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Physical exercise may improve cognitive function by modulating molecular and cellular mechanisms within the brain. We propose that the facilitation of long-term synaptic potentiation (LTP)-related pathways, by products induced by physical exercise (i.e., exerkines), is a crucial aspect of the exercise-effect on the brain. This review summarizes synaptic pathways that are activated by exerkines and may potentiate LTP. For a total of 16 exerkines, we indicated how blood and brain exerkine levels are altered depending on the type of physical exercise (i.e., cardiovascular or resistance exercise) and how they respond to a single bout (i.e., acute exercise) or multiple bouts of physical exercise (i.e., chronic exercise). This information may be used for designing individualized physical exercise programs. Finally, this review may serve to direct future research towards fundamental gaps in our current knowledge regarding the biophysical interactions between muscle activity and the brain at both cellular and system levels.

Physical exercise may improve cognitive function by modulating molecular and cellular mechanisms within the brain. We propose that the facilitation of long-term synaptic potentiation (LTP)-related pathways, by products induced by physical exercise (i.e., exerkines), is a crucial aspect of the exercise-effect on the brain. This review summarizes synaptic pathways that are activated by exerkines and may potentiate LTP. For a total of 16 exerkines, we indicated how blood and brain exerkine levels are altered depending on the type of physical exercise (i.e., cardiovascular or resistance exercise) and how they respond to a single bout (i.e., acute exercise) or multiple bouts of physical exercise (i.e., chronic exercise). This information may be used for designing individualized physical exercise programs. Finally, this review may serve to direct future research towards fundamental gaps in our current knowledge regarding the biophysical interactions between muscle activity and the brain at both cellular and system levels. ispartof: Frontiers In Neuroendocrinology vol:66 ispartof: location:United States status: Published online

Everyday memories are retained automatically in the hippocampus and then decay very rapidly. Memory retention can be boosted when novel experiences occur shortly before or shortly after the time of memory encoding via a memory stabilization process called "initial memory consolidation." The dopamine release and new protein synthesis in the hippocampus during a novel experience are crucial for this novelty-induced memory boost. The mechanisms underlying initial memory consolidation are not well-understood, but the synaptic tagging and capture (STC) hypothesis provides a conceptual basis of synaptic plasticity events occurring during initial memory consolidation. In this review, we provide an overview of the STC hypothesis and its relevance to dopaminergic signalling, in order to explore the cellular and molecular mechanisms underlying initial memory consolidation in the hippocampus. We summarize electrophysiological STC processes based on the evidence from two-pathway experiments and a behavioural tagging hypothesis, which translates the STC hypothesis into a related behavioural hypothesis. We also discuss the function of two types of molecules, "synaptic tags" and "plasticity-related proteins," which have a crucial role in the STC process and initial memory consolidation. We describe candidate molecules for the roles of synaptic tag and plasticity-related proteins and interpret their candidacy based on evidence from two-pathway experiments ex vivo, behavioural tagging experiments in vivo and recent cutting-edge optical imaging experiments. Lastly, we discuss the direction of future studies to advance our understanding of molecular mechanisms underlying the STC process, which are critical for initial memory consolidation in the hippocampus.

Calcium (Ca2+) plays a central role in cardiomyocyte excitation-contraction coupling. To ensure an optimal electrical impulse propagation and cardiac contraction, Ca2+ levels are regulated by a variety of Ca2+-handling proteins. In turn, Ca2+ modulates numerous electrophysiological processes. Accordingly, Ca2+-handling abnormalities can promote cardiac arrhythmias via various mechanisms, including the promotion of afterdepolarizations, ion-channel modulation and structural remodeling. In the last 30 years, significant improvements have been made in the computational modeling of cardiomyocyte Ca2+ handling under physiological and pathological conditions. However, numerous questions involving the Ca2+-dependent regulation of different macromolecular complexes, cross-talk between Ca2+-dependent regulatory pathways operating over a wide range of time scales, and bidirectional interactions between electrophysiology and mechanics remain to be addressed by in vitro and in silico studies. A better understanding of disease-specific Ca2+-dependent proarrhythmic mechanisms may facilitate the development of improved therapeutic strategies. In this review, we describe the fundamental mechanisms of cardiomyocyte Ca2+ handling in health and disease, and provide an overview of currently available computational models for cardiomyocyte Ca2+ handling. Finally, we discuss important uncertainties and open questions about cardiomyocyte Ca2+ handling and highlight how synergy between in vitro and in silico studies may help to answer several of these issues.

Deletion of Ca2+/calmodulin-dependent protein kinase II delta (CaMKII delta) has been shown to protect against in vivo ischemia/reperfusion (I/R) injury. It remains unclear which CaMKII delta isoforms and downstream mechanisms are responsible for the salutary effects of CaMKII delta gene deletion. In this study we sought to compare the roles of the CaMKII delta(B) and CaMKII delta(C) subtypes and the mechanisms by which they contribute to ex vivo I/R damage. WT, CaMKII delta KO, and mice expressing only CaMKII delta(B) or delta(C) were subjected to ex vivo global ischemia for 25 min followed by reperfusion. Infarct formation was assessed at 60 min reperfusion by triphenyl tetrazolium chloride (TTC) staining. Deletion of CaMKII delta conferred significant protection from ex vivo I/R. Re-expression of CaMKII delta(C) in the CaMKII delta KO background reversed this effect and exacerbated myocardial damage and dysfunction following I/R, while re-expression of CaMKII delta(B) was protective. Selective activation of CaMKII delta(C) in response to I/R was evident in a subcellular fraction enriched for cytosolic/membrane proteins. Further studies demonstrated differential regulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappa B) signaling and tumor necrosis factor alpha (TNF-alpha) expression by CaMKII delta(B) and CaMKII8c. Selective activation of CaMKII delta(C) was also observed and associated with NF-kappa B activation in neonatal rat ventricular myocytes (NRVMs) subjected to oxidative stress. Pharmacological inhibition of NF-kappa B or TNF-alpha significantly ameliorated infarct formation in WT mice and those that re-express CaMKII8c, demonstrating distinct roles for CaMKII delta subtypes in I/R and implicating acute activation of CaMKII delta(C) and NF-kappa B in the pathogenesis of reperfusion injury. (C) 2017 Published by Elsevier Ltd.

Introduction: Calcium-calmodulin-dependent protein kinase II (CaMKII) has emerged as a central mediator of cardiac stress responses which may serve several critical roles in the regulation of cardiac rhythm, cardiac contractility and growth. Sustained and excessive activation of CaMKII during cardiac disease has, however, been linked to arrhythmias, and maladaptive cardiac remodeling, eventually leading to heart failure (HF) and sudden cardiac death.Areas covered: In the current review, the authors describe the unique structural and biochemical properties of CaMKII and focus on its physiological effects in cardiomyocytes. Furthermore, they provide evidence for a role of CaMKII in cardiac pathologies, including arrhythmogenesis, myocardial ischemia and HF development. The authors conclude by discussing the potential for CaMKII as a target for inhibition in heart disease.Expert opinion: CaMKII provides a promising nodal point for intervention that may allow simultaneous prevention of HF progression and development of arrhythmias. For future studies and drug development there is a strong rationale for the development of more specific CaMKII inhibitors. In addition, an improved understanding of the differential roles of CaMKII subtypes is required.

Variations in the gene encoding for the major sodium channel (Na v 1.5) in the heart, SCN5A, has been shown to cause a number of arrhythmia syndromes (with or without structural changes in the myocardium), including the long-QT syndrome (type 3), Brugada syndrome, (progressive) cardiac conduction disease, sinus node dysfunction, atrial fibrillation, atrial standstill, and dilated cardiomyopathy. Of equal importance are variations in genes encoding for various subunits and regulatory proteins interacting with the α-subunit Na v 1.5 and modifying its function. Based on detailed studies of genotype–phenotype relationships in these disease entities, on detailed studies of the basic electrophysiological phenotypes (heterologous expressed wild-type and mutant sodium channels and their interacting proteins), and on attempts to integrate the obtained knowledge, the past 15 years has witnessed an explosion of knowledge about these disease entities.

The glycerophosphoinositols are diffusible phosphoinositide metabolites reported to modulate actin dynamics and tumour cell spreading. In particular, the membrane permeant glycerophosphoinositol 4-phosphate (GroPIns4P) has been shown to act at the level of the small GTPase Rac1, to induce the rapid formation of membrane ruffles. Here, we have investigated the signalling cascade involved in this process, and show that it is initiated by the activation of Src kinase. In NIH3T3 cells, exogenous addition of GroPIns4P induces activation and translocation of Rac1 and its exchange factor TIAM1 to the plasma membrane; in addition, in in-vitro assays, GroPIns4P favours the formation of a protein complex that includes Rac1 and TIAM1. Neither of these processes involves direct actions of GroPIns4P on these proteins. Thus, through the use of specific inhibitors of tyrosine kinases and phospholipase C (and by direct evaluation of kinase activities and inositol 1,4,5-trisphosphate production), we show that GroPIns4P activates Src, and as a consequence, phospholipase Cγ and Ca2+/calmodulin kinase II, the last of which directly phosphorylates TIAM1 and leads to TIAM1/Rac1-dependent ruffle formation.

The Heart Rhythm Society convened a research symposium on December 9–10, 2013, in Washington, DC, that focused on the prevention of atrial fibrillation (AF) as well as AF-related stroke and morbidity. Attendees sought to summarize advances in understanding AF since a 2008 National Institutes of Health (NIH) conference on this topic1 and to identify continued knowledge gaps and current research priorities. The research symposium also sought to identify key deficiencies and opportunities in research infrastructure, operations, and methodologies. The committee sought to identify both basic research targets and how clinical AF research could be improved in the current health care environment. This whitepaper summarizes our deliberations in an effort to accelerate progress toward preventing AF and its consequences. Although largely focused on primary prevention of AF, the paper also addresses some aspects of secondary prevention of recurrent AF due to the continuum of risk factors that contribute to arrhythmogenesis, permissive left atrial (LA) substrates, and the emergence of AF.

Cellular responses to Ca2+ require intermediary proteins such as calcium/calmodulin-dependent protein kinase II (CaMKII), which transduces the signal into downstream effects. We recently demonstrated that the cockroach genome encodes five different CaMKII isoforms, and only PaCaMKII-E isoform is specifically expressed in the dorsal unpaired median neurosecretory cells. In the present study, using antisense oligonucleotides, we demonstrated that PaCaMKII-E isoform inhibition reduced nicotine-induced currents through α-bungarotoxin-sensitive and -insensitive nicotinic acetylcholine receptor subtypes. Specifically, PaCaMKII-E isoform is sufficient to repress nicotinic current amplitudes as a result of its depression by antisense oligonucleotides. Similar results were found using the neonicotinoid insecticide clothianidin, which acted as a full agonist of dorsal unpaired median neuron nicotinic acetylcholine receptors. Clothianidin current amplitudes are strongly reduced under bath application of PaCaMKII-E antisense oligonucleotides but no significant results are found with α-bungarotoxin co-applied, demonstrating that CaMKII-E isoform affects nicotine currents through α-bungarotoxin-sensitive and -insensitive receptor subtypes whereas clothianidin currents are reduced via α-bungarotoxin-insensitive receptors. In addition, we found that intracellular calcium increase induced by nicotine and clothianidin were reduced by PaCaMKII-E antisense oligonucleotides, demonstrating that intracellular calcium increase induced by nicotine and clothianidin are affected by PaCaMKII-E inhibition. Cellular responses to Ca2+ require intermediary proteins such as calcium/calmodulin-dependent protein kinase II (CaMKII). We recently demonstrated that the cockroach genome encodes five different CaMKII isoforms and only PaCaMKII-E isoform was specifically expressed in the dorsal unpaired median neurosecretory cells. Here we show that specific inhibition of PaCaMKII-E isoform is associated with a decrease in nicotine- and clothianidin-induced currents. In addition, analysis of calcium changes demonstrates that PaCaMKII-E inhibition induces a decrease in intracellular calcium concentration.

Introduction: Calcium-calmodulin-dependent protein kinase II (CaMKII) has emerged as a central mediator of cardiac stress responses which may serve several critical roles in the regulation of cardiac rhythm, cardiac contractility and growth. Sustained and excessive activation of CaMKII during cardiac disease has, however, been linked to arrhythmias, and maladaptive cardiac remodeling, eventually leading to heart failure (HF) and sudden cardiac death. Areas covered: In the current review, the authors describe the unique structural and biochemical properties of CaMKII and focus on its physiological effects in cardiomyocytes. Furthermore, they provide evidence for a role of CaMKII in cardiac pathologies, including arrhythmogenesis, myocardial ischemia and HF development. The authors conclude by discussing the potential for CaMKII as a target for inhibition in heart disease. Expert opinion: CaMKII provides a promising nodal point for intervention that may allow simultaneous prevention of HF progression and development of arrhythmias. For future studies and drug development there is a strong rationale for the development of more specific CaMKII inhibitors. In addition, an improved understanding of the differential roles of CaMKII subtypes is required.

Since the beginnings of domestication, the craniofacial architecture of the domestic dog has morphed and radiated to human whims. By beginning to define the genetic underpinnings of breed skull shapes, we can elucidate mechanisms of morphological diversification while presenting a framework for understanding human cephalic disorders. Using intrabreed association mapping with museum specimen measurements, we show that skull shape is regulated by at least five quantitative trait loci (QTLs). Our detailed analysis using whole-genome sequencing uncovers a missense mutation in BMP3. Validation studies in zebrafish show that Bmp3 function in cranial development is ancient. Our study reveals the causal variant for a canine QTL contributing to a major morphologic trait., Author Summary As a result of selective breeding practices, modern dogs display a multitude of head shapes. Breeds such as the Pug and Bulldog popularize one of these morphologies, termed “brachycephaly.” A short, upward-pointing snout, a massive and rounded head, and an underbite typify brachycephalic breeds. Here, we have coupled the phenotypes collected from museum skulls with the genotypes collected from dogs and identified five regions of the dog genome that are associated with canine brachycephaly. Fine mapping at one of these regions revealed a causal mutation in the gene BMP3. Bmp3's role in regulating cranial development is evolutionarily ancient, as zebrafish require its function to generate a normal craniofacial morphology. Our data begin to expose the genetic mechanisms unknowingly employed by breeders to create and diversify the cranial shape of dogs.

Background and aims: The present study was designed to investigate the effects of a novel CaMKII inhibitor SMP-114, which was effective in a collagen-induced arthritis model in rats, on rheumatoid synovial fibroblasts. Methods: Rheumatoid synovial fibroblasts (RSF) were cultured under pro-inflammatory (IL-1 beta stimulation) and hypoxic conditions. Protein and mRNA expression of HIF-1 alpha and the effects of inhibitors of the CaMKII-, PI3K-, and ERK pathway on VEGF and IL-6 production were analyzed. Results: Stimulation under hypoxic conditions induced higher expression of HIF-1 alpha and VEGF mRNA than treatment with either IL-1 beta or hypoxia alone. However, incubation with a specific CaMKII inhibitor did not result in reduced VEGF production in RSF. Conclusions: CaMKII activation has been reported to be involved in HIF-1 alpha stabilization, but incubation with SMP-114, a specific CaMKII inhibitor, had no effect on HIF-1-induced VEGF production by rheumatoid synovial fibroblasts.

In astrocytes, the PGF(2 alpha) or ionomycin treatment induces the phosphorylation at Ser38 and Ser82 of vimentin, a type III intermediate filament, by Ca2+/calmodulin-dependent protein kinase II (CaMKII). We found here that vimentin phospho-Ser82 was dephosphorylated much slower than phospho-Ser38. Vimentin phospho-Ser38 was dephosphorylated quickly by purified PP1 catalytic subunit (PP1c) in vitro, whereas phospho-Ser82 was insensitive to PP1c. Because PP1c directly bound to vimentin through a VxF motif (Val83-Asp84-Phe85), the PP1c active site appeared to be unable to approach phospho-Ser82, leading to the prolongation of the phosphorylation at Ser-82. In astrocytes, PP1c alpha was in vivo associated with vimentin filaments. The repetitive treatment by ionomycin at a short interval resulted in the sustained elevation of Ser82 phosphorylation, leading to the marked disassembly of vimentin filaments. Taken together, these results suggest that vimentin is a novel member of binding partner of PP1c in astrocytes, and vimentin-Ser82 may act as a memory phosphorylation site.

This review will be focused on the functional studies which have outlined the role played by synapsins in the regulation of neurotransmitter release.