Sustained Glutamate Receptor Activation Down-regulates GABAB Receptors by Shifting the Balance from Recycling to Lysosomal Degradation

Metabotropic GABAB receptors are abundantly expressed at glutamatergic synapses where they control excitability of the synapse. Here, we tested the hypothesis that glutamatergic neurotransmission may regulate GABAB receptors. We found that application of glutamate to cultured cortical neurons led to rapid down-regulation of GABAB receptors via lysosomal degradation. This effect was mimicked by selective activation of AMPA receptors and further accelerated by coactivation of group I metabotropic glutamate receptors. Inhibition of NMDA receptors, blockade of L-type Ca2+ channels, and removal of extracellular Ca2+ prevented glutamate-induced down-regulation of GABAB receptors, indicating that Ca2+ influx plays a critical role. We further established that glutamate-induced down-regulation depends on the internalization of GABAB receptors. Glutamate did not affect the rate of GABAB receptor endocytosis but led to reduced recycling of the receptors back to the plasma membrane. Blockade of lysosomal activity rescued receptor recycling, indicating that glutamate redirects GABAB receptors from the recycling to the degradation pathway. In conclusion, the data indicate that sustained activation of AMPA receptors down-regulates GABAB receptors by sorting endocytosed GABAB receptors preferentially to lysosomes for degradation on the expense of recycling. This mechanism may relieve glutamatergic synapses from GABAB receptor-mediated inhibition resulting in increased synaptic excitability.