Abstract
SummaryHere, we uncover a mechanism for regulating the number of active presynaptic GABAB receptors (GABABRs) at nerve terminals, an important determinant of neurotransmitter release. We find that GABABRs gain access to axon terminals by lateral diffusion in the membrane. Their relative accumulation is dependent upon agonist activation and the presence of the two distinct sushi domains that are found only in alternatively spliced GABABR1a subunits. Following brief activation of NMDA receptors (NMDARs) using glutamate, GABABR diffusion is reduced, causing accumulation at presynaptic terminals in a Ca2+-dependent manner that involves phosphorylation of GABABR2 subunits at Ser783. This signaling cascade indicates how synaptically released glutamate can initiate, via a feedback mechanism, increased levels of presynaptic GABABRs that limit further glutamate release and excitotoxicity.
Highlights
Maintaining spatio-temporal stability over neural network activity is important for brain function (Davis, 2006; Marder and Goaillard, 2006; Turrigiano, 1999)
Lateral Diffusion of GABAB receptors (GABABRs) on Hippocampal Neurons To determine whether single GABABRs can diffuse to discrete synaptic membrane domains, we labeled them with quantum
NMDA receptors (NMDARs) Activation Recruits GABABRs to Presynaptic Terminals We studied which GluR isoform was involved in the accumulation of GABABRs at presynaptic terminals
Summary
Hannan et al report a GABA-mediated inhibitory homeostatic mechanism by which lateral diffusion of presynaptic GABAB receptors and their accumulation on presynaptic excitatory terminals causes a reduction of presynaptic activity initiated by NMDA receptor activation. The underlying mechanism requires elevated intracellular Ca2+ and AMPKdependent phosphorylation of presynaptic GABAB receptor subunits on serine 783. 2016, Cell Reports 16, 1962–1973 August 16, 2016 a 2016 The Author(s).
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