Abstract
GABAA receptors (GABAA-Rs) play critical roles in brain development and synchronization of neural network activity. While synaptic GABAA-Rs can exert rapid inhibition, the extrasynaptic GABAA-Rs can tonically inhibit neuronal activity due to constant activation by ambient GABA. The δ subunit-containing GABAA-Rs are expressed abundantly in the cerebellum, hippocampus and thalamus to mediate the major tonic inhibition in the brain. While electrophysiological and pharmacological properties of the δ-GABAA-Rs have been well characterized, the molecular interacting partners of the δ-GABAA-Rs are not clearly defined. Here, using a yeast two-hybrid screening assay, we identified transthyretin (TTR) as a novel regulatory molecule for the δ-GABAA-Rs. Knockdown of TTR in cultured cerebellar granule neurons significantly decreased the δ receptor expression; whereas overexpressing TTR in cortical neurons increased the δ receptor expression. Electrophysiological analysis confirmed that knockdown or overexpression of TTR in cultured neurons resulted in a corresponding decrease or increase of tonic currents. Furthermore, in vivo analysis of TTR-/- mice revealed a significant decrease of the surface expression of the δ-GABAA-Rs in cerebellar granule neurons. Together, our studies identified TTR as a novel regulator of the δ-GABAA-Rs.
Highlights
GABA (γ-aminobutyric acid) activates GABAA and GABAB receptors to mediate the majority of inhibition in the brain [1, 2]
Transthyretin identified as the interacting partner for GABAA receptor δ subunit The structure of GABAA-R δ subunit includes one extracellular domain, one cytoplasmic domain and four transmembrane domains
We found that normal human TTR (hTTR) protein significantly increased the expression level of δ-GABAA-Rs as expected, but monomeric hTTR had no effect on the δ-GABAA-Rs (Fig 5A)
Summary
GABA (γ-aminobutyric acid) activates GABAA and GABAB receptors to mediate the majority of inhibition in the brain [1, 2]. GABAA receptors (GABAA-Rs) are located on both synaptic and extrasynaptic membranes to mediate phasic and tonic inhibition. We have recently demonstrated that synaptic and extrasynaptic GABAA-Rs compete with each other to regulate the homeostasis of inhibition [3]. The δ subunit-containing GABAA-Rs (δ-GABAA-Rs) are one of the major subtypes of extrasynaptic GABAA-Rs, localizing in the cerebellum (α6βδ), hippocampus and thalamus (α4βδ) [9, 12,13,14].
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