Phosphorylation of eIF2alpha is involved in the signaling of indispensable amino acid deficiency in the anterior piriform cortex of the brain in rats.

Sensing of indispensable amino acid (IAA) deficiency, an acute challenge to protein homeostasis, is demonstrated by rats as rejection of IAA-deficient diets within 20 min. The anterior piriform cortex (APC) of the brain in rats and birds is essential for this nutrient sensing, and is activated by IAA deficiency. Yet the mechanisms that sense and transduce IAA reduction to signaling in the APC, or indeed in any animal cells, are unknown. Because rejection of a deficient diet within 20 min is too rapid to be explained by transcription-derived signals, brain tissue was taken from rats after 20 min access to either a threonine-basal, -devoid, or -corrected diet and examined for proteins associated with early signaling of IAA deficiency in the yeast model. Western blots and immunohistochemistry showed that the phosphorylation of eukaryotic initiation factor 2-alpha (p-eIF2alpha[Ser51]) and translation of its downstream product, c-Jun, were increased (47%, P < 0.005, and 55%, P < 0.025, respectively) in APC from rats offered devoid, but not corrected diets, compared with those offered basal diets. This was not seen in other brain areas. In cells intensely labeled for cytoplasmic p-eIF2alpha, there was intense fluorescence for c-Jun in the nucleus. Thus, p-eIF2alpha, which is pivotal in the initiation of global protein translation, and its downstream product, the leucine zipper protein, c-Jun, are increased in the mammalian APC within the time frame necessary for the behavioral response. We suggest that p-eIF2alpha and c-Jun participate in signaling nutrient deficiency in the IAA-sensitive neurons of the APC.