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PMID:10692483

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Citation

Li, M, Bermak, JC, Wang, ZW and Zhou, QY (2000) Modulation of dopamine D(2) receptor signaling by actin-binding protein (ABP-280). Mol. Pharmacol. 57:446-52

Abstract

Proteins that bind to G protein-coupled receptors have recently been identified as regulators of receptor anchoring and signaling. In this study, actin-binding protein 280 (ABP-280), a widely expressed cytoskeleton-associated protein that plays an important role in regulating cell morphology and motility, was found to associate with the third cytoplasmic loop of dopamine D(2) receptors. The specificity of this interaction was originally identified in a yeast two-hybrid screen and confirmed by protein binding. The functional significance of the D(2) receptor-ABP-280 association was evaluated in human melanoma cells lacking ABP-280. D(2) receptor agonists were less potent in inhibiting forskolin-stimulated cAMP production in these cells. Maximal inhibitory responses of D(2) receptor activation were also reduced. Further yeast two-hybrid experiments showed that ABP-280 association is critically dependent on the carboxyl domain of the D(2) receptor third cytoplasmic loop, where there is a potential serine phosphorylation site (S358). Serine 358 was replaced with aspartic acid to mimic the effects of receptor phosphorylation. This mutant (D(2)S358D) displayed compromised binding to ABP-280 and coupling to adenylate cyclase. PKC activation also generated D(2) receptor signaling attenuation, but only in ABP-containing cells, suggesting a PKC regulatory role in D(2)-ABP association. A mechanism for these results may be derived from a role of ABP-280 in the clustering of D(2) receptors, as determined by immunocytochemical analysis in ABP-deficient and replete cells. Our results suggest a new molecular mechanism of modulating D(2) receptor signaling by cytoskeletal protein interaction.

Links

PubMed

Keywords

Adenylate Cyclase/metabolism; Amino Acid Sequence; Animals; Binding Sites; CHO Cells; Contractile Proteins/metabolism; Cricetinae; Humans; Immunohistochemistry; Microfilament Proteins/metabolism; Molecular Sequence Data; Phosphorylation; Protein Conformation; Protein Kinase C/metabolism; Receptors, Cell Surface/metabolism; Receptors, Dopamine D2/metabolism; Sequence Homology, Amino Acid; Signal Transduction; Tumor Cells, Cultured

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:DRD2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P21333

F

Seeded From UniProt

complete

HUMAN:FLNA

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P35462

F

Seeded From UniProt

complete

HUMAN:FLNA

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P14416

F

Seeded From UniProt

complete

HUMAN:DRD3

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P21333

F

Seeded From UniProt

complete

HUMAN:FLNA

involved_in

GO:0043113: receptor clustering

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:FLNA

involved_in

GO:0007195: adenylate cyclase-inhibiting dopamine receptor signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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