KCTD12 modulation of GABA(B) receptor function
Melody Li1, Carol J Milligan1, Haiyan Wang2
1The Florey Institute of Neuroscience and Mental Health Parkville Victoria Australia.
Pharmacology Research & Perspectives
|July 18, 2017
Summary
Human KCTD12 speeds up GABAB receptor kinetics and enhances allosteric modulation. KCTD12 knockout mice show reduced seizure susceptibility and ethanol consumption, highlighting its physiological role in GABAB receptor modulation.
Area of Science:
- Neuroscience
- Molecular Pharmacology
- GABAergic Signaling
Background:
- Native GABAB receptors (GABABR) and their functional diversity are not fully understood, limiting the development of selective ligands.
- Potassium channel tetramerization domain-containing protein 12 (KCTD12) is an auxiliary subunit that modulates GABABR function.
Purpose of the Study:
- To characterize the effects of human KCTD12 on GABABR kinetics and pharmacology in vitro.
- To investigate the in vivo function of KCTD12 by examining seizure susceptibility and ethanol consumption in a KCTD12 knockout mouse model.
Main Methods:
- Automated electrophysiological assays were used to study GABABR-mediated GIRK channel kinetics and pharmacology.
- Concentration-response curves were analyzed for agonists and a positive allosteric modulator (CGP7930).
- KCTD12 knockout mice were subjected to pentylenetetrazole challenge and a two-bottle preference test for ethanol.
Main Results:
- Human KCTD12 co-expression accelerated GABABR activation and desensitization kinetics.
- KCTD12 did not alter the effects of GABA or baclofen but enhanced the potentiation by CGP7930.
- KCTD12 knockout mice exhibited reduced seizure susceptibility and lower ethanol consumption at high concentrations.
Conclusions:
- Human KCTD12 significantly alters GABABR kinetics and allosteric modulation in vitro.
- The KCTD12-GABABR interaction has physiological relevance in vivo, impacting seizure susceptibility and ethanol consumption.
- Targeting the KCTD12-GABABR interaction may offer a novel strategy for selective GABABR modulation.
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