Editors' ChoiceNeuroscience

Lending a Helping Hand

Science Signaling  18 May 2010:
Vol. 3, Issue 122, pp. ec148
DOI: 10.1126/scisignal.3122ec148

The effects of γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain, are mediated by ionotropic GABAA receptors and G protein–coupled GABAB receptors. GABAB receptors, which have been thought to exist as heterodimers of GABAB1 and GABAB2 receptors, activate voltage-activated Ca2+ (Cav) channels and inward-rectifier K+ (Kir) channels in neurons. Noting that cells that are reconstituted with GABAB1 and GABAB2 receptors fail to exhibit the functional diversity of responses shown by cells that contain native GABAB receptors, Schwenk et al. hypothesized that additional subunits might be involved. They performed a proteomic analysis that combined affinity purification of receptor subunits from membrane fractions of rat and mouse brains with mass spectrometry and found that four members of the potassium channel tetramerization domain–containing (KCTD) family of proteins copurified with GABAB receptors through interactions with the C terminus of the GABAB2 subunit. Subsequent analysis showed that native GABAB receptors consisted of one subunit each of GABAB1 and GABAB2 and a tetramer of KCTD proteins. Immunohistochemical analysis of brain tissue showed that KCTD proteins were found in distinct patterns that partly overlapped with clusters of GABAB receptors. Different KCTD proteins had differential effects on the kinetics, desensitization, and agonist dose-dependency of GABAB-mediated activation of Cav and Kir channels in Xenopus oocytes and transfected CHO cells. Finally, the effects of KCTD proteins on functional responses of GABAB receptors in cultured hippocampal neurons were demonstrated by experiments with specific short hairpin RNAs (shRNAs). Together, these data suggest that the functional diversity of GABAB receptors depends on the identity of the KCTD proteins present in the receptor complex.

J. Schwenk, M. Metz, G. Zolles, R. Turecek, T. Fritzius, W. Bildl, E. Tarusawa, A. Kulik, A. Unger, K. Ivankova, R. Seddik, J. Y. Tiao, M. Rajalu, J. Trojanova, V. Rohde, M. Gassmann, U. Schulte, B. Fakler, B. Bettler, Native GABAB receptors are heteromultimers with a family of auxiliary subunits. Nature 465, 231–235 (2010). [PubMed]