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The Journal of Neuroscience, November 7, 2007, 27(45):12390-12395; doi:10.1523/JNEUROSCI.1689-07.2007

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Brief Communications
Evidence That the BLOC-1 Protein Dysbindin Modulates Dopamine D₂ Receptor Internalization and Signaling But Not D₁ Internalization

Yukihiko Iizuka, Yoshitatsu Sei, Daniel R. Weinberger, and Richard E. Straub

Genes, Cognition, and Psychosis Program, Clinical Brain Disorders Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, United States Department of Health and Human Services, Bethesda, Maryland 20892-1385

Correspondence should be addressed to Richard E. Straub, Genes, Cognition, and Psychosis Program, Clinical Brain Disorders Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, United States Department of Health and Human Services, 10 Center Drive Building 10, Room 4D18, Bethesda, MD 20892-1385. Email: straubr{at}intra.nimh.nih.gov

The schizophrenia susceptibility gene dystrobrevin-binding protein 1 (DTNBP1) encodes dysbindin, which along with its binding partner Muted is an essential component of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Dysbindin expression is reduced in schizophrenic brain tissue, but the molecular mechanisms by which this contributes to pathogenesis and symptomatology are unknown. We studied the effects of transfection of DTNBP1 siRNA on cell surface levels of dopamine D₂ receptor (DRD2) in human SH-SY5Y neuroblastoma cells and in rat primary cortical neurons. DTNBP1 siRNA decreased dysbindin protein, increased cell surface DRD2 and blocked dopamine-induced DRD2 internalization. MUTED siRNA produced similar effects. In contrast, decreased dysbindin did not change dopamine D₁ receptor (DRD1) levels, or its basal or dopamine-induced internalization. The DRD2 agonist quinpirole reduced phosphorylation of CREB (cAMP response element-binding protein) in dysbindin downregulated cells, demonstrating enhanced intracellular signaling caused by the upregulation of DRD2. This is the first demonstration of a schizophrenia susceptibility gene exerting a functional effect on DRD2 signaling, a pathway that has long been implicated in the illness. We propose a molecular mechanism for pathogenesis in which risk alleles in DTNBP1, or other factors that also downregulate dysbindin, compromise the ability of BLOC-1 to traffic DRD2 toward degradation, but has little effect on DRD1 trafficking. Impaired trafficking of DRD2 decreases dopamine-induced internalization, and with more receptors retained on the cell surface, dopamine stimulation produces excess intracellular signaling. Such an increase in DRD2 signaling relative to DRD1 would contribute to the imbalances in dopaminergic neurotransmission characteristic of schizophrenia.

Key words: DTNBP1; dysbindin; MUTED; BLOC-1; dopamine D₂ receptor; DRD2; dopamine D₁ receptor; DRD1; internalization; endocytosis; CREB; schizophrenia

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Received Dec. 7, 2006; revised Sept. 18, 2007; accepted Sept. 29, 2007.

Correspondence should be addressed to Richard E. Straub, Genes, Cognition, and Psychosis Program, Clinical Brain Disorders Branch, National Institute of Mental Health Intramural Research Program, National Institutes of Health, United States Department of Health and Human Services, 10 Center Drive Building 10, Room 4D18, Bethesda, MD 20892-1385. Email: straubr{at}intra.nimh.nih.gov

This article has been cited by other articles:

				N. J. Bray Gene Expression in the Etiology of Schizophrenia Schizophr Bull, May 1, 2008; 34(3): 412 - 418. [Abstract] [Full Text] [PDF]

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