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CBL-CIPK module-mediated phosphoregulation: facts and hypothesis.
Sanyal, SK, Mahiwal, S, Nambiar, DM, Pandey, GK
The Biochemical journal. 2020;(5):853-871
Abstract
Calcium (Ca2+) signaling is a versatile signaling network in plant and employs very efficient signal decoders to transduce the encoded message. The CBL-CIPK module is one of the sensor-relay decoders that have probably evolved with the acclimatization of land plant. The CBLs are unique proteins with non-canonical Ca2+ sensing EF-hands, N-terminal localization motif and a C-terminal phosphorylation motif. The partner CIPKs are Ser/Thr kinases with kinase and regulatory domains. Phosphorylation plays a major role in the functioning of the module. As the module has a functional kinase to transduce signal, it employs phosphorylation as a preferred mode for modulation of targets as well as its interaction with CBL. We analyze the data on the substrate regulation by the module from the perspective of substrate phosphorylation. We have also predicted some of the probable sites in the identified substrates that may be the target of the CIPK mediated phosphorylation. In addition, phosphatases have been implicated in reversing the CIPK mediated phosphorylation of substrates. Therefore, we have also presented the role of phosphatases in the modulation of the CBL-CIPK and its targets. We present here an overview of the phosphoregulation mechanism of the CBL-CIPK module.
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2.
The Endoplasmic Reticulum-Plasma Membrane Junction: A Hub for Agonist Regulation of Ca2+ Entry.
Ong, HL, Ambudkar, IS
Cold Spring Harbor perspectives in biology. 2020;(2)
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Abstract
Stimulation of cell-surface receptors induces cytosolic Ca2+ ([Ca2+]i) increases that are detected and transduced by effector proteins for regulation of cell function. Intracellular Ca2+ release, via endoplasmic reticulum (ER) proteins inositol 1,4,5-trisphosphate receptors (IP3R) and ryanodine receptors (RyR), and Ca2+ influx, via store-operated Ca2+ entry (SOCE), contribute to the increase in [Ca2+]i The amplitude, frequency, and spatial characteristics of the [Ca2+]i increases are controlled by the compartmentalization of proteins into signaling complexes such as receptor-signaling complexes and SOCE complexes. Both complexes include protein and lipid components, located in the plasma membrane (PM) and ER. Receptor signaling initiates in the PM via phospholipase C (PLC)-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2), and culminates with the activation of IP3R in the ER. Conversely, SOCE is initiated in the ER by Ca2+-sensing stromal interaction molecule (STIM) proteins, which then interact with PM channels Orai1 and TRPC1 to activate Ca2+ entry. This review will address how ER-PM junctions serve a central role in agonist regulation of SOCE.
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A Non-Canonical Calmodulin Target Motif Comprising a Polybasic Region and Lipidated Terminal Residue Regulates Localization.
Grant, BMM, Enomoto, M, Ikura, M, Marshall, CB
International journal of molecular sciences. 2020;(8)
Abstract
Calmodulin (CaM) is a Ca2+-sensor that regulates a wide variety of target proteins, many of which interact through short basic helical motifs bearing two hydrophobic 'anchor' residues. CaM comprises two globular lobes, each containing a pair of EF-hand Ca2+-binding motifs that form a Ca2+-induced hydrophobic pocket that binds an anchor residue. A central flexible linker allows CaM to accommodate diverse targets. Several reported CaM interactors lack these anchors but contain Lys/Arg-rich polybasic sequences adjacent to a lipidated N- or C-terminus. Ca2+-CaM binds the myristoylated N-terminus of CAP23/NAP22 with intimate interactions between the lipid and a surface comprised of the hydrophobic pockets of both lobes, while the basic residues make electrostatic interactions with the negatively charged surface of CaM. Ca2+-CaM binds farnesylcysteine, derived from the farnesylated polybasic C-terminus of KRAS4b, with the lipid inserted into the C-terminal lobe hydrophobic pocket. CaM sequestration of the KRAS4b farnesyl moiety disrupts KRAS4b membrane association and downstream signaling. Phosphorylation of basic regions of N-/C-terminal lipidated CaM targets can reduce affinity for both CaM and the membrane. Since both N-terminal myristoylated and C-terminal prenylated proteins use a Singly Lipidated Polybasic Terminus (SLIPT) for CaM binding, we propose these polybasic lipopeptide elements comprise a non-canonical CaM-binding motif.
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4.
Regulation of cellular senescence by eukaryotic members of the FAH superfamily - A role in calcium homeostasis?
Weiss, AKH, Albertini, E, Holzknecht, M, Cappuccio, E, Dorigatti, I, Krahbichler, A, Damisch, E, Gstach, H, Jansen-Dürr, P
Mechanisms of ageing and development. 2020;:111284
Abstract
Fumarylacetoacetate hydrolase (FAH) superfamily members are commonly expressed in the prokaryotic kingdom, where they take part in the committing steps of degradation pathways of complex carbon sources. Besides FAH itself, the only described FAH superfamily members in the eukaryotic kingdom are fumarylacetoacetate hydrolase domain containing proteins (FAHD) 1 and 2, that have been a focus of recent work in aging research. Here, we provide a review of current knowledge on FAHD proteins. Of those, FAHD1 has recently been described as a regulator of mitochondrial function and senescence, in the context of mitochondrial dysfunction associated senescence (MiDAS). This work further describes data based on bioinformatics analysis, 3D structure comparison and sequence alignment, that suggests a putative role of FAHD proteins as calcium binding proteins.
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Modulation of Calcium Signaling in Glioblastoma Multiforme: A Therapeutic Promise for Natural Products.
Afshari, AR, Mollazadeh, H, Soukhtanloo, M, Hosseini, A, Mohtashami, E, Jalili-Nik, M, Modaresi, SMS, Soltani, A, Sahebkar, A
Mini reviews in medicinal chemistry. 2020;(18):1879-1899
Abstract
Glioblastoma multiforme (GBM) continues as one of the most lethal cerebral cancers despite standard therapeutic modalities, such as maximum surgical resection and chemoradiation. The minimal effectiveness of existing therapies necessitates the development of additional drug candidates that could improve the prognosis of GBM patients. Accumulating evidence suggests that calcium (Ca2+) is involved in the processes of cell proliferation, metastasis, angiogenesis, migration, and invasiveness. Therefore, Ca2+ could serve as a crucial regulator of tumorigenesis and a potential treatment target in GBM. In this context, specific natural products are known to modulate Ca2+ signaling pathways implicated in tumor growth, apoptosis, angiogenesis, and development of GBM. Here, the focus is on the function of Ca2+ as a therapeutic target in GBM and reviewing certain natural products that affect the signaling pathways of Ca2+.
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The Interplay Between Depression and Parkinson´s Disease: Learning the Link Through Ca2+/cAMP Signaling.
Bergantin, LB
Current protein & peptide science. 2020;(12):1223-1228
Abstract
BACKGROUND Parkinson´s disease (PD) and depression have an interplay at multiple cellular levels, a phenomenon which is translated into clinical data showing that depressive patients presented an enhanced risk for developing PD. The pathogenesis of both diseases is under intensive debate as correlated to dysregulations related to Ca2+ signaling. OBJECTIVE Then, revealing this interplay between these diseases may provide novel insights into the pathogenesis of them. METHODS Publications involving Ca2+ signaling, PD and depression (alone or combined) were collected by searching PubMed and EMBASE. RESULTS Not surprisingly, calcium (Ca2+) channel blockers (CCBs), classical antihypertensive medicines, have been demonstrated off-label effects, such as alleviating both PD and depression symptoms. DISCUSSION A mechanism under debate for the antiparkinsonism and antidepressant effects associated to CCBs is focused on the restoration of Ca2+ signaling dysregulations. In addition, previous studies have observed that CCBs can affect Ca2+/cAMP signaling. CONCLUSION Thus, this article discussed the role of Ca2+/cAMP signaling in the interplay between depression and PD, including the implications for the pharmacotherapy involving CCBs.
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Lessons from the Endoplasmic Reticulum Ca2+ Transporters-A Cancer Connection.
Zhai, X, Sterea, AM, Hiani, YE
Cells. 2020;(6)
Abstract
Ca2+ is an integral mediator of intracellular signaling, impacting almost every aspect of cellular life. The Ca2+-conducting transporters located on the endoplasmic reticulum (ER) membrane shoulder the responsibility of constructing the global Ca2+ signaling landscape. These transporters gate the ER Ca2+ release and uptake, sculpt signaling duration and intensity, and compose the Ca2+ signaling rhythm to accommodate a plethora of biological activities. In this review, we explore the mechanisms of activation and functional regulation of ER Ca2+ transporters in the establishment of Ca2+ homeostasis. We also contextualize the aberrant alterations of these transporters in carcinogenesis, presenting Ca2+-based therapeutic interventions as a means to tackle malignancies.
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8.
Microglial Store-operated Calcium Signaling in Health and in Alzheimer's Disease.
McLarnon, JG
Current Alzheimer research. 2020;(12):1057-1064
Abstract
The dysregulation of calcium signaling mechanisms in neurons has been considered a contributing factor to the pathogenesis evident in early-onset Alzheimer's Disease (AD). However, considerably less is known concerning the possible impairment of Ca2+ mobilization in resident immune cell microglia. This review considers findings which suggest that a prominent pathway for non-excitable microglial cells, store-operated calcium entry (SOCE), is altered in the sporadic form of AD. The patterns of Ca2+ mobilization are first discussed with platelet-activating factor (PAF) stimulation of SOCE in adult, fetal and immortalized cell-line, human microglia in the healthy brain. In all cases, PAF was found to induce a rapid transient depletion of Ca2+ from endoplasmic reticulum (ER) stores, followed by a sustained entry of Ca2+ (SOCE). A considerably attenuated duration of SOCE is observed with ATP stimulation of human microglia, suggested as due to agonist actions on differential subtype purinergic receptors. Microglia obtained from AD brain tissue, or microglia treated with full-length amyloid-β peptide (Aβ42), show significant reductions in the amplitude of SOCE relative to controls. In addition, AD brain and Aβ42-treated microglia exhibit decreased levels of Ca2+ release from ER stores compared to controls. Changes in properties of SOCE in microglia could lead to altered immune cell response and neurovascular unit dysfunction in the inflamed AD brain.
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9.
Sensing of tubular flow and renal electrolyte transport.
Verschuren, EHJ, Castenmiller, C, Peters, DJM, Arjona, FJ, Bindels, RJM, Hoenderop, JGJ
Nature reviews. Nephrology. 2020;(6):337-351
Abstract
The kidney is a remarkable organ that accomplishes the challenge of removing waste from the body and simultaneously regulating electrolyte and water balance. Pro-urine flows through the nephron in a highly dynamic manner and adjustment of the reabsorption rates of water and ions to the variable tubular flow is required for electrolyte homeostasis. Renal epithelial cells sense the tubular flow by mechanosensation. Interest in this phenomenon has increased in the past decade since the acknowledgement of primary cilia as antennae that sense renal tubular flow. However, the significance of tubular flow sensing for electrolyte handling is largely unknown. Signal transduction pathways regulating flow-sensitive physiological responses involve calcium, purinergic and nitric oxide signalling, and are considered to have an important role in renal electrolyte handling. Given that mechanosensation of tubular flow is an integral role of the nephron, defective tubular flow sensing is probably involved in renal disease. Studies investigating tubular flow and electrolyte transport differ in their methodology, subsequently hampering translational validity. This Review provides the basis for understanding electrolyte disorders originating from altered tubular flow sensing as a result of pathological conditions.
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10.
On a Magical Mystery Tour with 8-Bromo-Cyclic ADP-Ribose: From All-or-None Block to Nanojunctions and the Cell-Wide Web.
Evans, AM
Molecules (Basel, Switzerland). 2020;(20)
Abstract
A plethora of cellular functions are controlled by calcium signals, that are greatly coordinated by calcium release from intracellular stores, the principal component of which is the sarco/endooplasmic reticulum (S/ER). In 1997 it was generally accepted that activation of various G protein-coupled receptors facilitated inositol-1,4,5-trisphosphate (IP3) production, activation of IP3 receptors and thus calcium release from S/ER. Adding to this, it was evident that S/ER resident ryanodine receptors (RyRs) could support two opposing cellular functions by delivering either highly localised calcium signals, such as calcium sparks, or by carrying propagating, global calcium waves. Coincidentally, it was reported that RyRs in mammalian cardiac myocytes might be regulated by a novel calcium mobilising messenger, cyclic adenosine diphosphate-ribose (cADPR), that had recently been discovered by HC Lee in sea urchin eggs. A reputedly selective and competitive cADPR antagonist, 8-bromo-cADPR, had been developed and was made available to us. We used 8-bromo-cADPR to further explore our observation that S/ER calcium release via RyRs could mediate two opposing functions, namely pulmonary artery dilation and constriction, in a manner seemingly independent of IP3Rs or calcium influx pathways. Importantly, the work of others had shown that, unlike skeletal and cardiac muscles, smooth muscles might express all three RyR subtypes. If this were the case in our experimental system and cADPR played a role, then 8-bromo-cADPR would surely block one of the opposing RyR-dependent functions identified, or the other, but certainly not both. The latter seemingly implausible scenario was confirmed. How could this be, do cells hold multiple, segregated SR stores that incorporate different RyR subtypes in receipt of spatially segregated signals carried by cADPR? The pharmacological profile of 8-bromo-cADPR action supported not only this, but also indicated that intracellular calcium signals were delivered across intracellular junctions formed by the S/ER. Not just one, at least two. This article retraces the steps along this journey, from the curious pharmacological profile of 8-bromo-cADPR to the discovery of the cell-wide web, a diverse network of cytoplasmic nanocourses demarcated by S/ER nanojunctions, which direct site-specific calcium flux and may thus coordinate the full panoply of cellular processes.