Synaptic and Non‐Synaptic Functions of <scp>PTPRD</scp> : A Receptor Tyrosine Phosphatase at the Crossroads of Neural Circuitry and Metabolism

Protein-tyrosine phosphatase receptor-type D (PTPRD) is an adhesion-coupled phosphatase that translates extracellular binding codes into intracellular phosphotyrosine signaling from embryogenesis through adulthood. Alternative inclusion of the Ig-domain mini-exons meA and meB tailors the ectodomain surface, thereby dictating high-affinity engagement with IL1RAPL1, IL1RAP, Slitrks, LRFN4/5 (SALM3/5), neuroligin-3, and other postsynaptic partners. Intracellularly, the catalytically active D1 domain and scaffold-like D2 module, anchored to liprin-α, coordinate presynaptic vesicle release, postsynaptic receptor composition, and synaptic plasticity. Beyond synapses, PTPRD restrains embryonic neurogenesis, promotes STAT3-dependent gliogenesis, accelerates oligodendrocyte myelination, and guides Sema3a/Fyn-mediated axon and dendrite patterning. In the adult brain it serves as the high-affinity hypothalamic and cerebellar receptor for asprosin, thereby coupling systemic energy and hydration states to feeding and drinking behavior. Human genetic studies and mouse models link these molecular activities to a spectrum of conditions-including restless legs syndrome, addiction, Alzheimer's disease, ADHD, OCD, autism spectrum disorder, and metabolic syndrome. Because PTPRD functions are pathway-specific and shaped by mini-exon usage or redundancy with other family members (PTPRS/PTPRF), domain- or ligand-selective interventions represent plausible therapeutic strategies. Elucidating its full ligand repertoire, substrate landscape, and structural basis for allosteric regulation will be critical for converting this versatile receptor from a mechanistic curiosity into a tractable target for neurodevelopmental, neuropsychiatric, and metabolic disorders.