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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 novel flow cytometry-based assay to measure compromised B cell receptor signaling as a prognostic factor in chronic lymphocytic leukemia.
Heitmann, JS, Märklin, M, Truckenmüller, FM, Hinterleitner, C, Dörfel, D, Haap, M, Kopp, HG, Wirths, S, Müller, MR
Journal of leukocyte biology. 2020;(6):1851-1857
Abstract
Chronic lymphocytic leukemia (CLL) is the most common leukemia in adults. In the past years, new therapeutic approaches (e.g., ibrutinib or venetoclax) have been established and greatly improved treatment of CLL. However, complete control or cure of the disease have not been reached so far. Thus, reliable prognostic markers are an imperative for treatment decisions. Recent studies have revealed an essential role for B cell receptor (BCR) signaling in the pathogenesis, prognosis, and therapy of CLL. A heterogeneous response to receptor stimulation with anti-IgM treatment culminating in different calcium flux capabilities has been demonstrated by several authors. However, the methods employed have not reached clinical application. Here, we report on a flow cytometry-based assay to evaluate calcium flux capabilities in CLL and demonstrate that compromised BCR signaling with diminished calcium flux is associated with a significantly better clinical outcome and progression free survival. In summary, our data strongly support the role of compromised BCR signaling as an important prognostic marker in CLL and establish a novel diagnostic tool for its assessment in clinical settings.
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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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5.
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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7.
A calcium-influx-dependent plasticity model exhibiting multiple STDP curves.
Houben, AM, Keil, MS
Journal of computational neuroscience. 2020;(1):65-84
Abstract
Hebbian plasticity means that if the firing of two neurons is correlated, then their connection is strengthened. Conversely, uncorrelated firing causes a decrease in synaptic strength. Spike-timing-dependent plasticity (STDP) represents one instantiation of Hebbian plasticity. Under STDP, synaptic changes depend on the relative timing of the pre- and post-synaptic firing. By inducing pre- and post-synaptic firing at different relative times the STDP curves of many neurons have been determined, and it has been found that there are different curves for different neuron types or synaptic sites. Biophysically, strengthening (long-term potentiation, LTP) or weakening (long-term depression, LTD) of glutamatergic synapses depends on the post-synaptic influx of calcium (Ca2+): weak influx leads to LTD, while strong, transient influx causes LTP. The voltage-dependent NMDA receptors are the main source of Ca2+ influx, but they will only open if a post-synaptic depolarisation coincides with pre-synaptic neurotransmitter release. Here we present a computational mechanism for Ca2+-dependent plasticity in which the interplay between the pre-synaptic neurotransmitter release and the post-synaptic membrane potential leads to distinct Ca2+ time-courses, which in turn lead to the change in synaptic strength. It is shown that the model complies with classic STDP results, as well as with results obtained with triplets of spikes. Furthermore, the model is capable of displaying different shapes of STDP curves, as observed in different experimental studies.
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8.
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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9.
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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10.
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.