The Sushi Domains of Secreted GABAB1 Isoforms Selectively Impair GABAB Heteroreceptor Function

GABAB receptors are the G-protein-coupled receptors for γ-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain. GABAB receptors are promising drug targets for a wide spectrum of psychiatric and neurological disorders. Receptor subtypes exhibit no pharmacological differences and are based on the subunit isoforms GABAB1a and GABAB1b. GABAB1a differs from GABAB1b in its ectodomain by the presence of a pair of conserved protein binding motifs, the sushi domains (SDs). Previous work showed that selectively GABAB1a contributes to heteroreceptors at glutamatergic terminals, whereas both GABAB1a and GABAB1b contribute to autoreceptors at GABAergic terminals or to postsynaptic receptors. Here, we describe GABAB1j, a secreted GABAB1 isoform comprising the two SDs. We show that the two SDs, when expressed as a soluble protein, bind to neuronal membranes with low nanomolar affinity. Soluble SD protein, when added at nanomolar concentrations to dissociated hippocampal neurons or to acute hippocampal slices, impairs the inhibitory effect of GABAB heteroreceptors on evoked and spontaneous glutamate release. In contrast, soluble SD protein neither impairs the activity of GABAB autoreceptors nor impairs the activity of postsynaptic GABAB receptors. We propose that soluble SD protein scavenges an extracellular binding partner that retains GABAB1a-containing heteroreceptors in proximity of the presynaptic release machinery. Soluble GABAB1 isoforms like GABAB1j may therefore act as dominant-negative inhibitors of heteroreceptors and control the level of GABAB-mediated inhibition at glutamatergic terminals. Of importance for drug discovery, our data also demonstrate that it is possible to selectively impair GABAB heteroreceptors by targeting their SDs.