GABAA receptor subunit composition and competition at synapses are tuned by GABAB receptor activity

GABA(B)Rs have a well-established role in controlling neuronal excitability and presynaptic neurotransmitter release. We examined the role of GABA(B)R activity in modulating the number and lateral diffusion of GABA(A)Rs at inhibitory synapses. Changes in diffusion of GABA(A0)Rs at synapses were observed when subunit heterogeneity was taken into account While alpha 1-GABA(A)Rs were unaffected, alpha 2- and alpha 5-GABA(A)R5 showed inverse changes in enrichment and diffusion. The intracellular TM3-4 loop of alpha 2 was sufficient to observe the changes in diffusion by GABABR activity, whereas the loop of alpha 5 was not The opposing effect on alpha 2- and alpha 5-GABA(A)R5 was caused by a competition between GABA(A)Rs for binding slots at synapses. Receptor immobilization by cross-linking revealed that alpha 5-GABAAR trapping at synapses is regulated by modulation of alpha 2-GABA(A)R mobility. Finally, PKC activity was determined to be part of the signaling pathway through which GABA(B)R activity modulates alpha 2-GABA(A)R diffusion at synapses. These results outline a novel mechanism for tuning inhibitory transmission in a subunit-specific manner, and for the first time describe competition between GABA(A)Rs with different subunit compositions for binding slots at synapses. (C) 2014 Elsevier Inc. All rights reserved.