Pharmacological characterization of GABAB receptor subtypes assembled with auxiliary KCTD subunits

Neuropharmacology. 2015 Jan:88:145-54. doi: 10.1016/j.neuropharm.2014.08.020. Epub 2014 Sep 6.


GABAB receptors (GABABRs) are considered promising drug targets for the treatment of mental health disorders. GABABRs are obligate heteromers of principal GABAB1 and GABAB2 subunits. GABABRs can additionally associate with auxiliary KCTD8, 12, 12b and 16 subunits, which also bind the G-protein and differentially regulate G-protein signaling. It is unknown whether the KCTDs allosterically influence pharmacological properties of GABABRs. Here we show that KCTD8 and KCTD16 slightly but significantly increase GABA affinity at recombinant receptors. However, KCTDs clearly do not account for the 10-fold higher GABA affinity of native compared to recombinant GABABRs. The positive allosteric modulator (PAM) GS39783, which binds to GABAB2, increases both potency and efficacy of GABA-mediated G-protein activation ([(35)S]GTPγS binding, BRET between G-protein subunits), irrespective of whether KCTDs are present or not. Of note, the increase in efficacy was significantly larger in the presence of KCTD8, which likely is the consequence of a reduced tonic G-protein activation in the combined presence of KCTD8 and GABABRs. We recorded Kir3 currents to study the effects of GS39783 on receptor-activated G-protein βγ-signaling. In transfected CHO cells and cultured hippocampal neurons GS39783 increased Kir3 current amplitudes activated by 1 μM of baclofen in the absence and presence of KCTDs. Our data show that auxiliary KCTD subunits exert marginal allosteric influences on principal GABABR subunits. PAMs at principal subunits will therefore not be selective for receptor subtypes owing to KCTD subunits. However, PAMs can differentially modulate the responses of receptor subtypes because the KCTDs differentially regulate G-protein signaling.

Keywords: Baclofen; G-protein-coupled receptor; GABA-B; GS93783; KCTD; Kir3.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Allosteric Regulation / drug effects
  • Allosteric Regulation / physiology
  • Animals
  • Baclofen / pharmacology
  • CHO Cells
  • Cells, Cultured
  • Cricetulus
  • Cyclopentanes / pharmacology
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels / metabolism
  • GABA Modulators / pharmacology
  • GABA-B Receptor Agonists / pharmacology
  • GTP-Binding Proteins / metabolism
  • HEK293 Cells
  • Hippocampus / drug effects
  • Hippocampus / physiology
  • Humans
  • Mice
  • Neurons / drug effects
  • Neurons / physiology
  • Potassium / metabolism
  • Pyrimidines / pharmacology
  • Rats
  • Receptors, GABA-B / genetics
  • Receptors, GABA-B / metabolism*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / metabolism
  • gamma-Aminobutyric Acid / metabolism


  • Cyclopentanes
  • G Protein-Coupled Inwardly-Rectifying Potassium Channels
  • GABA Modulators
  • GABA-B Receptor Agonists
  • N,N'-dicyclopentyl-2-methylsulfanyl-5-nitro-pyrimidine-4,6-diamine
  • Pyrimidines
  • Receptors, GABA-B
  • Recombinant Proteins
  • gamma-Aminobutyric Acid
  • GTP-Binding Proteins
  • Baclofen
  • Potassium