TY - JOUR T1 - Commentary on "Novel Interaction of the Dopamine D2 Receptor and the Ca<sup>2+</sup> Binding Protein S100B: Role in D2 Receptor Function" JF - Molecular Pharmacology JO - Mol Pharmacol DO - 10.1124/molpharm.121.000284 SP - MOLPHARM-COM-2021-000284 AU - Hun-Joo Lee AU - Dayana Rodriguez-Contreras AU - Kim A. Neve Y1 - 2021/01/01 UR - http://molpharm.aspetjournals.org/content/early/2021/05/27/molpharm.121.000284.abstract N2 - We previously proposed that the dopamine D2 receptor-interacting protein S100B binds to a putative S100B-binding motif at residues R233-L240 towards the N-terminus of the 3rd cytoplasmic loop. We used in vitro pull-down assays with FLAG-tagged fragments of the rat D2 receptor third cytoplasmic loop and in vitro-synthesized S100B to evaluate this hypothesis. Our results indicate that the putative S100B-binding motif is neither necessary nor sufficient for strong binding of S100B. Instead, two residues at the junction of the 5th membrane-spanning domain and the cytoplasmic extension of that a-helical domain, K211-I212, are required for robust, calcium-sensitive binding of S100B. This is also the approximate location of previously identified determinants for the binding of arrestin and calmodulin. A D2 receptor mutation converting I212 to phenylalanine has been described in patients with a hyperkinetic movement disorder. Significance Statement S100B is a small calcium-binding protein that modulates signaling by the dopamine D2 receptor. Our new data suggest that our previous hypothesis about the involvement of an S100B-binding motif is incorrect, and that an important determinant of S100B binding includes a residue that is mutated in patients with a hyperkinetic movement disorder. ER -