@article {Bogardmol.115.099457, author = {Amy S Bogard and Steven J. Tavalin}, title = {Protein Kinase C (PKC)ζ Pseudosubstrate Inhibitor Peptide (ZIP) Promiscuously Binds PKC family Isoforms and Disrupts Conventional PKC Targeting and Translocation}, elocation-id = {mol.115.099457}, year = {2015}, doi = {10.1124/mol.115.099457}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {PKMζ is generated via an alternative transcriptional start site in the atypical PKCζ isoform which removes N-terminal regulatory elements including the inhibitory pseudosubstrate domain, consequently rendering the kinase constitutively active. Persistent PKMζ activity has been proposed as a molecular mechanism for the long-term maintenance of synaptic plasticity underlying some forms of memory. Many studies supporting a role for PKMζ in synaptic plasticity and memory have relied on the PKCζ pseudosubstrate-derived zeta inhibitory peptide (ZIP). However, recent studies demonstrate that ZIP-induced impairments to synaptic plasticity and memory occur even in the absence of PKCζ, suggesting that ZIP exerts its actions via additional cellular targets. Here, we demonstrate that ZIP interacts with conventional and novel PKC, in addition to atypical PKC isoforms. Moreover, when brain abundance of each PKC isoform and affinity for ZIP is taken into account, the signaling capacity of ZIP-responsive pools of conventional and novel PKCs pools may match and/or exceed that for atypical PKCs. Pseudosubstrate-derived peptides, like ZIP, are primarily thought to exert their cellular action by inhibiting PKC catalytic activity. However, the ZIP-sensitive catalytic core of PKC is known to participate in the enzyme{\textquoteright}s subcellular targeting, suggesting an additional mode of ZIP action. Indeed, we demonstrate that ZIP potently disrupts PKCα interaction with the PKC targeting protein AKAP79 and interferes with ionomycin-induced translocation of conventional PKC to the plasma membrane. Thus, ZIP exhibits broad spectrum action towards the PKC family of enzymes which may contribute to its unique ability to impair memory.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/early/2015/07/21/mol.115.099457}, eprint = {https://molpharm.aspetjournals.org/content/early/2015/07/21/mol.115.099457.full.pdf}, journal = {Molecular Pharmacology} }