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

PLoS One. 2015 Oct 13;10(10):e0140369. doi: 10.1371/journal.pone.0140369. eCollection 2015.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Barium / pharmacology
  • Bee Venoms / pharmacology
  • Benzazepines / pharmacology
  • Dorsal Raphe Nucleus / drug effects
  • Dorsal Raphe Nucleus / metabolism*
  • Electric Conductivity
  • Estrenes / pharmacology
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / metabolism*
  • Male
  • Maleates / pharmacology
  • Pyrrolidinones / pharmacology
  • Rats, Wistar
  • Receptor, Serotonin, 5-HT1A / metabolism*
  • Serotonergic Neurons / drug effects
  • Serotonergic Neurons / metabolism*

Substances

  • Bee Venoms
  • Benzazepines
  • Estrenes
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • Maleates
  • Pyrrolidinones
  • SCH 23390
  • Receptor, Serotonin, 5-HT1A
  • U 73343
  • Barium
  • tertiapin

Grants and funding

Funding for this study was provided by the University of Florence. A. Montalbano was recipient of a fellowship from the Regione Toscana and Aziende Chimiche Riunite Angelini Francesco A.C.R.A.F. SpA (POR CRO FSE 2007–2013: 5-HT@DRUGeMOOD).