PT  - JOURNAL ARTICLE
AU  - Hun-Joo Lee
AU  - Dayana Rodriguez-Contreras
AU  - Kim A. Neve
TI  - Commentary on “Novel Interaction of the Dopamine D2 Receptor and the Ca<sup>2+</sup> Binding Protein S100B: Role in D2 Receptor Function”
AID  - 10.1124/molpharm.121.000284
DP  - 2021 Aug 01
TA  - Molecular Pharmacology
PG  - 91--94
VI  - 100
IP  - 2
4099  - http://molpharm.aspetjournals.org/content/100/2/91.short
4100  - http://molpharm.aspetjournals.org/content/100/2/91.full
SO  - Mol Pharmacol2021 Aug 01; 100
AB  - We previously proposed that the dopamine D2 receptor–interacting protein S100B binds to a putative S100B-binding motif at residues R233–L240 toward the N terminus of the third intracellular loop. We used in vitro pull-down assays with FLAG-tagged fragments of the rat dopamine D2 receptor third intracellular loop (D2-IC3) 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 to D2-IC3. Instead, two residues at the junction of the fifth membrane-spanning domain and the cytoplasmic extension of that α-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. New data suggest that the 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.