Calcium-Dependent Eukaryotic Initiation Factor 2α Phosphatase Complexed with Calcineurin Restores Control to Anterior Piriform Cortex Neural Circuitry after Activation by Essential Amino acid Deficiency
2016
Essential (dietary-indispensable) amino acids (IAA)s are vital precursors for protein synthesis; they cannot be synthesized in metazoans but must be obtained from food to survive. In sensing a reduction of an IAA, the mammalian anterior piriform cortex (APC) is rapidly activated. The initial behavioral response is an abrupt end to an IAA deficient meal about 20 min after meal onset. IAA depletion in the APC activates the conserved eukaryotic initiation factor 2α (eIF2α) kinase, GCN2, via uncharged tRNA. GCN2 kinase activity increases phosphorylation of eIF2α (P-eIF2α), which blocks global protein synthesis. The result is that APC inhibitory elements with short half-lives cannot be replaced. Without their inhibition in this highly sensitive brain area, activation of the glutamatergic output cells ensues. Following APC activation, P-eIF2α must be reduced to release the blockade on protein synthesis and allow recovery of inhibition in the circuit. This completes the homeostatic response, restoring control in the APC. A role for calcium (Ca 2+ ) in regulating P-eIF2α was explored here using Ca 2+ blockers, immunoblotting and electrophysiology in APC brain slices. The responses to IAA depletion in the APC were Ca 2+ dependent, showing a role for Ca 2+ in the system. Yet, the kinase activity of GCN2 was unaffected by intracellular Ca 2+ chelation. Thus, control must be accomplished by phosphatase activity. We suggest that regulation of P-eIF2α, and neuronal stability in the APC, require the activity of protein phosphatase1, a Ca 2+ -dependent subunit of the phosphatase acting on P-eIF2α. This implicates the Ca2+/ calmodulin-dependent calcineurin (Protein Phosphatase 2B/PP2B) as acting with the constitutive repressor of eIF2 phosphorylation (PPP1R15B/CReP) after GCN2 activation in the brain.
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