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Summary 275 I. Introduction 276 II. Ca²⁺ signalling pathways 276 III. Shaping Ca²⁺ signatures 278 IV. Ca²⁺ influx channels 278 V. Ca²⁺ influx channels as modulators of Ca²⁺ signatures 281 VI. Ca²⁺ efflux transporters 282 VII. Ca²⁺ efflux transporters as modulators of Ca²⁺ signatures 284 VIII. The shaping of noncytosolic Ca²⁺ signatures 285 IX. Future insights into the role of Ca²⁺ oscillators from modelling studies 287 X. Conclusions and perspectives 288 Acknowledgements 288 References 288 In numerous plant signal transduction pathways, Ca²⁺ is a versatile second messenger which controls the activation of many downstream actions in response to various stimuli. There is strong evidence to indicate that information encoded within these stimulus-induced Ca²⁺ oscillations can provide signalling specificity. Such Ca²⁺ signals, or 'Ca²⁺ signatures', are generated in the cytosol, and in noncytosolic locations including the nucleus and chloroplast, through the coordinated action of Ca²⁺ influx and efflux pathways. An increased understanding of the functions and regulation of these various Ca²⁺ transporters has improved our appreciation of the role these transporters play in specifically shaping the Ca²⁺ signatures. Here we review the evidence which indicates that Ca²⁺ channel, Ca²⁺-ATPase and Ca²⁺ exchanger isoforms can indeed modulate specific Ca²⁺ signatures in response to an individual signal.

Abstract Primary age-related tauopathy (PART) is a neurodegenerative entity defined as Alzheimer-type neurofibrillary degeneration primarily affecting the medial temporal lobe with minimal to absent amyloid-β (Aβ) plaque deposition. The extent to which PART can be differentiated pathoanatomically from Alzheimer disease (AD) is unclear. Here, we examined the regional distribution of tau pathology in a large cohort of postmortem brains (n = 914). We found an early vulnerability of the CA2 subregion of the hippocampus to neurofibrillary degeneration in PART, and semiquantitative assessment of neurofibrillary degeneration in CA2 was significantly greater than in CA1 in PART. In contrast, subjects harboring intermediate-to-high AD neuropathologic change (ADNC) displayed relative sparing of CA2 until later stages of their disease course. In addition, the CA2/CA1 ratio of neurofibrillary degeneration in PART was significantly higher than in subjects with intermediate-to-high ADNC burden. Furthermore, the distribution of tau pathology in PART diverges from the Braak NFT staging system and Braak stage does not correlate with cognitive function in PART as it does in individuals with intermediate-to-high ADNC. These findings highlight the need for a better understanding of the contribution of PART to cognitive impairment and how neurofibrillary degeneration interacts with Aβ pathology in AD and PART.

The consolidation of spatial memory depends on the reactivation (‘replay’) of hippocampal place cells that were active during recent behaviour. Such reactivation is observed during sharp-wave ripples (SWRs)—synchronous oscillatory electrical events that occur during non-rapid-eye-movement (non-REM) sleep 1 – 8 and whose disruption impairs spatial memory 3 , 5 , 6 , 8 . Although the hippocampus also encodes a wide range of non-spatial forms of declarative memory, it is not yet known whether SWRs are necessary for such memories. Moreover, although SWRs can arise from either the CA3 or the CA2 region of the hippocampus 7 , 9 , the relative importance of SWRs from these regions for memory consolidation is unknown. Here we examine the role of SWRs during the consolidation of social memory—the ability of an animal to recognize and remember a member of the same species—focusing on CA2 because of its essential role in social memory 10 – 12 . We find that ensembles of CA2 pyramidal neurons that are active during social exploration of previously unknown conspecifics are reactivated during SWRs. Notably, disruption or enhancement of CA2 SWRs suppresses or prolongs social memory, respectively. Thus, SWR-mediated reactivation of hippocampal firing related to recent experience appears to be a general mechanism for binding spatial, temporal and sensory information into high-order memory representations, including social memory. Social memory is consolidated in the brain through the reactivation of neuronal firing by sharp-wave ripples in the CA2 region of the hippocampus, in a similar way to the consolidation of spatial memory.

Calcium (Ca 2+ ) serves as a ubiquitous second messenger by mediating various signaling pathways and responding to numerous environmental conditions in eukaryotes. Therefore, plant cells have developed complex mechanisms of Ca 2+ communication across the membrane, receiving the message from their surroundings and transducing the information into cells and organelles. A wide range of biotic and abiotic stresses cause the increase in [Ca 2+ ] cyt as a result of the Ca 2+ influx permitted by membrane-localized Ca 2+ permeable cation channels such as C YCLIC N UCLEOTIDE- G ATE C HANNELs (CNGCs), and voltage-dependent H YPERPOLARIZATION- A CTIVATED C ALCIUM 2+ PERMEABLE C HANNELs (HACCs), as well as G LUTAMATE RECEPTOR- L IKE R ECEPTORs (GLRs) and T WO- P ORE C HANNELs (TPCs). Recently, resistosomes formed by some N UCLEOTIDE-BINDING L EUCINE-RICH R EPEAT RECEPTORs (NLRs) are also proposed as a new type of Ca 2+ permeable cation channels. On the contrary, some Ca 2+ transporting membrane proteins, mainly Ca 2+ -ATPase and Ca 2+ /H + exchangers, are involved in Ca 2+ efflux for removal of the excessive [Ca 2+ ] cyt in order to maintain the Ca 2+ homeostasis in cells. The Ca 2+ efflux mechanisms mediate the wide ranges of cellular activities responding to external and internal stimuli. In this review, we will summarize and discuss the recent discoveries of various membrane proteins involved in Ca 2+ influx and efflux which play an essential role in fine-tuning the processing of information for plant responses to abiotic and biotic stresses.

The ability to recognize information that is incongruous with previous experience is critical for survival. Novelty signals have therefore evolved in the mammalian brain to enhance attention, perception and memory 1 , 2 . Although the importance of regions such as the ventral tegmental area 3 , 4 and locus coeruleus 5 in broadly signalling novelty is well-established, these diffuse monoaminergic transmitters have yet to be shown to convey specific information on the type of stimuli that drive them. Whether distinct types of novelty, such as contextual and social novelty, are differently processed and routed in the brain is unknown. Here we identify the supramammillary nucleus (SuM) as a novelty hub in the hypothalamus 6 . The SuM region is unique in that it not only responds broadly to novel stimuli, but also segregates and selectively routes different types of information to discrete cortical targets—the dentate gyrus and CA2 fields of the hippocampus—for the modulation of mnemonic processing. Using a new transgenic mouse line, SuM-Cre, we found that SuM neurons that project to the dentate gyrus are activated by contextual novelty, whereas the SuM–CA2 circuit is preferentially activated by novel social encounters. Circuit-based manipulation showed that divergent novelty channelling in these projections modifies hippocampal contextual or social memory. This content-specific routing of novelty signals represents a previously unknown mechanism that enables the hypothalamus to flexibly modulate select components of cognition. The supramammillary nucleus in the hypothalamus acts as a novelty hub that selectively directs different types of novelty signals to different subregions of the hippocampus and flexibly modulates the encoding of memory.

Interstitial cells of Cajal (ICC) generate pacemaker activity responsible for phasic contractions in colonic segmentation and peristalsis. ICC along the submucosal border (ICC-SM) contribute to mixing and more complex patterns of colonic motility. We show the complex patterns of Ca 2+ signaling in ICC-SM and the relationship between ICC-SM Ca 2+ transients and activation of smooth muscle cells (SMCs) using optogenetic tools. ICC-SM displayed rhythmic firing of Ca 2+ transients ~ 15 cpm and paced adjacent SMCs. The majority of spontaneous activity occurred in regular Ca 2+ transients clusters (CTCs) that propagated through the network. CTCs were organized and dependent upon Ca 2+ entry through voltage-dependent Ca 2+ conductances, L- and T-type Ca 2+ channels. Removal of Ca 2+ from the external solution abolished CTCs. Ca 2+ release mechanisms reduced the duration and amplitude of Ca 2+ transients but did not block CTCs. These data reveal how colonic pacemaker ICC-SM exhibit complex Ca 2+- firing patterns and drive smooth muscle activity and overall colonic contractions.

Transient cytosolic calcium ([Ca(2+)](cyt)) elevation is an ubiquitous denominator of the signaling network when plants are exposed to literally every known abiotic and biotic stress. These stress-induced [Ca(2+)](cyt) elevations vary in magnitude, frequency, and shape, depending on the severity of the stress as well the type of stress experienced. This creates a unique stress-specific calcium \"signature\" that is then decoded by signal transduction networks. While most published papers have been focused predominantly on the role of Ca(2+) influx mechanisms to shaping [Ca(2+)](cyt) signatures, restoration of the basal [Ca(2+)](cyt) levels is impossible without both cytosolic Ca(2+) buffering and efficient Ca(2+) efflux mechanisms removing excess Ca(2+) from cytosol, to reload Ca(2+) stores and to terminate Ca(2+) signaling. This is the topic of the current review. The molecular identity of two major types of Ca(2+) efflux systems, Ca(2+)-ATPase pumps and Ca(2+)/H(+) exchangers, is described, and their regulatory modes are analyzed in detail. The spatial and temporal organization of calcium signaling networks is described, and the importance of existence of intracellular calcium microdomains is discussed. Experimental evidence for the role of Ca(2+) efflux systems in plant responses to a range of abiotic and biotic factors is summarized. Contribution of Ca(2+)-ATPase pumps and Ca(2+)/H(+) exchangers in shaping [Ca(2+)](cyt) signatures is then modeled by using a four-component model (plasma- and endo-membrane-based Ca(2+)-permeable channels and efflux systems) taking into account the cytosolic Ca(2+) buffering. It is concluded that physiologically relevant variations in the activity of Ca(2+)-ATPase pumps and Ca(2+)/H(+) exchangers are sufficient to fully describe all the reported experimental evidence and determine the shape of [Ca(2+)](cyt) signatures in response to environmental stimuli, emphasizing the crucial role these active efflux systems play in plant adaptive responses to environment.

In airway smooth muscle, the intracellular basal Ca2+ concentration [b(Ca2+)i] must be tightly regulated by several mechanisms in order to maintain a proper airway patency. The b[Ca2+]i is efficiently regulated by sarcoplasmic reticulum Ca2+-ATPase 2b, plasma membrane Ca2+-ATPase 1 or 4 and by the Na+/Ca2+ exchanger. Membranal Ca2+ channels, including the L-type voltage dependent Ca2+ channel (L-VDCC), T-type voltage dependent Ca2+ channel (T-VDCC) and transient receptor potential canonical 3 (TRPC3), appear to be constitutively active under basal conditions via the action of different signaling pathways, and are responsible for Ca2+ influx to maintain b[Ca2+]i. The two types of voltage-dependent Ca2+ channels (L- and T-type) are modulated by phosphorylation processes mediated by mitogen-activated protein kinase kinase (MEK) and extracellular-signal-regulated kinase 1 and 2 (ERK1/2). The MEK/ERK signaling pathway can be activated by G-protein-coupled receptors through the αq subunit when the endogenous ligand (i.e., acetylcholine, histamine, leukotrienes, etc.) is present under basal conditions. It may also be stimulated when receptor tyrosine kinases are occupied by the appropriate ligand (cytokines, growth factors, etc.). ERK1/2 phosphorylates L-VDCC on Ser496 of the β2 subunit and Ser1928 of the α1 subunit, decreasing or increasing the channel activity, respectively, and enabling it to switch between an open and closed state. T-VDCC is also probably phosphorylated by ERK1/2, although further research is required to identify the phosphorylation sites. TRPC3 is directly activated by diacylglycerol produced by phospholipase C (PLCβ or γ). Constitutive inositol 1,4,5-trisphosphate production induces the release of Ca2+ from the sarcoplasmic reticulum through inositol triphosphate receptor 1. This ion induces Ca2+-induced Ca2+ release through the ryanodine receptor 2 (designated as Ca2+ 'sparks'). Therefore, several Ca2+ handling mechanisms are finely tuned to regulate basal intracellular Ca2+ concentrations. It is conceivable that alterations in any of these processes may render airway smooth muscle susceptible to develop hyperresponsiveness that is observed in ailments such as asthma.

Calcium is an essential structural, metabolic and signalling element. The physiological functions of Ca2+ are enabled by its orchestrated transport across cell membranes, mediated by Ca2+-permeable ion channels,Ca2+-ATPases andCa2+/H+ exchangers. Bioinformatics analysis has not determined any Ca2+-selective filters in plant ion channels, but electrophysiological tests do reveal Ca2+ conductances in plant membranes. The biophysical characteristics of plant Ca2+ conductances have been studied in detail and were recently complemented by molecular genetic approaches. Plant Ca2+ conductances are mediated by several families of ion channels, including cyclic nucleotide-gated channels (CNGCs), ionotropic glutamate receptors, two-pore channel 1 (TPC1), annexins and several types of mechanosensitive channels. Key Ca2+-mediated reactions (e.g. sensing of temperature, gravity, touch and hormones, and cell elongation and guard cell closure) have now been associated with the activities of specific subunits from these families. Structural studies have demonstrated a unique selectivity filter in TPC1, which is passable for hydrated divalent cations. The hypothesis of a ROS-Ca2+ hub is discussed, linking Ca2+ transport to ROS generation. CNGC inactivation by cytosolic Ca2+, leading to the termination of Ca2+ signals, is now mechanistically explained. The structure–function relationships of Ca2+-ATPases and Ca2+/H+ exchangers, and their regulation and physiological roles are analysed.

Allium vegetables such as garlic (Allium sativum L.) are rich in organosulfur compounds that prevent human chronic diseases, including cancer. Of these, diallyl trisulfide (DATS) exhibits anticancer effects against a variety of tumors, including malignant melanoma. Although previous studies have shown that DATS increases intracellular calcium (Ca2+) in different cancer cell types, the role of Ca2+ in the anticancer effect is obscure. In the present study, we investigated the Ca2+ pathways involved in the anti-melanoma effect. We used melittin, the bee venom that can activate a store-operated Ca2+ entry (SOCE) and apoptosis, as a reference. DATS increased apoptosis in human melanoma cell lines in a Ca2+-dependent manner. It also induced mitochondrial Ca2+ (Ca2+mit) overload through intracellular and extracellular Ca2+ fluxes independently of SOCE. Strikingly, acidification augmented Ca2+mit overload, and Ca2+ channel blockers reduced the effect more significantly under acidic pH conditions. On the contrary, acidification mitigated SOCE and Ca2+mit overload caused by melittin. Finally, Ca2+ channel blockers entirely inhibited the anti-melanoma effect of DATS. Our findings suggest that DATS explicitly evokes Ca2+mit overload via a non-SOCE, thereby displaying the anti-melanoma effect.