Compartmentalization of the GABA(B) Receptor Signaling Complex Is Required for Presynaptic Inhibition at Hippocampal Synapses

作者：Laviv Tal; Vertkin Irena; Berdichevsky Yevgeny; Fogel Hilla; Riven Inbal; Bettler Bernhard; Slesinger Paul A; Slutsky Inna^*

来源：Journal of Neuroscience, 2011, 31(35): 12523-12532.

DOI：10.1523/JNEUROSCI.1527-11.2011

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 angstrom) complexes between GABA(B) receptors composed of GB(1a)/GB(2) subunits, G alpha(0)beta(1)gamma(2) G-protein heterotrimer, and Ca(V)2.2 channels in hippocampal boutons. GABA release was not required for the assembly but for structural reorganization of the precoupled complex. Unexpectedly, GB(1a) deletion disrupted intermolecular associations within the complex. The GB(1a) proximal C-terminal domain was essential for association of the receptor, Ca(V)2.2 and G beta gamma, 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 GABA(B1a) receptor, G beta gamma, and Ca(V)2.2 channel in a signaling complex is required for presynaptic inhibition at hippocampal synapses.

• 出版日期2011-8-31