Dopamine-2 receptor extracellular N-terminus regulates receptor surface availability and is the target of human pathogenic antibodies from children with movement and psychiatric disorders

摘要: Anti-Dopamine-2 receptor (D2R) antibodies have been recently identified in a subgroup of children with autoimmune movement and psychiatric disorders, however the epitope(s) mechanism pathogenicity remain unknown. Here we report major biological role for D2R extracellular N-terminus as regulator surface availability, epitope targeted impaired brain autoimmunity. In transfected human cells, purified anti-D2R antibody from patients specifically significantly reduced levels. Next, mutants modified their domains were subcloned, analyzed region bound by 35 antibody-positive patient sera using quantitative flow cytometry on live cells. We found that N-glycosylation at amino acids N5 and/or N17 was critical high expression interaction last 15 residues N-terminus. No to three loops, but all (35/35) Overall, binding dependent two main regions encompassing 20 29, 23 37. Residues 29 contributed majority (77%, 27/35), among which 26% (7/27) R20, P21, F22, 37% (10/27) positions 26 are different between humans mice, 30% (8/27) required N23, D26, A29. Seven 37 independently D26 A29, most exhibited N-glycosylation-independent recognition N23. Interestingly, no evident segregation pattern according clinical phenotype observed. is central disorders this knowledge could help design novel specific immune therapies tailored improve outcome.