Calcium-Dependent Eukaryotic Initiation Factor 2α Phosphatase Restores Control to Anterior Piriform Cortex Neural Circuitry after Activation by Essential Amino Acid Deficiency

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Gietzen DW
Ross-Inta CM
Rudell JB
Hao S
Donovan M


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)Ɨ 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 levels of phosphorylated eIF2α (P-eIF2α), which blocks global protein synthesis such that APC inhibitory elements with short half-lives cannot be replaced. This results in disinhibition of this highly sensitive brain area. Following APC activation, a reduction in P-eIF2α releases the blockade on protein synthesis to allow recovery of inhibition in the circuit and complete the homeostatic response, restoring control in the APC. A role for calcium (Ca2+) in regulating P-eIF2α was explored here using Ca2+ blockers with immunohistochemistry and electrophysiology in APC brain slices. The responses to IAA depletion in the APC were Ca2+ dependent, showing a role for Ca2+ in the system. Yet, the kinase activity of GCN2 was unaffected by intracellular Ca2+ 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 a Ca2+-dependent subunit, protein phosphatase1, of the phosphatase acting on P-eIF2α. This would implicate the Ca2+/calmodlin dependent calcineurin, and the constitutive repressor of eIF2 phosphorylation (PPP1R15B/CReP) after GCN2 activation in the brain.


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