NRAP-1 Is a Presynaptically Released NMDA Receptor Auxiliary Protein that Modifies Synaptic Strength

NMDA receptors (NMDARs) are a subtype of postsynaptic ionotropic glutamate receptors that function as molecular coincidence detectors, have critical roles in models of learning, and are associated with a variety of neurological and psychiatric disorders. To date, no auxiliary proteins that modify NMDARs have been identified. Here, we report the identification of NRAP-1, an auxiliary protein in C. elegans that modulates NMDAR function. NMDAR-mediated currents were eliminated in nrap-1 mutants, as was NMDA-dependent behavior. We show that reconstitution of NMDA-gated current in Xenopus oocytes, or C. elegans muscle cells, depends on NRAP-1 and that recombinant NRAP-1 can convert silent NMDARs to functional channels. Our data indicate that NRAP-1, secreted from presynaptic neurons, localizes to glutamatergic synapses, where it associates with postsynaptic NMDARs to modify receptor gating. Thus, our studies reveal a novel mechanism for synaptic regulation via pre-synaptic control of NMDAR-mediated synaptic transmission.