Presynaptic mechanisms underlying GABAB-receptor-mediated inhibition of spontaneous neurotransmitter release

Inhibition of neurotransmitter release by neurotransmitter substances constitutes a fundamental means of neuromodulation. In contrast to well-delineated mechanisms that underlie inhibition of evoked release via suppression of voltage-gated Ca2+ channels, processes that underlie neuromodulatory inhibition of spontaneous release remain unclear. Here, we interrogated inhibition of spontaneous glutamate and GABA release by presynaptic metabotropic GABAB receptors. Our findings show that this inhibition relies on Gβγ subunit action at the membrane, and it is largely independent of presynaptic Ca2+ signaling for both forms of release. In the case of spontaneous glutamate release, inhibition requires Gβγ interaction with the C terminus of the key fusion machinery component SNAP25, and it is modulated by synaptotagmin-1. Inhibition of spontaneous GABA release, on the other hand, is independent of these pathways and likely requires alternative Gβγ targets at the presynaptic terminal. [Display omitted] •Scavenging Gβγ prevents GABAB-mediated inhibition of spontaneous release•Regulation of spontaneous glutamate release involves Gβγ-SNARE interactions•Synaptotagmin-1 modulates Gβγ-SNARE interactions for spontaneous glutamate release•Regulation of spontaneous GABA release utilizes Gβγ through alternative targets Alten et al. demonstrate how metabotropic GABAB receptors utilize Gβγ subunits to differentially regulate spontaneous excitatory and inhibitory neurotransmitter release. Their study identifies key Gβγ-mediated signaling pathways that target spontaneous neurotransmitter release.