title: Ubiquitin-dependent lysosomal targeting of GABA(A) receptors regulates neuronal inhibition.
abstract: 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.
authors.affiliation: Department of Neuroscience, Physiology, and Pharmacology, University College London, Gower Street, London, WC1E 6BT, United Kingdom.
authors.forename: I Lorena
authors.initials: IL
authors.lastname: Arancibia-Cárcamo
authors.forename: Eunice Y
authors.initials: EY
authors.lastname: Yuen
authors.forename: James
authors.initials: J
authors.lastname: Muir
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Lumb
authors.forename: Guido
authors.initials: G
authors.lastname: Michels
authors.forename: Richard S
authors.initials: RS
authors.lastname: Saliba
authors.forename: Trevor G
authors.initials: TG
authors.lastname: Smart
authors.forename: Zhen
authors.initials: Z
authors.lastname: Yan
authors.forename: Josef T
authors.initials: JT
authors.lastname: Kittler
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Moss
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000502:physiology; D007976:Leupeptins / Q000494:pharmacology; D008247:Lysosomes / Q000502:physiology*; D018613:Microscopy, Confocal; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D021122:Protein Subunits / Q000502:physiology; D051381:Rats; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D025801:Ubiquitin / Q000502:physiology*
chemical_list: D007976:Leupeptins; D021122:Protein Subunits; D011963:Receptors, GABA-A; D025801:Ubiquitin; C032854:leupeptin