Compartmentalization of the GABAB receptor signaling complex is required for presynaptic inhibition at hippocampal synapses

Tal Laviv, Irena Vertkin, Yevgeny Berdichevsky, Hilla Fogel, Inbal Riven, Bernhard Bettler, Paul A. Slesinger, Inna Slutsky*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Presynaptic inhibition via G-protein-coupled receptors (GPCRs) and voltage-gated Ca2+ channels constitutes a widespread regulatory mechanism of synaptic strength. Yet, the mechanism of intermolecular coupling underlying GPCR-mediated signaling at central synapses remains unresolved. Using FRET spectroscopy, we provide evidence for formation of spatially restricted (<100 Å) complexes between GABAB receptors composed of GB1a/GB2 subunits, Gαoβ1γ2 G-protein heterotrimer, and CaV2.2 channels in hippocampal boutons. GABA release was not required for the assembly but for structural reorganization of the precoupled complex. Unexpectedly, GB1a deletion disrupted intermolecular associations within the complex. The GB1a proximal C-terminal domain was essential for association of the receptor, CaV2.2 and Gβγ, but was dispensable for agonist-induced receptor activation and cAMP inhibition. Functionally, boutons lacking this complex-formation domain displayed impaired presynaptic inhibition of Ca2+ transients and synaptic vesicle release. Thus, compartmentalization of the GABAB1a receptor,Gβγ, and CaV2.2 channel in a signaling complex is required for presynaptic inhibition at hippocampal synapses.

Original languageEnglish
Pages (from-to)12523-12532
Number of pages10
JournalJournal of Neuroscience
Volume31
Issue number35
DOIs
StatePublished - 31 Aug 2011

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