␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type glutamate receptors mediate the majority of excitatory signaling in the CNS, and the functional properties and subcellular fate of these receptors depend on receptor subunit composition. Subunit assembly is thought to occur in the endoplasmic reticulum (ER), although we are just beginning to understand the underlying mechanism. Here we examine the trafficking of Caenorhabditis elegans glutamate receptors through the ER. Our data indicate that neurons require signaling by the unfolded protein response (UPR) to move GLR-1, GLR-2, and GLR-5 subunits out of the ER and through the secretory pathway. In contrast, other neuronal transmembrane proteins do not require UPR signaling for ER exit. The requirement for the UPR pathway is cell type and age dependent: impairment for receptor trafficking increases as animals age and does not occur in all neurons. Expression of XBP-1, a component of the UPR pathway, is elevated in neurons during development. Our results suggest that UPR signaling is a critical step in neural function that is needed for glutamate receptor assembly and secretion. INTRODUCTIONIon channels conduct electrochemical signaling in the nervous system, and ␣-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-type ionotropic glutamate receptors (AMPAR) in particular mediate the bulk of excitatory transmission in the CNS. AMPAR subunits (up to 4 in mammals, referred to as GluR1-R4) are multi-transmembrane-spanning proteins that can assemble into tetrameric channels of differing subunit composition (Hollmann and Heinemann, 1994;Dingledine et al., 1999). The specific subunit composition of a given AMPAR channel plays a critical role in determining the functional properties of that channel, including its channel opening probability, ion selectivity, and cytosolic binding partners (Hollmann and Heinemann, 1994;Dingledine et al., 1999;Sheng, 2001;Shi et al., 2001;Malinow, 2003). Subunit composition can also control the subcellular localization and regulated cell biological fate of a channel (Beattie et al., 2000;Lin et al., 2000). For example, heteromeric complexes of GluR1-R2 receptors have been shown to be added to hippocampal synapses in an activity-dependent manner, whereas GluR2-R3 complexes appear to cycle into synaptic membranes in a constitutive manner (Passafaro et al., 2001;Shi et al., 2001). To better understand AMPAR function in the nervous system, it is important to determine how individual subunits assemble into specific complexes of channels.Multisubunit channel assembly in general is tied to the movement of channels through the secretory pathway. Most proteins exit the ER without the need for specialized export signals (Wieland et al., 1987). However, many channels and receptors seem to defy this general rule by requiring channel assembly, sometimes specific export signals, and sometimes the interaction of scaffolding proteins and certain signal transduction events before exiting the ER (Ma and Jan, 2002). One explanation is ...