NMDA receptor activation increases presynaptic GABA receptor signaling by lateral diffusion

Activation of glutamate receptors recruits GABA_B receptors to presynaptic terminals to apply brakes on excitatory neurotransmission

GABA_B receptors are class C G-protein coupled receptors (GPCRs) that prevent glutamate release by inhibiting voltage-gated Ca²⁺ channels. Concentration of GABA_B receptors at presynaptic terminals is a crucial determinant of the efficacy of presynaptic inhibition via these receptors.

Here we uncover that activation of NMDA receptors recruits GABA_B receptors at presynaptic terminals to limit neurotransmitter release. This signaling cascade suggests how synaptically released glutamate can initiate, via a feedback mechanism, increased levels of presynaptic GABA_BRs that limit further glutamate release and excitotoxicity.

The approach

Using single particle tracking of quantum dots, we show that GABA_B receptors are recruited to presynaptic terminals by lateral diffusion

NMDAR activity recruits GABA_B receptors to axon terminals by slowing their mobility

GABA_B receptors are able to access presynaptic terminals by lateral diffusion.

Activation of NMDA receptors slows down lateral mobility of presynaptic and increases their synaptic residence times.

GABA_B receptor accumulation depends on intracellular Ca²⁺ and phosphorylation of GABA_BR2^S783

Following brief activation of NMDA receptors using glutamate, GABA_B receptor diffusion is reduced, causing accumulation at presynaptic terminals in a Ca²⁺-dependent manner that involves phosphorylation of GABA_BR2 subunits at Ser783.

Model of GABA_B receptor lateral mobility mediated brake on glutamatergic neurotransmission

Pre- or postsynaptic NMDA receptor activation would initiate Ca²⁺ influx via NMDA channels and, eventually, either directly or by retrograde transmitter release , increase terminal Ca²⁺ levels following Ca²⁺ channel activation and/or by internal Ca²⁺ release.

In terminal membranes, this would initially increase glutamate release but also enable AMPK activation to phosphorylate S783 on R2 subunits, slowing GABA_B receptor mobility in the terminal membrane and promoting receptor accumulation to increase presynaptic inhibition once GABA_B receptors are activated.

For more details please visit the publication:

S Hannan, K Gerrow, A Triller & TG Smart. (2016). Phospho-dependent enrichment of mobile GABA_BRs at presynaptic terminals after NMDAR activation. Cell Reports 16, 1962-19739