APB, flufenamic acid and ML204, enhanced by La(3+) in a subpopulation of cells, and unchanged by the TRPV1 antagonist capsazepine or a Na(+)/Ca(2+) exchanger blocker KB-R7943. TRH also enhanced hyperpolarization-activated low threshold spikes, a feature that was sensitive to pretreatment with either 2-APB or ML204. Collectively, the data imply that TRH enhances excitability in PVT neurons via concurrently decreasing a G-protein-gated inwardly rectifying K(+) conductance and activating a cationic conductance with characteristics reminiscent of TRPC-like channels, possibly involving TRPC4/C5 subunits.
authors: Ottawa Hospital Research Institute, Neuroscience Program and University of Ottawa, Department of Medicine, 725 Parkdale Ave., K1Y 4E9 Ottawa, Ontario, Canada.
authors: Li
authors: L
authors: Zhang
authors: Miloslav
authors: M
authors: Kolaj
authors: Leo P
authors: LP
authors: Renaud
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels / Q000502:physiology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology; D020644:Midline Thalamic Nuclei / Q000166:cytology*; D009474:Neurons / Q000187:drug effects*; D018408:Patch-Clamp Techniques; D010880:Piperidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D050052:TRPC Cation Channels / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D051676:G Protein-Coupled Inwardly-Rectifying Potassium Channels; D007211:Indoles; C567966:ML 204; D010880:Piperidines; D026941:Sodium Channel Blockers; D013449:Sulfonamides; D050052:TRPC Cation Channels; C523871:methyl N-((4-chlorophenyl)sulfonyl)-4-nitrobenzenesulfinimidoate; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013779:Tetrodotoxin; D013973:Thyrotropin-Releasing Hormone