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

Nicholas M. Graziane, Eunice Y. Yuen, Zhen Yan

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

The GABAA receptor-mediated inhibitory transmission in prefrontal cortex (PFC) is implicated in cognitive processes such as working memory. Our previous study has found that GABAAR 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 GABAARs. We found that the density of surface clusters of GABAAR β2/3 subunits was reduced by D4, suggesting that the D4 reduction of GABAAR current is associated with a decrease in functional GABAARs at the plasma membrane. Moreover, the D4 reduction of GABAAR current was blocked by the actin stabilizer phalloidin and was occluded by the actin destabilizer latrunculin, suggesting that D4 regulates GABAAR 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 GABAAR 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 GABAAR clusters to the surface.

Original languageEnglish (US)
Pages (from-to)8329-8336
Number of pages8
JournalJournal of Biological Chemistry
Volume284
Issue number13
DOIs
StatePublished - Mar 27 2009

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Dopamine D4 Receptors
Actin Depolymerizing Factors
GABA-A Receptors
Myosins
Actins
Prefrontal Cortex
Destrin
Phalloidine
Transport Vesicles
Depolymerization
Dialysis
Protein Transport
Cell membranes
Actin Cytoskeleton
Short-Term Memory
Mental Disorders
Neurotransmitter Agents
Chemical activation
Binding Sites
Cell Membrane

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

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title = "Dopamine D4 receptors regulate GABAA receptor trafficking via an actin/cofilin/myosin-dependent mechanism",
abstract = "The GABAA receptor-mediated inhibitory transmission in prefrontal cortex (PFC) is implicated in cognitive processes such as working memory. Our previous study has found that GABAAR 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 GABAARs. We found that the density of surface clusters of GABAAR β2/3 subunits was reduced by D4, suggesting that the D4 reduction of GABAAR current is associated with a decrease in functional GABAARs at the plasma membrane. Moreover, the D4 reduction of GABAAR current was blocked by the actin stabilizer phalloidin and was occluded by the actin destabilizer latrunculin, suggesting that D4 regulates GABAAR 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 GABAAR 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 GABAAR clusters to the surface.",
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Dopamine D4 receptors regulate GABAA receptor trafficking via an actin/cofilin/myosin-dependent mechanism. / Graziane, Nicholas M.; Yuen, Eunice Y.; Yan, Zhen.

In: Journal of Biological Chemistry, Vol. 284, No. 13, 27.03.2009, p. 8329-8336.

Research output: Contribution to journalArticle

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