Pharmacological Characterization of 5-HT1A Autoreceptor-Coupled GIRK Channels in Rat Dorsal Raphe 5-HT Neurons

• Published in: PloS one Vol. 10; no. 10; p. e0140369
• Main Authors: Montalbano, Alberto, Corradetti, Renato, Mlinar, Boris
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 13.10.2015; Public Library of Science (PLoS)
• Subjects: Animals; Antidepressants; Barium - pharmacology; Bee Venoms - pharmacology; Benzazepines - pharmacology; Brain; Brain research; Brain stem; Channels; Chemical compounds; Childrens health; Dorsal Raphe Nucleus - drug effects; Dorsal Raphe Nucleus - metabolism; Electric Conductivity; Estrenes - pharmacology; G Protein-Coupled Inwardly-Rectifying Potassium Channels - metabolism; Male; Maleates - pharmacology; Mood; Neurons; Neurosciences; Pharmacology; Potassium; Potassium channels; Potassium channels (inwardly-rectifying); Potassium conductance; Proteins; Pyrrolidinones - pharmacology; Rats, Wistar; Receptor, Serotonin, 5-HT1A - metabolism; Resistance; Rodents; Serotonergic Neurons - drug effects; Serotonergic Neurons - metabolism; Serotonin S1 receptors; Subunit structure; Tertiapin-Q; Trends; Whooping cough; Italy; Japan; Germany
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0140369

G protein-activated inwardly rectifying potassium (GIRK) channels in 5-HT neurons are assumed to be principal effectors of 5-hydroxytryptamine 1A (5-HT1A) autoreceptors, but their pharmacology, subunit composition and the role in regulation of 5-HT neuron activity have not been fully elucidated. We sought for a pharmacological tool for assessing the functional role of GIRK channels in 5-HT neurons by characterizing the effects of drugs known to block GIRK channels in the submicromolar range of concentrations. Whole-cell voltage-clamp recording in brainstem slices were used to determine concentration-response relationships for the selected GIRK channel blockers on 5-HT1A autoreceptor-activated inwardly rectifying K+ conductance in rat dorsal raphe 5-HT neurons. 5-HT1A autoreceptor-activated GIRK conductance was completely blocked by the nonselective inwardly rectifying potassium channels blocker Ba2+ (EC50 = 9.4 μM, full block with 100 μM) and by SCH23390 (EC50 = 1.95 μM, full block with 30 μM). GIRK-specific blocker tertiapin-Q blocked 5-HT1A autoreceptor-activated GIRK conductance with high potency (EC50 = 33.6 nM), but incompletely, i.e. ~16% of total conductance resulted to be tertiapin-Q-resistant. U73343 and SCH28080, reported to block GIRK channels with submicromolar EC50s, were essentially ineffective in 5-HT neurons. Our data show that inwardly rectifying K+ channels coupled to 5-HT1A autoreceptors display pharmacological properties generally expected for neuronal GIRK channels, but different from GIRK1-GIRK2 heteromers, the predominant form of brain GIRK channels. Distinct pharmacological properties of GIRK channels in 5-HT neurons should be explored for the development of new therapeutic agents for mood disorders.