Protein kinase C promotes N-methyl-D-aspartate (NMDA) receptor trafficking by indirectly triggering calcium/calmodulin-dependent protein kinase II (CaMKII) autophosphorylation.
ABSTRACT Regulation of neuronal NMDA receptor (NMDAR) is critical in synaptic transmission and plasticity. Protein kinase C (PKC) promotes NMDAR trafficking to the cell surface via interaction with NMDAR-associated proteins (NAPs). Little is known, however, about the NAPs that are critical to PKC-induced NMDAR trafficking. Here, we showed that calcium/calmodulin-dependent protein kinase II (CaMKII) could be a NAP that mediates the potentiation of NMDAR trafficking by PKC. PKC activation promoted the level of autophosphorylated CaMKII and increased association with NMDARs, accompanied by functional NMDAR insertion, at postsynaptic sites. This potentiation, along with PKC-induced long term potentiation of the AMPA receptor-mediated response, was abolished by CaMKII antagonist or by disturbing the interaction between CaMKII and NR2A or NR2B. Further mutual occlusion experiments demonstrated that PKC and CaMKII share a common signaling pathway in the potentiation of NMDAR trafficking and long-term potentiation (LTP) induction. Our results revealed that PKC promotes NMDA receptor trafficking and induces synaptic plasticity through indirectly triggering CaMKII autophosphorylation and subsequent increased association with NMDARs.
- SourceAvailable from: Mitsuhiko Yamada[Show abstract] [Hide abstract]
ABSTRACT: Childhood- or early adulthood-onset type 1 diabetes is associated with modest impairments in cognition, and has an elevated risk of cognitive decline. Although an earlier onset age of diabetes has been identified as one of the strongest risk factors associated with cognitive dysfunction, little is known about the effects of cognitive performance associated with hippocampal function. Our previous study showed impaired working memory and hippocampal long-term depression (LTD) deficits in juvenile-onset diabetes mellitus (JDM) rats. Here, we demonstrated that treatment with the NMDA open-channel blocker, memantine, rescued hippocampal LTD and hippocampal-dependent memory in JDM rats. In addition, the impairment in LTD was attributed to a malfunction in NR2B-containing NMDA receptors. JDM rats exhibited excessive PKA activity, which may play a role in altered NMDA receptor function and impaired LTD. The changes in NR2B-containing NMDA receptors and PKA activity may be involved in learning impairments in JDM rats. Our findings suggest that NMDA open-channel blockers offer a potential strategy to treat cognitive deficits in childhood-onset diabetes.Neuroscience Research 01/2014; · 2.20 Impact Factor
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ABSTRACT: The tumor suppressor function of the promyelocytic leukemia (PML) protein was first identified as a result of its dysregulation in acute promyelocytic leukemia, however, its importance is now emerging far beyond hematological neoplasms, to an extensive range of malignancies, including solid tumors. In response to stress signals, PML coordinates the regulation of numerous proteins, which activate fundamental cellular processes that suppress tumorigenesis. Importantly, PML itself is the subject of specific post-translational modifications, including ubiquitination, phosphorylation, acetylation, and SUMOylation, which in turn control PML activity and stability and ultimately dictate cellular fate. Improved understanding of the regulation of this key tumor suppressor is uncovering potential opportunities for therapeutic intervention. Targeting the key negative regulators of PML in cancer cells such as casein kinase 2, big MAP kinase 1, and E6-associated protein, with specific inhibitors that are becoming available, provides unique and exciting avenues for restoring tumor suppression through the induction of apoptosis and senescence. These approaches could be combined with DNA damaging drugs and cytokines that are known to activate PML. Depending on the cellular context, reactivation or enhancement of tumor suppressive PML functions, or targeted elimination of aberrantly functioning PML, may provide clinical benefit.Frontiers in Oncology 01/2013; 3:124.
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ABSTRACT: The P2X3 receptor plays a vital role in sensory processing and transmission. The assembly and trafficking of the P2X3 receptor are important for its function in primary sensory neurons. As an important inflammation mediator, ATP is released from different cell types around primary sensory neurons, especially under pathological pain conditions. Here, we show that α, β-MeATP dramatically promoted membrane delivery of the P2X3 receptor both in HEK293T cells expressing recombinant P2X3 receptor and in rat primary sensory neurons. α, β-MeATP induced P2X3 receptor-mediated Ca(2+) influx, which further activated Ca(2+)/calmodulin-dependent protein kinase IIα (CaMKIIα). The N terminus of the P2X3 receptor was responsible for CaMKIIα binding, whereas Thr(388) in the C terminus was phosphorylated by CaMKIIα. Thr(388) phosphorylation increased P2X3 receptor binding to caveolin-1. Caveolin-1 knockdown abrogated the α, β-MeATP-induced membrane insertion of the P2X3 receptor. Moreover, α, β-MeATP drove the CaMKIIα-mediated membrane coinsertion of the P2X2 receptor with the P2X3 receptor. The increased P2X3 receptors on the cell membrane that are due to Thr(388) phosphorylation facilitated P2X3 receptor-mediated signal transduction. Together, our data indicate that CaMKIIα and caveolin-1 cooperate to drive ligand-induced membrane delivery of the P2X3 receptor and may provide a mechanism of P2X3 receptor sensitization in pain development.Journal of Molecular Cell Biology 04/2014; 6(2):140-53. · 7.31 Impact Factor