Unconventional NMDA receptor signaling

In the classical view, NMDA receptors (NMDARs) are stably expressed at the postsynaptic membrane, where they act via Ca²⁺ to signal coincidence detection in Hebbian plasticity. More recently, it has been established that NMDAR-mediated transmission can be dynamically regulated by neural activity. In addition, NMDARs have been found presynaptically, where they cannot act as conventional coincidence detectors. Unexpectedly, NMDARs have also been shown to signal metabotropically, without the need for Ca²⁺. This review highlights novel findings concerning these unconventional modes of NMDAR action.