Encoding and Transducing the Synaptic or Extrasynaptic Origin of NMDA Receptor Signals to the Nucleus

The activation of N-methyl-D-aspartate-receptors (NMDARs) in synapses provides plasticity and cell survival signals, whereas NMDARs residing in the neuronal membrane outside synapses trigger neurodegeneration. At present, it is unclear how these opposing signals are transduced to and discriminated by the nucleus. In this study, we demonstrate that Jacob is a protein messenger that encodes the origin of synaptic versus extrasynaptic NMDAR signals and delivers them to the nucleus. Exclusively synaptic, but not extrasynaptic, NMDAR activation induces phosphorylation of Jacob at serine-180 by ERK1/2. Long-distance trafficking of Jacob from synaptic, but not extrasynaptic, sites depends on ERK activity, and association with fragments of the intermediate filament α-internexin hinders dephosphorylation of the Jacob/ERK complex during nuclear transit. In the nucleus, the phosphorylation state of Jacob determines whether it induces cell death or promotes cell survival and enhances synaptic plasticity. [Display omitted] ► Jacob is a synapto-nuclear protein messenger of NMDAR signaling to the nucleus ► Jacob encodes the origin of synaptic versus extrasynaptic NMDAR signals in the nucleus ► Jacob induces cell death or survival/plasticity depending upon phosphorylation by ERK ► α-internexin preserves plasticity signals during long-haul synapto-nuclear transport Signals that originate from neurotransmitter receptors within synapses versus those from receptors residing outside synaptic regions are distinguished in the nucleus by the differential phosphorylation and transport of a messenger protein, Jacob.