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    KCTD12 modulation of GABA(B) receptor function

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    Author
    Li, M; Milligan, CJ; Wang, H; Walker, A; Churilov, L; Lawrence, AJ; Reid, CA; Hopkins, SC; Petrou, S
    Date
    2017-08-01
    Source Title
    Pharmacology Research and Perspectives
    Publisher
    JOHN WILEY & SONS LTD
    University of Melbourne Author/s
    Petrou, Steven; Churilov, Leonid; Lawrence, Andrew; Li, Melody; Reid, Christopher; Walker, Andrew; Milligan, Carol
    Affiliation
    Florey Department of Neuroscience and Mental Health
    Medicine and Radiology
    Metadata
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    Document Type
    Journal Article
    Citations
    Li, M., Milligan, C. J., Wang, H., Walker, A., Churilov, L., Lawrence, A. J., Reid, C. A., Hopkins, S. C. & Petrou, S. (2017). KCTD12 modulation of GABA(B) receptor function. PHARMACOLOGY RESEARCH & PERSPECTIVES, 5 (4), https://doi.org/10.1002/prp2.319.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/256562
    DOI
    10.1002/prp2.319
    Abstract
    The molecular composition and functional diversity of native GABAB receptors (GABABR) are still poorly understood, thus hindering development of selective GABABR ligands. Potassium channel tetramerization domain-containing protein (KCTD) 12 is a GABABR auxiliary subunit and mouse KCTD12 can alter GABABR function. In this study, we sought to characterize the effects of human KCTD12 on GABABR kinetics and pharmacology, using an automated electrophysiological assay. Seizure susceptibility and ethanol consumption were also investigated in a KCTD12 knockout mouse model. Human KCTD12 co-expression altered the kinetics of GABABR-mediated GIRK channels, speeding rates of both activation and desensitization. Analysis of concentration-response curves showed that KCTD12 coexpression did not alter effects of the agonists GABA or baclofen on GABABR. KCTD12 coexpression enhanced the potentiating effects of the positive allosteric modulator CGP7930, and its effects on GABABR activation and desensitization. The function of KCTD12 in vivo was examined, using the KCTD12 knockout mouse model. The knockout mice were more resistant to a pentylenetetrazole proconvulsant challenge suggesting reduced seizure susceptibility. In the two bottle preference test, KCTD12 knockout mice demonstrated a reduced consumption at high ethanol concentrations. In summary, human KCTD12 accelerated the kinetics of GABABR in vitro, in a manner possibly sensitive to allosteric pharmacological modulation. This study also provides novel in vivo evidence that the interaction between KCTD12 and GABABR is of physiological significance, and may be a mechanism to more selectively modulate GABABR.

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