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Ubiquitin-dependent lysosomal targeting of GABA(A) receptors regulates neuronal inhibition.

The strength of synaptic inhibition depends partly on the number of GABA(A) receptors (GABA(A)Rs) found at synaptic sites. The trafficking of GABA(A)Rs within the endocytic pathway is a key determinant of surface GABA(A)R number and is altered in neuropathologies, such as cerebral ischemia. However, the molecular mechanisms and signaling pathways that regulate this trafficking are poorly understood. Here, we report the subunit specific lysosomal targeting of synaptic GABA(A)Rs. We demonstrate that the targeting of synaptic GABA(A)Rs into the degradation pathway is facilitated by ubiquitination of a motif within the intracellular domain of the gamma2 subunit. Blockade of lysosomal activity or disruption of the trafficking of ubiquitinated cargo to lysosomes specifically increases the efficacy of synaptic inhibition without altering excitatory currents. Moreover, mutation of the ubiquitination site within the gamma2 subunit retards the lysosomal targeting of GABA(A)Rs and is sufficient to block the loss of synaptic GABA(A)Rs after anoxic insult. Together, our results establish a previously unknown mechanism for influencing inhibitory transmission under normal and pathological conditions.

Pubmed ID: 19815531 RIS Download

Mesh terms: Animals | Cerebral Cortex | Leupeptins | Lysosomes | Microscopy, Confocal | Neurons | Protein Subunits | Rats | Receptors, GABA-A | Synapses | Ubiquitin

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Associated grants

  • Agency: NINDS NIH HHS, Id: NS056359
  • Agency: NINDS NIH HHS, Id: R01 NS048045
  • Agency: NINDS NIH HHS, Id: NS047478
  • Agency: NINDS NIH HHS, Id: NS048045
  • Agency: NINDS NIH HHS, Id: NS051195
  • Agency: Medical Research Council, Id: R01 NS051195
  • Agency: NINDS NIH HHS, Id: G120/972
  • Agency: Medical Research Council, Id: NS054900
  • Agency: NINDS NIH HHS, Id: P01 NS054900
  • Agency: NINDS NIH HHS, Id: G0601529
  • Agency: Medical Research Council, Id: R01 NS056359
  • Agency: NINDS NIH HHS, Id: R01 NS047478
  • Agency: NINDS NIH HHS, Id:

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