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Priyanka Purkayastha, Reshma Alokam, Aruna Malapati, Dharmarajan Sriram, Perumal Yogeeswari
An atypical protein kinase C, PKMzeta has become an attractive target for various neurological disorders including long term potentiation, cognition, neuropathic pain and cancer. Drug discovery efforts have been hindered due to the non-availability of the protein structure and hence in the present study we attempted to build the open and closed models of the protein PKMzeta using homology modeling. The models were then used to identify PKMzeta inhibitors utilizing a high-throughput virtual screening protocol from a large commercial chemical database...
October 2015: Molecular Informatics
Vladimir P Nikitin, Svetlana V Solntseva, Sergey A Kozyrev, Pavel V Nikitin, Alexey V Shevelkin
Memory reconsolidation processes and protein kinase Mzeta (PKMzeta) activity in memory maintenance and reorganization are poorly understood. Therefore, we examined memory reconsolidation and PKMzeta activity during the maintenance and reorganization of a conditioned food aversion memory among snails. These processes were specifically evaluated after administration of a serotonin receptor antagonist (methiothepin), NMDA glutamate receptor antagonist (MK-801), protein synthesis inhibitor (cycloheximide; CYH), or PKMzeta inhibitor (zeta inhibitory peptide; ZIP) either 2 or 10 days after aversion training...
March 23, 2016: Brain Research
V P Nikitin, S V Solntseva, S A Kozyrev
In snails trained for conditional food aversion, the effect of ZIP-protein kinase Mzeta (PKMzeta) inhibitor on mechanisms of memory retention and reconsolidation was studied. It was shown that two days after ZIP injections the dose of 1.25 mg/kg, which were not combined with a reminding procedure, there was no effects, but in dose of 2.5 mg/kg a transient memory impairment after 1 day after the injection with its spontaneous recovery on day 10 was disclosed. ZIP injection in a dose of 5 mg/kg without reminding procedure caused memory impairment and the development of persistent amnesia...
August 2014: Rossiĭskii Fiziologicheskiĭ Zhurnal Imeni I.M. Sechenova
Li-Li Ji, Lei Tong, Bao-Ku Xu, Chang-Hai Fu, Wan Shu, Jun-Bo Peng, Zhen-Yu Wang
BACKGROUND: Given that impairment of fear extinction has been implicated in the pathogenesis of posttraumatic stress disorder (PTSD), effective pharmacological interventions that facilitate fear extinction may provide alternative strategies to conventional treatment. It is generally accepted that the zeta inhibitory peptide (ZIP), a controversial inhibitor of protein kinase M zeta (PKMζ), could erase certain types of previously established long-term memories. However, it is unclear whether ZIP administration may alleviate PTSD-associated depressive and anxiety-like abnormalities...
2014: Behavioral and Brain Functions: BBF
Cristiane R G Furini, Jociane C Myskiw, Fernando Benetti, Ivan Izquierdo
We review recent work on three major lines of memory research: a) the possible role of the protein kinase M-zeta (PKMzeta) in memory persistence; b) the processes of "synaptic tagging and capture" in memory formation; c) the modulation of extinction learning, widely used in the psychotherapy of fear memories under the name of "exposure therapy". PKMzeta is a form of protein kinase C (PKC) that apparently remains stimulated for months after the consolidation of a given memory. Synaptic tagging is a mechanism whereby the weak activation of one synapse can tag it with a protein so other synapses in the same cell can reactivate it by producing other proteins that bind to the tag...
April 2013: Revista Brasileira de Psiquiatria
David L Glanzman
How can memories outlast the molecules from which they are made? Answers to this fundamental question have been slow coming but are now emerging. A novel kinase, an isoform of protein kinase C (PKC), PKMzeta, has been shown to be critical to the maintenance of some types of memory. Inhibiting the catalytic properties of this kinase can erase well-established memories without altering the ability of the erased synapse to be retrained. This article provides an overview of the literature linking PKMzeta to memory maintenance and identifies some of the controversial issues that surround the bold implications of the existing data...
2013: F1000 Biology Reports
Isabella Panaccione, Rachel King, Gemma Molinaro, Barbara Riozzi, Giuseppe Battaglia, Ferdinando Nicoletti, Zafar I Bashir
Synaptic transmission is essential for early development of the central nervous system. However, the mechanisms that regulate early synaptic transmission in the cerebral cortex are unclear. PKMζ is a kinase essential for the maintenance of LTP. We show for the first time that inhibition of PKMζ produces a profound depression of basal synaptic transmission in neonatal, but not adult, rat perirhinal cortex. This suggests that synapses in early development are in a constitutive LTP-like state. Furthermore, basal synaptic transmission in immature, but not mature, perirhinal cortex relies on persistent activity of metabotropic glutamate (mGlu) receptor, PI3Kinase and mammalian target of rapamycin (mTOR)...
March 2013: Neuropharmacology
Jose A Crespo, Petra Stöckl, Florian Ueberall, Marcel Jenny, Alois Saria, Gerald Zernig
One of the greatest challenges in the treatment of substance dependence is to reverse the control that drug-associated stimuli have gained over the addict's behavior, as these drug-associated memories increase the risk of relapse even after long periods of abstinence. We report here that inhibition of the atypical protein kinase C isoform PKCzeta and its constitutively active isoform PKMzeta with the pseudosubstrate inhibitor ZIP administered locally into the nucleus accumbens core reversibly inhibited the retrieval of drug-associated memory and drug (remifentanil) seeking, whereas a scrambled ZIP peptide or staurosporine, an effective inhibitor of c/nPKC-, CaMKII-, and PKA kinases that does not affect PKCzeta/PKMzeta activity, was without effect on these memory processes...
2012: PloS One
Yan-qin Li, Yan-xue Xue, Ying-ying He, Fang-qiong Li, Li-fen Xue, Chun-mei Xu, Todd Charlton Sacktor, Yavin Shaham, Lin Lu
During abstinence, memories of drug-associated cues persist for many months, and exposure to these cues often provokes relapse to drug use. The mechanisms underlying the maintenance of these memories are unknown. A constitutively active atypical protein kinase C (PKC) isozyme, protein kinase M ζ (PKMζ), is required for maintenance of spatial memory, conditioned taste aversion, and other memory forms. We used conditioned place preference (CPP) and conditioned place aversion (CPA) procedures to study the role of nucleus accumbens PKMζ in the maintenance of drug reward and aversion memories in rats...
April 6, 2011: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Sreedharan Sajikumar, Martin Korte
Activity-dependent synaptic plasticity is widely accepted to be the cellular correlate of learning and memory. It is believed that associativity between different synaptic inputs can transform short-lasting forms of synaptic plasticity (<3 h) to long-lasting ones. Synaptic tagging and capture (STC) might be able to explain this heterosynaptic support, because it distinguishes between local mechanisms of synaptic tags and cell-wide mechanisms responsible for the synthesis of plasticity-related proteins (PRPs)...
February 8, 2011: Proceedings of the National Academy of Sciences of the United States of America
Xiang-Yao Li, Hyoung-Gon Ko, Tao Chen, Giannina Descalzi, Kohei Koga, Hansen Wang, Susan S Kim, Yuze Shang, Chuljung Kwak, Soo-Won Park, Jaehoon Shim, Kyungmin Lee, Graham L Collingridge, Bong-Kiun Kaang, Min Zhuo
Synaptic plasticity is a key mechanism for chronic pain. It occurs at different levels of the central nervous system, including spinal cord and cortex. Studies have mainly focused on signaling proteins that trigger these plastic changes, whereas few have addressed the maintenance of plastic changes related to chronic pain. We found that protein kinase M zeta (PKMζ) maintains pain-induced persistent changes in the mouse anterior cingulate cortex (ACC). Peripheral nerve injury caused activation of PKMζ in the ACC, and inhibiting PKMζ by a selective inhibitor, ζ-pseudosubstrate inhibitory peptide (ZIP), erased synaptic potentiation...
December 3, 2010: Science
Lee Michael von Kraus, Todd Charlton Sacktor, Joseph Thachil Francis
Sensorimotor cortex has a role in procedural learning. Previous studies suggested that this learning is subserved by long-term potentiation (LTP), which is in turn maintained by the persistently active kinase, protein kinase Mzeta (PKMzeta). Whereas the role of PKMzeta in animal models of declarative knowledge is established, its effect on procedural knowledge is not well understood. Here we show that PKMzeta inhibition, via injection of zeta inhibitory peptide (ZIP) into the rat sensorimotor cortex, disrupts sensorimotor memories for a skilled reaching task even after several weeks of training...
2010: PloS One
Noelia Madroñal, Agnès Gruart, Todd C Sacktor, José M Delgado-García
A leading candidate in the process of memory formation is hippocampal long-term potentiation (LTP), a persistent enhancement in synaptic strength evoked by the repetitive activation of excitatory synapses, either by experimental high-frequency stimulation (HFS) or, as recently shown, during actual learning. But are the molecular mechanisms for maintaining synaptic potentiation induced by HFS and by experience the same? Protein kinase Mzeta (PKMzeta), an autonomously active atypical protein kinase C isoform, plays a key role in the maintenance of LTP induced by tetanic stimulation and the storage of long-term memory...
2010: PloS One
Paola Virginia Migues, Oliver Hardt, Dong Chuan Wu, Karine Gamache, Todd Charlton Sacktor, Yu Tian Wang, Karim Nader
The maintenance of long-term memory in hippocampus, neocortex and amygdala requires the persistent action of the atypical protein kinase C isoform, protein kinase Mzeta (PKMzeta). We found that inactivating PKMzeta in the amygdala impaired fear memory in rats and that the extent of the impairment was positively correlated with a decrease in postsynaptic GluR2. Blocking the GluR2-dependent removal of postsynaptic AMPA receptors abolished the behavioral impairment caused by PKMzeta inhibition and the associated decrease in postsynaptic GluR2 expression, which correlated with performance...
May 2010: Nature Neuroscience
Suhel Parvez, Binu Ramachandran, Julietta U Frey
The hippocampus is an ideal system to study synaptic plasticity in the context of learning and memory. The induction, expression, and interaction of long-term potentiation (LTP) as well as long-term depression (LTD) are essential elements for the functioning of complex networks in information processing and storage. Here we investigated whether different loci at the apical dendritic branch of CA1 pyramidal neurons are characterized by different capabilities to induce, express, and interact with LTP and LTD in hippocampal slices in vitro...
April 7, 2010: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Pamela R Westmark, Cara J Westmark, SuQing Wang, Jonathan Levenson, Kenneth J O'Riordan, Corinna Burger, James S Malter
Some forms of learning and memory and their electrophysiologic correlate, long-term potentiation (LTP), require dendritic translation. We demonstrate that Pin1 (protein interacting with NIMA 1), a peptidyl-prolyl isomerase, is present in dendritic spines and shafts and inhibits protein synthesis induced by glutamatergic signaling. Pin1 suppression increased dendritic translation, possibly through eukaryotic translation initiation factor 4E (eIF4E) and eIF4E binding proteins 1 and 2 (4E-BP1/2). Consistent with increased protein synthesis, hippocampal slices from Pin(-/-) mice had normal early LTP (E-LTP) but significantly enhanced late LTP (L-LTP) compared to wild-type controls...
2010: Science Signaling
Todd Charlton Sacktor
Long-term memories are thought to be maintained by persistent changes in the strength of synaptic connections among neurons, but how such changes can persist for days to years has been one of the fundamental enigmas of neuroscience. Recently, however, one mechanism that is dependent on the persistent increased activity of an enzyme has been shown to be necessary for the persistence of long-term memory. The transient inhibition of the brain-specific, constitutively active protein kinase C isoform PKMzeta erases memories that are even months old...
2010: Science Signaling
Hagit Cohen, Nitsan Kozlovsky, Michael A Matar, Zeev Kaplan, Joseph Zohar
BACKGROUND: Protein kinase M zeta (PKMzeta), a constitutively active isoform of protein kinase C, has been implicated in protein synthesis-dependent maintenance of long-term potentiation and memory storage in the brain. Recent studies reported that local application of ZIP, a membrane-permeant PKMzeta inhibitor, into the insular cortex (IC) of behaving rats abolished long-term memory of taste associations. METHOD: This study assessed the long-term effects of local applications of ZIP microinjected immediately (1 h) or 10 days after predator scent stress exposure, in a controlled prospectively designed animal model for PTSD...
April 2010: European Neuropsychopharmacology: the Journal of the European College of Neuropsychopharmacology
Oliver Hardt, Paola V Migues, Margaret Hastings, Jacinda Wong, Karim Nader
Continuous activity of the atypical protein kinase C isoform M zeta (PKMzeta) is necessary for maintaining long-term memory acquired in aversively or appetitively motivated associative learning tasks, such as active avoidance, aversive taste conditioning, auditory and contextual fear conditioning, radial arm maze, and watermaze. Whether unreinforced, nonassociative memory will also require PKMzeta for long-term maintenance is not known. Using recognition memory for object location and object identity, we found that inactivating PKMzeta in dorsal hippocampus abolishes 1-day and 6-day-old long-term recognition memory for object location, while recognition memory for object identity was not affected by this treatment...
June 2010: Hippocampus
Janine L Kwapis, Timothy J Jarome, Mary E Lonergan, Fred J Helmstetter
Recent work on the long-term stability of memory and synaptic plasticity has identified a potentially critical role for protein kinase Mzeta (PKMzeta). PKMzeta is a constitutively active, atypical isoform of protein kinase C that is believed to maintain long term potentiation at hippocampal synapses in vitro. In behaving animals, local inhibition of PKMzeta disrupts spatial memory in the hippocampus and conditioned taste aversion memory in the insular cortex. The role of PKMzeta in context fear memory is less clear...
August 2009: Behavioral Neuroscience
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