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Calcium/calmodulin-mediated signaling contributes in diverse roles in plant growth, development, and response to environmental stimuli.

Cardiovascular disease is the major cause of death worldwide. The success of medication and other preventive measures introduced in the last century have not yet halted the epidemic of cardiovascular disease. Although the molecular mechanisms of the pathophysiology of the heart and vessels have been extensively studied, the burden of ischemic cardiovascular conditions has risen to become a top cause of morbidity and mortality. Calcium has important functions in the cardiovascular system. Calcium is involved in the mechanism of excitation–contraction coupling that regulates numerous events, ranging from the production of action potentials to the contraction of cardiomyocytes and vascular smooth muscle cells. Both in the heart and vessels, the rise of intracellular calcium is sensed by calmodulin, a protein that regulates and activates downstream kinases involved in regulating calcium signalling. Among them is the calcium calmodulin kinase family, which is involved in the regulation of cardiac functions. In this review, we present the current literature regarding the role of calcium/calmodulin pathways in the heart and vessels with the aim to summarize our mechanistic understanding of this process and to open novel avenues for research.

Calcium (Ca²⁺) signaling and dynamic reorganization of the cytoskeleton are essential processes for the coordination and control of plant cell shape and cell growth. Calmodulin (CaM) and closely related calmodulin-like (CML) polypeptides are principal sensors of Ca²⁺ signals. CaM/CMLs decode and relay information encrypted by the second messenger via differential interactions with a wide spectrum of targets to modulate their diverse biochemical activities. The plant-specific IQ67 DOMAIN (IQD) family emerged as possibly the largest class of CaM-interacting proteins with undefined molecular functions and biological roles. Here, we show that the 33 members of the IQD family in Arabidopsis (Arabidopsis thaliana) differentially localize, using green fluorescent protein (GFP)-tagged proteins, to multiple and distinct subcellular sites, including microtubule (MT) arrays, plasma membrane subdomains, and nuclear compartments. Intriguingly, the various IQD-specific localization patterns coincide with the subcellular patterns of IQD-dependent recruitment of CaM, suggesting that the diverse IQD members sequester Ca²⁺-CaM signaling modules to specific subcellular sites for precise regulation of Ca²⁺-dependent processes. Because MT localization is a hallmark of most IQD family members, we quantitatively analyzed GFP-labeled MT arrays in Nicotiana benthamiana cells transiently expressing GFP-IQD fusions and observed IQD-specific MT patterns, which point to a role of IQDs in MT organization and dynamics. Indeed, stable overexpression of select IQD proteins in Arabidopsis altered cellular MT orientation, cell shape, and organ morphology. Because IQDs share biochemical properties with scaffold proteins, we propose that IQD families provide an assortment of platform proteins for integrating CaM-dependent Ca²⁺ signaling at multiple cellular sites to regulate cell function, shape, and growth.

Calcium dysregulation (“Calcium Hypothesis”) is an early and critical event in Alzheimer’s and other neurodegenerative diseases. Calcium binds to and regulates the small regulatory protein calmodulin that in turn binds to and regulates several hundred calmodulin binding proteins. Initial and continued research has shown that many calmodulin binding proteins mediate multiple events during the onset and progression of Alzheimer’s disease, thus establishing the “Calmodulin Hypothesis”. To gain insight into the general applicability of this hypothesis, the involvement of calmodulin in neuroinflammation in Alzheimer’s, amyotrophic lateral sclerosis, Huntington’s disease, Parkinson’s disease, frontotemporal dementia, and other dementias was explored. After a literature search for calmodulin binding, 11 different neuroinflammatory proteins (TREM2, CD33, PILRA, CR1, MS4A, CLU, ABCA7, EPHA1, ABCA1, CH3L1/YKL-40 and NLRP3) were scanned for calmodulin binding domains using the Calmodulin Target Database. This analysis revealed the presence of at least one binding domain within which visual scanning demonstrated the presence of valid binding motifs. Coupled with previous research that identified 13 other neuroinflammation linked proteins (BACE1, BIN1, CaMKII, PP2B, PMCA, NOS, NMDAR, AchR, Ado A2AR, Aβ, APOE, SNCA, TMEM175), this work shows that at least 24 critical proteins involved in neuroinflammation are putative or proven calmodulin binding proteins. Many of these proteins are linked to multiple neurodegenerative diseases indicating that calmodulin binding proteins lie at the heart of neuroinflammatory events associated with multiple neurodegenerative diseases. Since many calmodulin-based pharmaceuticals have been successfully used to treat Huntington’s and other neurodegenerative diseases, these findings argue for their immediate therapeutic implementation.

•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.

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.

Plant immune responses activated through the perception of microbe-associated molecular patterns, leading to pattern-triggered immunity, are tightly regulated. This results in low immune responses in the absence of pathogens and a rapid return to the resting state following an activation event. Here, we show that two CALMODULIN-LIKE genes, CML46 and CML47, negatively regulate salicylic acid accumulation and immunity in Arabidopsis (Arabidopsis thaliana). The double mutant cml46 cml47 is highly resistant to the pathogen Pseudomonas syringae pv maculicola (Pma). The effects of cml46 cml47 on Pma growth are genetically additive to that of cbp60a, a known negative regulator in the CALMODULIN-BINDING PROTEIN60 (CBP60) family. Transcriptome profiling revealed the effects of cbp60a and cml46 cml47 on both common and separate sets of genes, with the majorities of these differentially expressed genes being Pma responsive. CBP60g, a positive regulator of immunity in the CBP60 family, was found to be transcriptionally regulated by CBP60a, CML46, and CML47. Analysis of the flg22-induced mRNA levels of CBP60g in cbp60a and cml46 cml47 revealed that cml46 cml47 plants have higher induced expression while cbp60a plants retain elevated levels longer than wild-type plants. Assays for the effect of flg22 treatment on Pma growth showed that the effect is stronger in cml46 cml47 plants and lasts longer in cbp60a plants. Thus, the expression pattern of CBP60g is reflected in flg22-induced resistance to Pma.

Plant growth and development are a genetically predetermined series of events but can change dramatically in response to environmental stimuli, involving perpetual pattern formation and reprogramming of development. The rate of growth is determined by cell division and subsequent cell expansion, which are restricted and controlled by the cell wall–plasma membrane–cytoskeleton continuum, and are coordinated by intricate networks that facilitate intra- and intercellular communication. An essential role in cellular signaling is played by calcium ions, which act as universal second messengers that transduce, integrate, and multiply incoming signals during numerous plant growth processes, in part by regulation of the microtubule cytoskeleton. In this review, we highlight recent advances in the understanding of calcium-mediated regulation of microtubule-associated proteins, their function at the microtubule cytoskeleton, and their potential role as hubs in crosstalk with other signaling pathways.

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.

Dictyostelium discoideum is gaining increasing attention as a model organism for the study of calcium binding and calmodulin function in basic biological events as well as human diseases. After a short overview of calcium-binding proteins, the structure of Dictyostelium calmodulin and the conformational changes effected by calcium ion binding to its four EF hands are compared to its human counterpart, emphasizing the highly conserved nature of this central regulatory protein. The calcium-dependent and -independent motifs involved in calmodulin binding to target proteins are discussed with examples of the diversity of calmodulin binding proteins that have been studied in this amoebozoan. The methods used to identify and characterize calmodulin binding proteins is covered followed by the ways Dictyostelium is currently being used as a system to study several neurodegenerative diseases and how it could serve as a model for studying calmodulinopathies such as those associated with specific types of heart arrythmia. Because of its rapid developmental cycles, its genetic tractability, and a richly endowed stock center, Dictyostelium is in a position to become a leader in the field of calmodulin research.