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Filamin A (FLNA) is known to act as platform for the signaling and intracellular trafficking of various GPCRs including dopamine D 2 and D 3 receptors (D 2 R, D 3 R). To understand molecular mechanisms involved in the FLNA-mediated regulation of D 2 R and D 3 R, comparative studies were conducted on the signaling and intracellular trafficking of the D 2 R and D 3 R in FLNA-knockdown cells, with a specific focus on the roles of the proteins that interact with FLNA and the D 2 R and D 3 R. Lowering the level of cellular FLNA caused an elevation in RalA activity and resulted in selective interference with the normal intracellular trafficking and signaling of the D 2 R and D 3 R, through GRK2 and β-arrestins, respectively. Knockdown of FLNA or coexpression of active RalA interfered with the recycling of the internalized D 2 R and resulted in the development of receptor tolerance. Active RalA was found to interact with GRK2 to sequester it from D 2 R. Knockdown of FLNA or coexpression of active RalA prevented D 3 R from coupling with G protein. The selective involvement of GRK2- and β-arrestins in the RalA-mediated cellular processes of the D 2 R and D 3 R was achieved via their different modes of interactions with the receptor and their distinct functional roles in receptor regulation. Our results show that FLNA is a multi-functional protein that acts as a platform on which D 2 R and D 3 R can interact with various proteins, through which selective regulation of these receptors occurs in combination with GRK2 and β-arrestins. [ABSTRACT FROM AUTHOR]