Zeta Inhibitory Peptide attenuates learning and memory by inducing NO-mediated downregulation of AMPA receptors

• Published in: Nature communications Vol. 11; no. 1; p. 3688
• Main Authors: Bingor, Alexey, Haham, Tomer, Thornton, Claire, Stern-Bach, Yael, Yaka, Rami
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 23-07-2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/1; 13/106; 13/51; 13/95; 14; 14/19; 631/378/1595/2167; 631/378/1595/2638; 631/443/376; 64; 64/86; 9/74; Alanine; Arginine; Attenuation; Cocaine; Down-regulation; Humanities and Social Sciences; Inhibitors; Learning; Maintenance; multidisciplinary; Mutants; NG-Nitroarginine methyl ester; Nitric oxide; Nuclei (cytology); Nucleus accumbens; Peptidase; Peptides; Phosphorylation; Reinforcement; Science; Science (multidisciplinary); Serine; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-17484-y

Zeta inhibitory peptide (ZIP), a PKMζ inhibitor, is widely used to interfere with the maintenance of acquired memories. ZIP is able to erase memory even in the absence of PKMζ, via an unknown mechanism. We found that ZIP induces redistribution of the AMPARGluA1 in HEK293 cells and primary cortical neurons, and decreases AMPAR-mediated currents in the nucleus accumbens (NAc). These effects were mimicked by free arginine or by a modified ZIP in which all but the arginine residues were replaced by alanine. Redistribution was blocked by a peptidase-resistant version of ZIP and by treatment with the nitric oxide (NO)-synthase inhibitor L-NAME. ZIP increased GluA1-S831 phosphorylation and ZIP-induced redistribution was blocked by nitrosyl-mutant GluA1-C875S or serine-mutant GluA1-S831A. Introducing the cleavable arginine-alanine peptide into the NAc attenuated expression of cocaine-conditioned reward. Together, these results suggest that ZIP may act as an arginine donor, facilitating NO-dependent downregulation of AMPARs, thereby attenuating learning and memory.
Zeta inhibitory peptide (ZIP) impairs the maintenance of acquired memories. ZIP is known as an inhibitor of PKMζ. Here, the authors unveil how ZIP impairs memory maintenance acting as an arginine donor, facilitating NO-dependent down-regulation of AMPARs, independently of its action on PKMζ.