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Reactive oxygen species (ROS) are not only harmful to cell survival but also essential to cell signaling through cysteine-based redox switches. In fact, ROS triggers the potential activation of mitogen-activated protein kinases (MAPKs). The 90 kDa ribosomal S6 kinase 1 (RSK1), one of the downstream mediators of the MAPK pathway, is implicated in various cellular processes through phosphorylating different substrates. As such, RSK1 associates with and phosphorylates neuronal nitric oxide (NO) synthase (nNOS) at Ser847, leading to a decrease in NO generation. In addition, the RSK1 activity is sensitive to inhibition by reversible cysteine-based redox modification of its Cys223 during oxidative stress. Aside from oxidative stress, nitrosative stress also contributes to cysteine-based redox modification. Thus, the protein kinases such as Ca2+/calmodulin (CaM)-dependent protein kinase I (CaMKI) and II (CaMKII) that phosphorylate nNOS could be potentially regulated by cysteine-based redox modification. In this review, we focus on the role of post-translational modifications in regulating nNOS and nNOS-phosphorylating protein kinases and communication among themselves.

Learning and memory are thought to require hippocampal long-term potentiation (LTP), and one of the few central dogmas of molecular neuroscience that has stood undisputed for more than three decades is that LTP induction requires enzymatic activity of the Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) 1 – 3 . However, as we delineate here, the experimental evidence is surprisingly far from conclusive. All previous interventions inhibiting enzymatic CaMKII activity and LTP 4 – 8 also interfere with structural CaMKII roles, in particular binding to the NMDA-type glutamate receptor subunit GluN2B 9 – 14 . Thus, we here characterized and utilized complementary sets of new opto-/pharmaco-genetic tools to distinguish between enzymatic and structural CaMKII functions. Several independent lines of evidence demonstrated LTP induction by a structural function of CaMKII rather than by its enzymatic activity. The sole contribution of kinase activity was autoregulation of this structural role via T286 autophosphorylation, which explains why this distinction has been elusive for decades. Directly initiating the structural function in a manner that circumvented this T286 role was sufficient to elicit robust LTP, even when enzymatic CaMKII activity was blocked. Several independent lines of evidence demonstrated long-term potentiation induction by a structural function of calmodulin-dependent protein kinase II rather than by its enzymatic activity.

The integral role of calmodulin in the amyloid pathway and neurofibrillary tangle formation in Alzheimer’s disease was first established leading to the “Calmodulin Hypothesis”. Continued research has extended our insight into the central function of the small calcium sensor and effector calmodulin and its target proteins in a multitude of other events associated with the onset and progression of this devastating neurodegenerative disease. Calmodulin’s involvement in the contrasting roles of calcium/CaM-dependent kinase II (CaMKII) and calcineurin (CaN) in long term potentiation and depression, respectively, and memory impairment and neurodegeneration are updated. The functions of the proposed neuronal biomarker neurogranin, a calmodulin binding protein also involved in long term potentiation and depression, is detailed. In addition, new discoveries into calmodulin’s role in regulating glutamate receptors (mGluR, NMDAR) are overviewed. The interplay between calmodulin and amyloid beta in the regulation of PMCA and ryanodine receptors are prime examples of how the buildup of classic biomarkers can underly the signs and symptoms of Alzheimer’s. The role of calmodulin in the function of stromal interaction molecule 2 (STIM2) and adenosine A2A receptor, two other proteins linked to neurodegenerative events, is discussed. Prior to concluding, an analysis of how targeting calmodulin and its binding proteins are viable routes for Alzheimer’s therapy is presented. In total, calmodulin and its binding proteins are further revealed to be central to the onset and progression of Alzheimer’s disease.

Plants have developed elaborate mechanisms for perceiving extracellular stimuli and subsequently activating defense reactions through a multifaceted interaction of signaling cascades. Calcium ion (Ca²⁺), an essential and ubiquitous intracellular second messenger molecules, whose concentration ([Ca 2+ ]cyt) has been observed to rise in response to numerous environmental stresses. The calcium/calmodulin (Ca²⁺/CaM) complex triggers apposite cellular responses through modifying the activities of a varied array of CaM-binding proteins (CBPs). Among CBPs , the CBP60 gene family has been identified as key regulators of stress responses in several crop species. Recently, we have demonstrated the expanded and diversified role of OsCBP60 in rice against devastating pathogens. Here, we analyzed the diversified roles of OsCBP60s in two major abiotic stresses, namely reproductive drought and submergence stress. OsCBP60bcd -2 and OsCBP60g-1/OsSARD1 were consistently upregulated during reproductive drought stress in rice. However, OsCBP60g-5 and OsCBP60g-6 were steadily up-regulated under submergence stress in rice. Interestingly, OsCBP60g-4 was consistently upregulated in both abiotic stresses, except on the third day of reproductive drought. The differential expression of OsCBP60s under water stress highlights the importance of further studying these genes as potential targets for enhancing stress resilience in rice.

Calcium/calmodulin-dependent kinase II (CaMKII) plays a key role in the plasticity of dendritic spines. Calcium signals cause calcium−calmodulin to activate CaMKII, which leads to remodeling of the actin filament (F-actin) network in the spine. We elucidate the mechanism of the remodeling by combining computer simulations with protein array experiments and electronmicroscopic imaging, to arrive at a structural model for the dodecameric complex of CaMKII with F-actin. The binding interface involves multiple domains of CaMKII. This structure explains the architecture of the micrometer-scale CaMKII/F-actin bundles arising from the multivalence of CaMKII. We also show that the regulatory domain of CaMKII may bind either calmodulin or F-actin, but not both. This frustration, along with the multipartite nature of the binding interface, allows calmodulin transiently to strip CaMKII from actin assemblies so that they can reorganize. This observation therefore provides a simple mechanism by which the structural dynamics of CaMKII establishes the link between calcium signaling and the morphological plasticity of dendritic spines.

•Engineered protein switches are increasingly used in molecular diagnostics.•Engineered protein switches can be used to sense and actuate cellular functions.•Empirical design rules to construct tailor-engineered protein switches are emerging.•Future synthetic signaling circuits will see networks of engineered protein switches. Protein switches are ubiquitous in biological signal transduction systems, enabling cells to sense and respond to a variety of molecular queues in a rapid, specific, and integrated fashion. Analogously, tailor-engineered protein switches with custom input and output functions have become invaluable research tools for reporting on distinct physiological states and actuating molecular functions in real time and in situ. Here, we analyze recent progress in constructing protein-based switches while assessing their potential in the assembly of defined signaling motifs. We anticipate such systems will ultimately pave the way towards a new generation of molecular diagnostics and facilitate the construction of artificial signaling systems that operate in parallel to the signaling machinery of a host cell for applications in synthetic biology.

[This corrects the article DOI: 10.1371/journal.pcbi.1010263.].

Transient information input to the brain leads to persistent changes in synaptic circuits, contributing to the formation of memory engrams. Pre- and postsynaptic structures undergo coordinated functional and structural changes during this process, but how such changes are achieved by their component molecules remains largely unknown. We found that activated CaMKII, a central player of synaptic plasticity, undergoes liquid–liquid phase separation with the NMDA-type glutamate receptor subunit GluN2B. Due to CaMKII autophosphorylation, the condensate stably persists even after Ca 2+ is removed. The selective binding of activated CaMKII with GluN2B cosegregates AMPA receptors and the synaptic adhesion molecule neuroligin into a phase-in-phase assembly. In this way, Ca 2+ -induced liquid–liquid phase separation of CaMKII has the potential to act as an activity-dependent mechanism to crosslink postsynaptic proteins, which may serve as a platform for synaptic reorganization associated with synaptic plasticity. The authors find that calcium signaling triggers liquid–liquid phase separation of CaMKII. This reorganizes the postsynaptic structure, acting as a potential mechanism to increase the efficacy of synaptic transmission during memory formation.

In the cardiomyocyte, CaMKII has been identified as a nodal influencer of excitation–contraction and also excitation–transcription coupling. Its activity can be regulated in response to changes in intracellular calcium content as well as after several post-translational modifications. Some of the effects mediated by CaMKII may be considered adaptive, while effects of sustained CaMKII activity may turn into the opposite and are detrimental to cardiac integrity and function. As such, CaMKII has long been noted as a promising target for pharmacological inhibition, but the ubiquitous nature of CaMKII has made it difficult to target CaMKII specifically where it is detrimental. In this review, we provide a brief overview of the physiological and pathophysiological properties of CaMKII signaling, but we focus on the physiological and adaptive functions of CaMKII. Furthermore, special consideration is given to the emerging role of CaMKII as a mediator of inflammatory processes in the heart.

Salicylic acid (SA) and pipecolic acid (Pip) play important roles in plant immunity. Here we analyzed the roles of transcription factors TGACG-BINDING FACTOR 1 (TGA1) and TGA4 in regulating SA and Pip biosynthesis in Arabidopsis thaliana. We quantified the expression levels of SYSTEMIC ACQUIRED RESISTANCE DEFICIENT 1 (SARD1) and CALMODULIN-BINDING PROTEIN 60g (CBP60g), which encode two master transcription factors of plant immunity, and the accumulation of SA and Pip in tga1-1 tga4-1 mutant plants. We tested whether SARD1 and CBP60g are direct targets of TGA1 by chromatin immunoprecipitation–polymerase chain reaction (ChIP-PCR). In addition to promoting pathogen-induced SA biosynthesis, we found that SARD1 and CBP60g also positively regulated Pip biosynthesis by targeting genes encoding key biosynthesis enzymes of Pip. TGA1/TGA4 were required for full induction of SARD1 and CBP60g in plant defense. ChIP-PCR analysis showed that SARD1 was a direct target of TGA1. In tga1-1 tga4-1 mutant plants, the expression levels of SARD1 and CBP60g along with SA and Pip accumulation following pathogen infection were dramatically reduced compared with those in wild-type plants. Consistent with reduced expression of SARD1 and CBP60g, pathogen-associated molecular pattern (PAMP)-induced pathogen resistance and systemic acquired resistance were compromised in tga1-1 tga4-1. Our study showed that TGA1 and TGA4 regulate Pip and SA biosynthesis by modulating the expression of SARD1 and CBP60g.