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Opposite Regulation of Human D1‐like Dopaminergic Responsiveness by Protein Kinase C is Shaped by Two Critical Serine Residues of the Third Intracellular Loop of Human D5 Dopaminergic Receptor

Phorbol‐12‐myristate‐13‐acetate (PMA), an activator of serine/threonine protein kinase C, promotes in a strikingly opposite fashion sensitization and desensitization of the highly homologous human dopamine D1 and D5 receptors (D1R, D5R), respectively. We identified the third intracellular loop (IL3) as the main structural determinant controlling the opposite PMA‐mediated regulation of D1R and D5R responsiveness using a chimeric approach. Single‐point mutations were made to delineate the residues of D5R‐IL3 region implicated in PMA‐induced D5R desensitization. Dopamine responsiveness of cells transfected with wild‐type or mutant forms of D5R following PMA treatment was assessed using whole cell cAMP assays. Our results show that serine residues 261 and 271 of D5R‐IL3 (corresponding to alanine 230 and asparagine 240 in D1R‐IL3) impart PMA‐induced desensitization to D5R. In fact, D5R mutants harboring single serine‐to‐alanine substitution of residue 261 or 271 display a sensitized responsiveness following PKC activation that was reminiscent of D1R sensitization observed in PMA‐treated cells. Overall, our work suggests that the presence or absence of serine residues located at positions 261 and 271 of D5R‐IL3 or positions 230 and 240 of D1R‐IL3 control the fate of PMA‐mediated regulation of D1‐like responsiveness. Supported by CIHR grant (MOP‐81341 to MT) and FRSQ Graduate Scholarship (to BP).