Dopamine D4 Receptors Regulate GABAA Receptor Trafficking via an Actin/Cofilin/Myosin-dependent Mechanism

Nicholas M Graziane,Eunice Y Yuen,Zhen Yan

doi:10.1074/jbc.m807387200

Nicholas M Graziane, Eunice Y Yuen + Show 1 more

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https://doi.org/10.1074/jbc.m807387200

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Abstract

The GABA(A) receptor-mediated inhibitory transmission in prefrontal cortex (PFC) is implicated in cognitive processes such as working memory. Our previous study has found that GABA(A)R current is subject to the regulation of dopamine D(4) receptors, a PFC-enriched neuromodulator critically involved in various mental disorders associated with PFC dysfunction. In this study, we have investigated the cellular mechanism underlying D(4) modulation of GABA(A)Rs. We found that the density of surface clusters of GABA(A)R beta2/3 subunits was reduced by D(4), suggesting that the D(4) reduction of GABA(A)R current is associated with a decrease in functional GABA(A)Rs at the plasma membrane. Moreover, the D(4) reduction of GABA(A)R current was blocked by the actin stabilizer phalloidin and was occluded by the actin destabilizer latrunculin, suggesting that D(4) regulates GABA(A)R trafficking via an actin-dependent mechanism. Cofilin, a major actin depolymerizing factor whose activity is strongly increased by dephosphorylation at Ser(3), provides the possible link between D(4) signaling and the actin dynamics. Because myosin motor proteins are important for the transport of vesicles along actin filaments, we also tested the potential involvement of myosin in D(4) regulation of GABA(A)R trafficking. We found that dialysis with a myosin peptide, which competes with endogenous myosin proteins for actin-binding sites, prevented the D(4) reduction of GABA(A)R current. These results suggest that D(4) receptor activation increases cofilin activity presumably via its dephosphorylation, resulting in actin depolymerization, thus causing a decrease in the myosin-based transport of GABA(A)R clusters to the surface.

Highlights

Pyramidal neurons between the temporary presentation of a stimulus cue and the later initiation of a behavioral response [2]
Evidence suggests that the dopamine D4 receptor, which is highly enriched in prefrontal cortex (PFC) [19, 20], is critically involved in neuropsychiatric disorders associated with PFC dysfunction
PD168077 did not cause a significant change in the size of GABAAR surface clusters or the fluorescence intensity of GABAAR surface clusters. These results suggest that D4 receptor activation leads to a decrease of GABAAR surface cluster density, which is associated with the D4-induced reduction of whole cell GABAAR current, evoked IPSC, and miniature IPSC amplitude

Summary

Introduction

Pyramidal neurons between the temporary presentation of a stimulus cue and the later initiation of a behavioral response [2]. Application of PD168077 (30 ␮M) caused a reversible reduction of GABAAR current amplitudes in dissociated PFC pyramidal neurons (16.8 Ϯ 1.7%, n ϭ 15). These results suggest that D4 receptor activation leads to a decrease of GABAAR surface cluster density, which is associated with the D4-induced reduction of whole cell GABAAR current, evoked IPSC, and miniature IPSC amplitude.

Results

Conclusion