Association of dopamine D₃ receptors with actin-binding protein 280 (ABP-280)

Proteins that bind to G protein-coupled receptors have been identified as regulators of receptor localization and signaling. In our previous studies, a cytoskeletal protein, actin-binding protein 280 (ABP-280), was found to associate with the third cytoplasmic loop of dopamine D₂ receptors. In this study, we demonstrate that ABP-280 also interacts with dopamine D₃ receptors, but not with D₄ receptors. Similar to the dopamine D₂ receptor, the D₃/ABP-280 association is of signaling importance. In human melanoma M2 cells lacking ABP-280, D₃ receptors were unable to inhibit forskolin-stimulated cyclic AMP (cAMP) production significantly. D₄ receptors, however, exhibited a similar degree of inhibition of forskolin-stimulated cAMP production in ABP-280-deficient M2 cells and ABP-280-replent M2 subclones (A7 cells). Further experiments revealed that the D₃/ABP-280 interaction was critically dependent upon a 36 amino acid carboxyl domain of the D₃ receptor third loop, which is conserved in the D₂ receptor but not in the D₄ receptor. Our results demonstrate a subtype-specific regulation of dopamine D₂-family receptor signaling by the cytoskeletal protein ABP-280.