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.