Open AccessKCTD 12 modulation of GABA (B) receptor function
Author(s) -
Li Melody,
Milligan Carol J.,
Wang Haiyan,
Walker Andrew,
Churilov Leonid,
Lawrence Andrew J.,
Reid Christopher A.,
Hopkins Seth C.,
Petrou Steven
Publication year - 2017
Publication title -
pharmacology research and perspectives
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.975
H-Index - 27
ISSN - 2052-1707
DOI - 10.1002/prp2.319
Subject(s) - allosteric regulation , knockout mouse , g protein coupled inwardly rectifying potassium channel , gabab receptor , in vivo , gabaa receptor , chemistry , allosteric modulator , receptor , pharmacology , gamma aminobutyric acid , biochemistry , biology , g protein , microbiology and biotechnology
The molecular composition and functional diversity of native GABA B receptors ( GABA B R ) are still poorly understood, thus hindering development of selective GABA B R ligands. Potassium channel tetramerization domain‐containing protein ( KCTD ) 12 is a GABA B R auxiliary subunit and mouse KCTD 12 can alter GABA B R function. In this study, we sought to characterize the effects of human KCTD 12 on GABA B R kinetics and pharmacology, using an automated electrophysiological assay. Seizure susceptibility and ethanol consumption were also investigated in a KCTD 12 knockout mouse model. Human KCTD 12 co‐expression altered the kinetics of GABA B R ‐mediated GIRK channels, speeding rates of both activation and desensitization. Analysis of concentration‐response curves showed that KCTD 12 coexpression did not alter effects of the agonists GABA or baclofen on GABA B R . KCTD 12 coexpression enhanced the potentiating effects of the positive allosteric modulator CGP 7930, and its effects on GABA B R activation and desensitization. The function of KCTD 12 in vivo was examined, using the KCTD 12 knockout mouse model. The knockout mice were more resistant to a pentylenetetrazole proconvulsant challenge suggesting reduced seizure susceptibility. In the two bottle preference test, KCTD 12 knockout mice demonstrated a reduced consumption at high ethanol concentrations. In summary, human KCTD 12 accelerated the kinetics of GABA B R in vitro, in a manner possibly sensitive to allosteric pharmacological modulation. This study also provides novel in vivo evidence that the interaction between KCTD 12 and GABA B R is of physiological significance, and may be a mechanism to more selectively modulate GABA B R .