Structural studies on the regulation of Ca2+/calmodulin dependent protein kinase II

Stratton, Margaret M.; Chao, Luke H.; Schulman, Howard; Kuriyan, John

doi:10.1016/j.sbi.2013.04.002

Cited by 79 publications

(77 citation statements)

References 62 publications

(61 reference statements)

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“…It is notable that phosphorylated CaMKII-Thr286 in postsynaptic densities (PSDs) can be dephosphorylated by soluble PP1, but is not accessible to PP1 that is embedded in PSDs, indicating structural constraints could affect the ability of PSD-PP1 to dephosphorylate PSDCaMKII (32,33) that may be relieved by agonist binding to the NMDAR during LTD. NMDA binding also reduced the interaction between the NMDARcd and CaMKII that was delayed but persistent and blocked by PP1 inhibition. The delay may indicate that several Thr286 sites on the CaMKII complex, which normally exists as a 12-subunit holoenzyme (34,35), require dephosphorylation for the holoenzyme to move with respect to the NMDARcd. Our immunoprecipitation experiments support the view that agonist binding to the NMDAR leads to Thr286 dephosphorylation of associated CaMKII without its unbinding to the NMDARcd, suggesting a reorientation of CaMKII within the complex to a new location, maintaining catalytic activity (20) with potentially different substrates, necessary for LTD (28,36).…”

Section: Discussionmentioning

confidence: 99%

Conformational signaling required for synaptic plasticity by the NMDA receptor complex

Aow

Doré

Malinow

2015

Proc. Natl. Acad. Sci. U.S.A.

112

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The NMDA receptor (NMDAR) is known to transmit important information by conducting calcium ions. However, some recent studies suggest that activation of NMDARs can trigger synaptic plasticity in the absence of ion flow. Does ligand binding transmit information to signaling molecules that mediate synaptic plasticity? Using Förster resonance energy transfer (FRET) imaging of fluorescently tagged proteins expressed in neurons, conformational signaling is identified within the NMDAR complex that is essential for downstream actions. Ligand binding transiently reduces FRET between the NMDAR cytoplasmic domain (cd) and the associated protein phosphatase 1 (PP1), requiring NMDARcd movement, and persistently reduces FRET between the NMDARcd and calcium/calmodulin-dependent protein kinase II (CaMKII), a process requiring PP1 activity. These studies directly monitor agonist-driven conformational signaling at the NMDAR complex required for synaptic plasticity.A gonist binding to the NMDAR is required for two major forms of synaptic plasticity: long-term potentiation (LTP) and longterm depression (LTD) (1). Surprisingly, activation of NMDARs can produce plasticity in opposite directions, with LTP enhancing transmission and LTD reducing transmission. A model was developed (2, 3) to explain how activation of NMDAR could produce these opposing phenomena: strong stimuli during LTP induction drive a large flux of Ca 2+ through NMDARs, leading to a large increase in intracellular calcium ion concentration ([Ca 2+ ] i ) that activates one series of biochemical steps leading to synaptic potentiation; a weaker stimulus during LTD induction drives a more reduced flux of Ca 2+ through NMDARs, producing a modest increase in [Ca 2+ ] i that activates a different series of biochemical steps, leading to synaptic depression. However, this model is not consistent with recent studies suggesting that no change in [Ca 2+ ] i is required for LTD, and instead invokes metabotropic signaling by the NMDAR (4). Studies supporting an ion-flow-independent role for NMDARs in LTD (4-7) and other processes (7-13) stand in contrast to studies proposing that flow of Ca 2+ through NMDAR is required for LTD (14) Results Transient NMDAR Agonist Binding Without Ion Flux DepressesSpontaneous Excitatory Postsynaptic Currents. In the accompanying study (16), Förster resonance energy transfer (FRET)-fluorescence lifetime imaging microscopy (FLIM) imaging was used to show that agonist binding to the NMDAR produces conformational movement of the NMDARcd. This effect displayed the same pharmacological profile as the electrically induced LTD recently published (4) and independently confirmed (7), suggesting that the conformational changes measured in the NMDARcd are associated with LTD induction. To test whether the stimulation protocol that drives conformational changes in the NMDARcd produces changes in synaptic function, spontaneous synaptic activity was recorded in primary hippocampal neurons, and NMDA was transiently applied in the presence of 7CK, a noncompetit...

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Section: Discussionmentioning

confidence: 99%

Conformational signaling required for synaptic plasticity by the NMDA receptor complex

Aow

Doré

Malinow

2015

Proc. Natl. Acad. Sci. U.S.A.

112

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“…CaMK2 is a broadly distributed Ser/Thr protein kinase that is activated by Ca 2+ /Calmodulin (CaM) binding (32). It has essential roles in synaptic plasticity and memory (32); nevertheless, recent findings indicate that CaMK2 is activated by cyclic mechanical stress loading and that CaMK2 activation induces aggrecan expression in articular chondrocytes (33,34).…”

Section: Discussionmentioning

confidence: 99%

Transcription factor Hes1 modulates osteoarthritis development in cooperation with calcium/calmodulin-dependent protein kinase 2

Sugita¹,

Hosaka

Okada³

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Notch signaling modulates skeletal formation and pathogenesis of osteoarthritis (OA) through induction of catabolic factors. Here we examined roles of Hes1, a transcription factor and important target of Notch signaling, in these processes. SRY-box containing gene 9 (Sox9)-Cre mice were mated with Hes1 fl/fl mice to generate tissue-specific deletion of Hes1 from chondroprogenitor cells; this deletion caused no obvious abnormality in the perinatal period. Notably, OA development was suppressed when Hes1 was deleted from articular cartilage after skeletal growth in type II collagen (Col2a1)-Cre ERT ;Hes1 fl/fl mice. In cultured chondrocytes, Hes1 induced metallopeptidase with thrombospondin type 1 motif, 5 (Adamts5) and matrix metalloproteinase-13 (Mmp13), which are catabolic enzymes that break down cartilage matrix. ChIP-seq and luciferase assays identified Hes1-responsive regions in intronic sites of both genes; the region in the ADAMTS5 gene contained a typical consensus sequence for Hes1 binding, whereas that in the MMP13 gene did not. Additionally, microarray analysis, together with the ChIP-seq, revealed novel Hes1 target genes, including Il6 and Il1rl1, coding a receptor for IL-33. We further identified calcium/calmodulin-dependent protein kinase 2δ (CaMK2δ) as a cofactor of Hes1; CaMK2δ was activated during OA development, formed a protein complex with Hes1, and switched it from a transcriptional repressor to a transcriptional activator to induce cartilage catabolic factors. Therefore, Hes1 cooperated with CaMK2δ to modulate OA pathogenesis through induction of catabolic factors, including Adamts5, Mmp13, Il6, and Il1rl1. Our findings have contributed to further understanding of the molecular pathophysiology of OA, and may provide the basis for development of novel treatments for joint disorders.

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“…The catalytic cleft is nested in the cleft between the two domains. Adopted with permission from (Stratton et al, 2013). …”

Section: Figurementioning

confidence: 99%

CaMKII: Claiming Center Stage in Postsynaptic Function and Organization

Hell

2014

Neuron

300

306

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SUMMARY While CaMKII has long been known to be essential for synaptic plasticity and learning, recent work points to new dimensions of CaMKII function in the nervous system, revealing that CaMKII also plays an important role in synaptic organization. Ca2+-triggered autophosphorylation of CaMKII not only provides molecular memory by prolonging CaMKII activity during long-term plasticity (LTP) and learning but also represents a mechanism for autoactivation of CaMKII’s multifaceted protein docking functions. New details are also emerging about the distinct roles of CaMKIIα and CaMKIIβ in synaptic homeostasis, further illustrating the multilayered and complex nature of CaMKII’s involvement in synaptic regulation. Here, I review novel molecular and functional insight into how CaMKII supports synaptic function.

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Structural studies on the regulation of Ca2+/calmodulin dependent protein kinase II

Cited by 79 publications

References 62 publications

Conformational signaling required for synaptic plasticity by the NMDA receptor complex

Conformational signaling required for synaptic plasticity by the NMDA receptor complex

Transcription factor Hes1 modulates osteoarthritis development in cooperation with calcium/calmodulin-dependent protein kinase 2

CaMKII: Claiming Center Stage in Postsynaptic Function and Organization

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