Conserved and divergent features of neuronal CaMKII holoenzyme structure, function, and high-order assembly DOI Creative Commons
Olivia R. Buonarati, Adam Miller, Steven J. Coultrap

et al.

Cell Reports, Journal Year: 2021, Volume and Issue: 37(13), P. 110168 - 110168

Published: Dec. 1, 2021

Neuronal CaMKII holoenzymes (α and β isoforms) enable molecular signal computation underlying learning memory but also mediate excitotoxic neuronal death. Here, we provide a comparative analysis of these signaling devices, using single-particle electron microscopy (EM) in combination with biochemical live-cell imaging studies. In the basal state, both isoforms assemble mainly as 12-mers (but 14-mers even 16-mers for isoform). CaMKIIα adopt an ensemble extended activatable states (with average radius 12.6 versus 16.8 nm, respectively), characterized by multiple transient intra- inter-holoenzyme interactions associated distinct functional properties. The state CaMKIIβ allows direct resolution intra-holoenzyme kinase domain dimers. These dimers could cooperative activation calmodulin, which is observed isoforms. High-order clustering mediated dimerization reduced isoform excitotoxicity-induced clusters, vitro neurons.

Language: Английский

CaMKII: a central molecular organizer of synaptic plasticity, learning and memory DOI
Ryohei Yasuda, Yasunori Hayashi, Johannes Hell

et al.

Nature reviews. Neuroscience, Journal Year: 2022, Volume and Issue: 23(11), P. 666 - 682

Published: Sept. 2, 2022

Language: Английский

Citations

243
CaMKII as a Therapeutic Target in Cardiovascular Disease DOI Creative Commons
Oscar E. Reyes Gaido, Lubika J. Nkashama, Kate L. Schole

et al.

The Annual Review of Pharmacology and Toxicology, Journal Year: 2022, Volume and Issue: 63(1), P. 249 - 272

Published: Aug. 17, 2022

CaMKII (the multifunctional Ca

Language: Английский

Citations

73
LTP induction by structural rather than enzymatic functions of CaMKII DOI Creative Commons

Jonathan E. Tullis,

Matthew E. Larsen, Nicole L. Rumian

et al.

Nature, Journal Year: 2023, Volume and Issue: 621(7977), P. 146 - 153

Published: Aug. 30, 2023

Learning and memory are thought to require hippocampal long-term potentiation (LTP), one of the few central dogmas molecular neuroscience that has stood undisputed for more than three decades is LTP induction requires enzymatic activity Ca

Language: Английский

Citations

64
Synaptic memory and CaMKII DOI Creative Commons
Roger A. Nicoll, Howard Schulman

Physiological Reviews, Journal Year: 2023, Volume and Issue: 103(4), P. 2897 - 2945

Published: June 8, 2023

Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) and long-term potentiation (LTP) were discovered within a decade of each other have been inextricably intertwined ever since. However, like many marriages, it has had its up downs. Based on the unique biochemical properties CaMKII, was proposed as memory molecule before any physiological linkage made to LTP. reviewed here, convincing CaMKII synaptic physiology behavior took decades. New technologies critical in this journey, including vitro brain slices, mouse genetics, single-cell molecular pharmacological reagents, structure, two-photon microscopy, new investigators attracted by exciting challenge. This review tracks journey assesses state marriage 40 years on. The collective literature impels us propose relatively simple model for involving following steps that drive process: 1) entry through N-methyl-d-aspartate (NMDA) receptors activates CaMKII. 2) undergoes autophosphorylation resulting constitutive, -independent activity exposure binding site NMDA receptor subunit GluN2B. 3) Active translocates postsynaptic density (PSD) binds cytoplasmic C-tail 4) CaMKII-GluN2B complex initiates structural rearrangement PSD may involve liquid-liquid phase separation. 5) involves PSD-95 scaffolding protein, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPARs), their transmembrane AMPAR-regulatory (TARP) auxiliary subunits, an accumulation AMPARs underlies potentiation. 6) stability modified is maintained complex. 7) By process exchange or interholoenzyme phosphorylation maintains face turnover. There are important proteins participate enlargement spine modulation maintain In we critically discuss data underlying steps. As will become clear, some these more firmly grounded than others, provide suggestions how evidence supporting can be strengthened or, based data, replaced. Although long one, prospect having detailed cellular understanding learning at hand.

Language: Английский

Citations

58
The Yin and Yang of GABAergic and Glutamatergic Synaptic Plasticity: Opposites in Balance by Crosstalking Mechanisms DOI Creative Commons
Caitlyn A. Chapman, Jessica L. Nuwer, Tija C. Jacob

et al.

Frontiers in Synaptic Neuroscience, Journal Year: 2022, Volume and Issue: 14

Published: May 19, 2022

Synaptic plasticity is a critical process that regulates neuronal activity by allowing neurons to adjust their synaptic strength in response changes activity. Despite the high proximity of excitatory glutamatergic and inhibitory GABAergic postsynaptic zones functional integration within dendritic regions, concurrent has historically been underassessed. Growing evidence for pathological disruptions excitation inhibition (E/I) balance neurological neurodevelopmental disorders indicates need an improved, more "holistic" understanding interplay. There continues be long-standing focus on persistent strengthening (excitatory long-term potentiation; eLTP) its role learning memory, although importance potentiation (iLTP) depression (iLTD) become increasingly apparent. Emerging further points dynamic dialogue between synapses, but much remains understood regarding mechanisms extent this exchange. In mini-review, we explore calcium signaling crosstalk play regulating excitability. We examine current knowledge synapse responses perturbances activity, with induced short-term pharmacological treatments which act either enhance or reduce excitability via ionotropic receptor regulation culture. To delve deeper into potential crosstalk, discuss influence key regulatory proteins, including kinases, phosphatases, structural/scaffolding proteins. Finally, briefly suggest avenues future research better understand synapses.

Language: Английский

Citations

41
Shared biological mechanisms of depression and obesity: focus on adipokines and lipokines DOI Creative Commons

Xiying Fu,

Yicun Wang, Fangyi Zhao

et al.

Aging, Journal Year: 2023, Volume and Issue: unknown

Published: June 29, 2023

Depression and obesity are both common disorders currently affecting public health, frequently occurring simultaneously within individuals, the relationship between these is bidirectional. The association depression highly co-morbid tends to significantly exacerbate metabolic related depressive symptoms. However, neural mechanism under mutual control of largely inscrutable. This review focuses particularly on alterations in systems that may mechanistically explain vivo homeostatic regulation link, such as immune-inflammatory activation, gut microbiota, neuroplasticity, HPA axis dysregulation well neuroendocrine regulators energy metabolism including adipocytokines lipokines. In addition, summarizes potential future treatments for raises several questions need be answered research. will provide a comprehensive description localization biological connection better understand co-morbidity depression.

Language: Английский

Citations

35
Studying CaMKII: Tools and standards DOI Creative Commons
Carolyn N. Brown, K. Ulrich Bayer

Cell Reports, Journal Year: 2024, Volume and Issue: 43(4), P. 113982 - 113982

Published: March 21, 2024

The Ca2+/calmodulin (CaM)-dependent protein kinase II (CaMKII) is a ubiquitous mediator of cellular Ca2+ signals with both enzymatic and structural functions. Here, we briefly introduce the complex regulation CaMKII then provide comprehensive overview expanding toolbox to study CaMKII. Beyond variety distinct mutants, these tools now include optical methods for measurement manipulation, latter including light-induced inhibition, stimulation, sequestration. Perhaps most importantly, there are three mechanistically classes specific inhibitors, their combined use enables interrogation functions in manner that powerful sophisticated yet also accessible. This review aims guidelines interpretation results obtained tools, careful consideration direct indirect effects.

Language: Английский

Citations

13
Oxygen/glucose-deprivation causes long-term impairment of synaptic CaMKII movement DOI Creative Commons
Olivia R. Buonarati, Nidia Quillinan, K. Ulrich Bayer

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: March 4, 2025

SUMMARY Learning and memory are thought to require hippocampal long-term potentiation (LTP), a form of synaptic plasticity that is persistently impaired after cerebral ischemia requires movement the Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) excitatory synapses. We show here oxygen/glucose-deprivation (OGD) in cultures neurons causes long-lasting impairment CaMKII movement. Notably, inhibition at 30 min onset OGD prevented Thus, mediates both, LTP mechanisms their ischemia-induced impairment. These findings provide mechanism by which ischemic conditions can impair explain how prevent these impairments.

Language: Английский

Citations

1
Role of Ca2+/Calmodulin-Dependent Protein Kinase Type II in Mediating Function and Dysfunction at Glutamatergic Synapses DOI Creative Commons

Archana G. Mohanan,

Sowmya Gunasekaran,

Reena Sarah Jacob

et al.

Frontiers in Molecular Neuroscience, Journal Year: 2022, Volume and Issue: 15

Published: June 20, 2022

Glutamatergic synapses harbor abundant amounts of the multifunctional Ca 2+ /calmodulin-dependent protein kinase type II (CaMKII). Both in postsynaptic density as well cytosolic compartment terminals, CaMKII plays major roles. In addition to its -stimulated activity, it can also bind a variety membrane proteins at synapse and thus exert spatially restricted activity. The abundance glutamatergic is akin scaffolding although prominent function still appears be that kinase. multimeric structure confers several functional capabilities on enzyme. versatility enzyme has prompted hypotheses proposing roles for such signal transduction, memory molecule scaffolding. article will review multiple played by how they are affected disease conditions.

Language: Английский

Citations

32
Distinct phosphorylation states of mammalian CaMKIIβ control the induction and maintenance of sleep DOI Creative Commons

Daisuke Tone,

Koji L. Ode,

Qianhui Zhang

et al.

PLoS Biology, Journal Year: 2022, Volume and Issue: 20(10), P. e3001813 - e3001813

Published: Oct. 4, 2022

The reduced sleep duration previously observed in Camk2b knockout mice revealed a role for Ca 2+ /calmodulin-dependent protein kinase II (CaMKII)β as sleep-promoting kinase. However, the underlying mechanism by which CaMKIIβ supports regulation is largely unknown. Here, we demonstrate that activation or inhibition of can increase decrease almost 2-fold, supporting core regulator mammals. Importantly, show this depends on activity CaMKIIβ. A mutant mimicking constitutive-active (auto)phosphorylation state promotes transition from awake to state, while mutants subsequent multisite states suppress state. These results suggest phosphorylation differently control induction and maintenance processes, leading us propose “phosphorylation hypothesis sleep” molecular

Language: Английский

Citations

32