PT - JOURNAL ARTICLE AU - Thorsten Fritzius AU - Rostislav Turecek AU - Riad Seddik AU - Hiroyuki Kobayashi AU - Jim Tiao AU - Pascal D. Rem AU - Michaela Metz AU - Michaela Kralikova AU - Michel Bouvier AU - Martin Gassmann AU - Bernhard Bettler TI - KCTD hetero-oligomers confer unique kinetic properties on hippocampal GABA<sub>B</sub> receptor-induced K<sup>+</sup>-currents AID - 10.1523/JNEUROSCI.2181-16.2016 DP - 2016 Dec 21 TA - The Journal of Neuroscience PG - 2181-16 4099 - http://www.jneurosci.org/content/early/2016/12/21/JNEUROSCI.2181-16.2016.short 4100 - http://www.jneurosci.org/content/early/2016/12/21/JNEUROSCI.2181-16.2016.full AB - GABAB receptors are the G-protein coupled receptors for the main inhibitory neurotransmitter in the brain, γ-aminobutyric acid (GABA). GABAB receptors were shown to associate with homo-oligomers of auxiliary KCTD8, -12, -12b and -16 subunits (named after their T1 K+-channel tetramerization domain) that regulate G-protein signaling of the receptor. Here we provide evidence that GABAB receptors also associate with hetero-oligomers of KCTD subunits. Co-immunoprecipitation experiments indicate that two-thirds of the KCTD16 proteins in the hippocampus of adult mice associate with KCTD12. We show that the KCTD proteins hetero-oligomerize through self-interacting T1 and H1 homology domains. Bioluminescence resonance energy transfer (BRET) measurements in live cells reveal that KCTD12/16 hetero-oligomers associate with both the receptor and the G-protein. Electrophysiological experiments demonstrate that KCTD12/16 hetero-oligomers impart unique kinetic properties on G-protein activated Kir3-currents. During prolonged receptor activation (one minute) KCTD12/16 hetero-oligomers produce moderately desensitizing fast deactivating K+ currents while KCTD12 and KCTD16 homo-oligomers produce strongly desensitizing fast deactivating currents and non-desensitizing slowly deactivating currents, respectively. During short activation (2 seconds) KCTD12/16 hetero-oligomers produce non-desensitizing slowly deactivating currents. Electrophysiological recordings from hippocampal neurons of KCTD knock-out mice are consistent with these findings and indicate that KCTD12/16 hetero-oligomers increase the duration of slow inhibitory postsynaptic currents (sIPSCs). In summary, our data demonstrate that simultaneous assembly of distinct KCTDs at the receptor increases the molecular and functional repertoire of native GABAB receptors and modulates physiologically induced K+-current responses in the hippocampus.SIGNIFICANCE STATEMENTThe KCTD proteins 8, 12 and 16 are auxiliary subunits of GABAB receptors that differentially regulate G-protein signaling of the receptor. The KCTD proteins are generally assumed to function as homo-oligomers. Here we show that the KCTD proteins also assemble hetero-oligomers in all possible dual combinations. Experiments in live cells demonstrate that KCTD hetero-oligomers form at least tetramers and that these tetramers directly interact with the receptor and the G-protein. KCTD12/16 hetero-oligomers impart unique kinetic properties to GABAB receptor-induced Kir3 currents in heterologous cells. KCTD12/16 hetero-oligomers are abundant in the hippocampus, where they prolong the duration of slow inhibitory postsynaptic currents in pyramidal cells. Our data therefore support that KCTD hetero-oligomers modulate physiologically induced K+ current responses in the brain.