Dopamine D₄ receptors regulate GABA_A receptor trafficking via an actin/cofilin/myosin-dependent mechanism

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_AR current is subject to the regulation of dopamine D₄ 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 D₄ modulation of GABA_ARs. We found that the density of surface clusters of GABA_AR β2/3 subunits was reduced by D₄, suggesting that the D₄ reduction of GABA_AR current is associated with a decrease in functional GABA_ARs at the plasma membrane. Moreover, the D₄ reduction of GABA_AR current was blocked by the actin stabilizer phalloidin and was occluded by the actin destabilizer latrunculin, suggesting that D₄ regulates GABA_AR trafficking via an actin-dependent mechanism. Cofilin, a major actin depolymerizing factor whose activity is strongly increased by dephosphorylation at Ser³, provides the possible link between D₄ 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 D₄ regulation of GABAAR trafficking. We found that dialysis with a myosin peptide, which competes with endogenous myosin proteins for actin-binding sites, prevented the D₄ reduction of GABA_AR current. These results suggest that D₄ receptor activation increases cofilin activity presumably via its dephosphorylation, resulting in actin depolymerization, thus causing a decrease in the myosin-based transport of GABA_AR clusters to the surface.