Phosphorylation of NMDA receptors by cyclin B/CDK1 modulates calcium dynamics and mitosis

AbstractN-methyl-D-aspartate receptors (NMDAR) are glutamate-gated calcium channels named after their artificial agonist. NMDAR are implicated in cell proliferation under normal and pathophysiological conditions. However, the role of NMDAR during mitosis has not yet been explored in individual cells. We found that neurotransmitter-evoked calcium entry via endogenous NMDAR in cortical astrocytes was transient during mitosis. The same occurred in HEK293 cells transfected with the NR1/NR2A subunits of NMDAR. This transient calcium entry during mitosis was due to phosphorylation of the first intracellular loop of NMDAR (S584 of NR1 and S580 of NR2A) by cyclin B/CDK1. Expression of phosphomimetic mutants resulted in transient calcium influx and enhanced NMDAR inactivation independent of the cell cycle phase. Phosphomimetic mutants increased entry of calcium in interphase and generated several alterations during mitosis: increased mitotic index, increased number of cells with lagging chromosomes and fragmentation of pericentriolar material. In summary, by controlling cytosolic calcium, NMDAR modulate mitosis and probably cell differentiation/proliferation. Our results suggest that phosphorylation of NMDAR by cyclin B/CDK1 during mitosis is required to preserve mitotic fidelity. Altering the modulation of the NMDAR by cyclin B/CDK1 may conduct to aneuploidy and cancer.

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Dominant regulation of interendothelial cell gap formation by calcium-inhibited type 6 adenylyl cyclase

The Journal of Cell Biology ◽

10.1083/jcb.200204022 ◽

2002 ◽

Vol 157 (7) ◽

pp. 1267-1278 ◽

Cited By ~ 72

Author(s):

Donna L. Cioffi ◽

Timothy M. Moore ◽

Jerry Schaack ◽

Judy R. Creighton ◽

Dermot M.F. Cooper ◽

...

Keyword(s):

Adenylyl Cyclase ◽

Physiological Role ◽

Cell Types ◽

Cytosolic Calcium ◽

Calcium Entry ◽

Gap Formation ◽

Calcium Stimulation ◽

Store Operated Calcium Entry ◽

Stimulation Of

Acute transitions in cytosolic calcium ([Ca2+]i) through store-operated calcium entry channels catalyze interendothelial cell gap formation that increases permeability. However, the rise in [Ca2+]i only disrupts barrier function in the absence of a rise in cAMP. Discovery that type 6 adenylyl cyclase (AC6; EC 4.6.6.1) is inhibited by calcium entry through store-operated calcium entry pathways provided a plausible explanation for how inflammatory [Ca2+]i mediators may decrease cAMP necessary for endothelial cell gap formation. [Ca2+]i mediators only modestly decrease global cAMP concentrations and thus, to date, the physiological role of AC6 is unresolved. Present studies used an adenoviral construct that expresses the calcium-stimulated AC8 to convert normal calcium inhibition into stimulation of cAMP, within physiologically relevant concentration ranges. Thrombin stimulated a dose-dependent [Ca2+]i rise in both pulmonary artery (PAECs) and microvascular (PMVEC) endothelial cells, and promoted intercellular gap formation in both cell types. In PAECs, gap formation was progressive over 2 h, whereas in PMVECs, gap formation was rapid (within 10 min) and gaps resealed within 2 h. Expression of AC8 resulted in a modest calcium stimulation of cAMP, which virtually abolished thrombin-induced gap formation in PMVECs. Findings provide the first direct evidence that calcium inhibition of AC6 is essential for endothelial gap formation.

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Mechanisms of cytosolic calcium elevation in plants: the role of ion channels, calcium extrusion systems and NADPH oxidase-mediated 'ROS-Ca2+ Hub'

Functional Plant Biology ◽

10.1071/fp16420 ◽

2018 ◽

Vol 45 (2) ◽

pp. 9 ◽

Cited By ~ 49

Author(s):

Vadim Demidchik ◽

Sergey Shabala

Keyword(s):

Calcium Influx ◽

Gene Families ◽

Cytosolic Calcium ◽

Recent Experimental Data ◽

Free Calcium ◽

Cyclic Nucleotide Gated Channels ◽

Physiological Reactions ◽

Calcium Extrusion ◽

Calcium Elevation

Elevation in the cytosolic free calcium is crucial for plant growth, development and adaptation. Calcium influx into plant cells is mediated by Ca2+ depolarisation-activated, hyperpolarisation-activated and voltage-independent Ca2+-permeable channels (DACCs, HACCs and VICCs respectively). These channels are encoded by the following gene families: (1) cyclic nucleotide-gated channels (CNGCs), (2) ionotropic glutamate receptors (GLRs), (3) annexins, (4) ‘mechanosensitive channels of small (MscS) conductance’-like channels (MSLs), (5) ‘mid1-complementing activity’ channels (MCAs), Piezo channels, and hyperosmolality-induced [Ca2+]cyt. channel 1 (OSCA1). Also, a ‘tandem-pore channel1’ (TPC1) catalyses Ca2+ efflux from the vacuole in response to the plasma membrane-mediated Ca2+ elevation. Recent experimental data demonstrated that Arabidopsis thaliana (L.) Heynh. CNGCs 2, 5–10, 14, 16 and 18, GLRs 1.2, 3.3, 3.4, 3.6 and 3.7, TPC1, ANNEXIN1, MSL9 and MSL10,MCA1 and MCA2, OSCA1, and some their homologues counterparts in other species, are responsible for Ca2+ currents and/or cytosolic Ca2+ elevation. Extrusion of Ca2+ from the cytosol is mediated by Ca2+-ATPases and Ca2+/H+ exchangers which were recently examined at the level of high resolution crystal structure. Calcium-activated NADPH oxidases and reactive oxygen species (ROS)-activated Ca2+ conductances form a self-amplifying ‘ROS-Ca2+hub’, enhancing and transducing Ca2+ and redox signals. The ROS-Ca2+ hub contributes to physiological reactions controlled by ROS and Ca2+, demonstrating synergism and unity of Ca2+ and ROS signalling mechanisms.

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The role of STIM1 in the receptor- and store-operated calcium influx in HEK293 cells

Biochemistry (Moscow) Supplement Series A Membrane and Cell Biology ◽

10.1134/s199074781002011x ◽

2010 ◽

Vol 4 (2) ◽

pp. 200-205 ◽

Cited By ~ 1

Author(s):

O. A. Zimina ◽

V. A. Vigont ◽

I. A. Pozdnjakov ◽

L. N. Glushankova ◽

S. V. L’vovskaja ◽

...

Keyword(s):

Calcium Influx ◽

Hek293 Cells

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Peroxisomes contribute to intracellular calcium dynamics

10.1101/2020.09.02.279174 ◽

2020 ◽

Author(s):

Yelena Sargsyan ◽

Uta Bickmeyer ◽

Katrin Streckfuss-Bömeke ◽

Ivan Bogeski ◽

Sven Thoms

Keyword(s):

Intracellular Calcium ◽

Hela Cells ◽

Calcium Influx ◽

Induced Pluripotent Stem Cell ◽

Cytosolic Calcium ◽

Neonatal Rat ◽

Calcium Handling ◽

Calcium Stores ◽

Calcium Dynamics ◽

Rat Cardiomyocytes

AbstractPeroxisomes communicate with other cellular compartments by transfer of various metabolites. However, whether peroxisomes are sites for calcium handling and exchange has remained contentious. Here we generated sensors for assessment of peroxisomal calcium and applied them for single cell-based calcium imaging in HeLa cells and cardiomyocytes. We found that peroxisomes in HeLa cells take up calcium upon depletion of intracellular calcium stores and upon calcium influx across the plasma membrane. Further, we show that peroxisomes of neonatal rat cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes can take up calcium in a controlled manner. Our results indicate that peroxisomal and cytosolic calcium signals are tightly interconnected. Hence, peroxisomes may play an important role in shaping cellular calcium dynamics by serving as buffers or sources of intracellular calcium.

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Morphological heterogeneity of renal glomerular arterioles and distinct [Ca2+]i responses to ANG II

AJP Renal Physiology ◽

10.1152/ajprenal.1997.273.1.f84 ◽

1997 ◽

Vol 273 (1) ◽

pp. F84-F96 ◽

Cited By ~ 10

Author(s):

C. M. Helou ◽

J. Marchetti

Keyword(s):

Calcium Influx ◽

Cytosolic Calcium ◽

Calcium Entry ◽

Calcium Entry Blocker ◽

Ang Ii ◽

Outer Cortex ◽

Morphological Heterogeneity ◽

Morphological Differences ◽

Glomerular Arterioles ◽

Inner Cortex

The present study compares cytosolic calcium concentration ([Ca2+]i) responses to angiotensin II (ANG II) of afferent (AA) and efferent arterioles (EA) by taking account of the localization and morphological differences of EA. In outer cortex, 1 nM ANG II induced smaller [Ca2+]i increases in thin EA than in AA[48 +/- 10 (n = 12) vs. 94 +/- 7 nM (n = 11); P < 0.001]. In inner cortex, two types of EA were considered, i.e., thin and muscular ones. The response to 1 nM ANG II was 35% lower in thin than in muscular EA (P < 0.05) but did not differ from that obtained with corresponding AA. In EA of the outer cortex, 1 microM nifedipine, a dihydropyridine blocker of voltage-operated channels (VOCC), did not affect calcium influx, which was suppressed by 1 mM NiCl2, a nonselective calcium entry blocker. In other arterioles, nifedipine inhibited by approximately 40% calcium entry, and remaining influx was blocked by NiCl2. These results indicate a relationship between the magnitude of [Ca2+]i responses, activation of dihydropyridine-sensitive VOCC by ANG II, and the muscular morphology in renal glomerular arterioles. They suggest that ANG II regulates differently local renal microcirculation. They do not, however, support the hypothesis of a greater sensitivity to ANG II of EA compared with the AA of a given nephron.

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Peroxisomes contribute to intracellular calcium dynamics in cardiomyocytes and non-excitable cells

Life Science Alliance ◽

10.26508/lsa.202000987 ◽

2021 ◽

Vol 4 (9) ◽

pp. e202000987

Author(s):

Yelena Sargsyan ◽

Uta Bickmeyer ◽

Christine S Gibhardt ◽

Katrin Streckfuss-Bömeke ◽

Ivan Bogeski ◽

...

Keyword(s):

Intracellular Calcium ◽

Hela Cells ◽

Calcium Influx ◽

Induced Pluripotent Stem Cell ◽

Cytosolic Calcium ◽

Neonatal Rat ◽

Calcium Handling ◽

Calcium Stores ◽

Calcium Dynamics ◽

Rat Cardiomyocytes

Peroxisomes communicate with other cellular compartments by transfer of various metabolites. However, whether peroxisomes are sites for calcium handling and exchange has remained contentious. Here we generated sensors for assessment of peroxisomal calcium and applied them for single cell-based calcium imaging in HeLa cells and cardiomyocytes. We found that peroxisomes in HeLa cells take up calcium upon depletion of intracellular calcium stores and upon calcium influx across the plasma membrane. Furthermore, we show that peroxisomes of neonatal rat cardiomyocytes and human induced pluripotent stem cell–derived cardiomyocytes can take up calcium. Our results indicate that peroxisomal and cytosolic calcium signals are tightly interconnected both in HeLa cells and in cardiomyocytes. Cardiac peroxisomes take up calcium on beat-to-beat basis. Hence, peroxisomes may play an important role in shaping cellular calcium dynamics of cardiomyocytes.

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Calcium signaling and secretory granule pool dynamics underlie biphasic insulin secretion and its amplification by glucose: experiments and modeling

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00380.2018 ◽

2019 ◽

Vol 316 (3) ◽

pp. E475-E486 ◽

Cited By ~ 4

Author(s):

Morten Gram Pedersen ◽

Alessia Tagliavini ◽

Jean-Claude Henquin

Keyword(s):

Insulin Secretion ◽

Glucose Concentration ◽

Calcium Influx ◽

Secretory Granules ◽

Cytosolic Calcium ◽

Second Phase ◽

Calcium Dynamics ◽

Β Cells ◽

Biphasic Insulin ◽

Biphasic Insulin Secretion

Glucose-stimulated insulin secretion from pancreatic β-cells is controlled by a triggering pathway that culminates in calcium influx and regulated exocytosis of secretory granules, and by a less understood amplifying pathway that augments calcium-induced exocytosis. In response to an abrupt increase in glucose concentration, insulin secretion exhibits a first peak followed by a lower sustained second phase. This biphasic secretion pattern is disturbed in diabetes. It has been attributed to depletion and subsequent refilling of a readily releasable pool of granules or to the phasic cytosolic calcium dynamics induced by glucose. Here, we apply mathematical modeling to experimental data from mouse islets to investigate how calcium and granule pool dynamics interact to control dynamic insulin secretion. Experimental calcium traces are used as inputs in three increasingly complex models of pool dynamics, which are fitted to insulin secretory patterns obtained using a set of protocols of glucose and tolbutamide stimulation. New calcium and secretion data for so-called staircase protocols, in which the glucose concentration is progressively increased, are presented. These data can be reproduced without assuming any heterogeneity in the model, in contrast to previous modeling, because of nontrivial calcium dynamics. We find that amplification by glucose can be explained by increased mobilization and priming of granules. Overall, our results indicate that calcium dynamics contribute substantially to shaping insulin secretion kinetics, which implies that better insight into the events creating phasic calcium changes in human β-cells is needed to understand the cellular mechanisms that disturb biphasic insulin secretion in diabetes.

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Adenosine Triphosphate-Evoked Cytosolic Calcium Oscillations in Human Granulosa-Luteal Cells: Role of Protein Kinase C1

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.86.2.7231 ◽

2001 ◽

Vol 86 (2) ◽

pp. 773-777 ◽

Cited By ~ 1

Author(s):

Chen-Jei Tai ◽

Sung Keun Kang ◽

Peter C. K. Leung

Keyword(s):

Protein Kinase ◽

Calcium Influx ◽

Purinergic Receptor ◽

Cytosolic Calcium ◽

Inhibitory Effect ◽

Calcium Oscillations ◽

Dependent Manner ◽

Luteal Cells

ATP has been shown to modulate progesterone production in human granulosa-luteal cells (hGLCs) in vitro. After binding to a G protein-coupled P2 purinergic receptor, ATP stimulates phospholipase C. The resultant production of diacylglycerol and inositol triphosphate activates protein kinase C (PKC) and intracellular calcium [Ca2+]i mobilization, respectively. In the present study, we examined the potential cross-talk between the PKC and Ca2+ pathway in ATP signal transduction. Specifically, the effect of PKC on regulating ATP-evoked[ Ca2+]i oscillations were examined in hGLCs. Using microspectrofluorimetry, [Ca2+]i oscillations were detected in Fura-2 loaded hGLCs in primary culture. The amplitudes of the ATP-triggered [Ca2+]i oscillations were reduced in a dose-dependent manner by pretreating the cells with various concentrations (1 nm to 10μ m) of the PKC activator, phorbol-12-myristate-13-acetate (PMA). A 10 μm concentration of PMA completely suppressed 10 μm ATP-induced oscillations. The inhibitory effect occurred even when PMA was given during the plateau phase of ATP evoked [Ca2+]i oscillations, suggesting that extracellular calcium influx was inhibited. The role of PKC was further substantiated by the observation that, in the presence of a PKC inhibitor, bisindolylmaleimide I, ATP-induced[ Ca2+]i oscillations were not completely suppressed by PMA. Furthermore, homologous desensitization of ATP-induced calcium oscillations was partially reversed by bisindolylmaleimide I, suggesting that activated PKC may be involved in the mechanism of desensitization. These results demonstrate that PKC negatively regulates the ATP-evoked [Ca2+]i mobilization from both intracellular stores and extracellular influx in hGLCs and further support a modulatory role of ATP and P2 purinoceptor in ovarian steroidogenesis.

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Role of cAMP and calcium influx in endothelin-1-induced ANP release in rat cardiomyocytes

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1997.273.5.e922 ◽

1997 ◽

Vol 273 (5) ◽

pp. E922-E931 ◽

Cited By ~ 5

Author(s):

M. C. Rebsamen ◽

D. J. Church ◽

D. Morabito ◽

M. B. Vallotton ◽

U. Lang

Keyword(s):

Calcium Influx ◽

Cytosolic Calcium ◽

Neonatal Rat ◽

Rat Cardiomyocytes ◽

Endothelin 1 ◽

Kinase C ◽

Ventricular Cardiomyocytes ◽

Camp Formation ◽

Prostacyclin Production

The mechanism of endothelin-1 (ET-1)-induced atrial natriuretic peptide (ANP) release was studied in neonatal rat ventricular cardiomyocytes. These cells expressed a single high-affinity class of ETAreceptor (dissociation constant = 54 ± 18 pM, n = 3), but no ETB receptors. Incubation of cardiomyocytes with ET-1 led to concentration-dependent ANP release and prostacyclin production. ET-1-induced ANP release was affected by neither protein kinase C (PKC) inhibition or downregulation nor by cyclooxygenase inhibition, indicating that ET-1-stimulated ANP secretion is not a PKC-mediated, prostaglandin-dependent process. Furthermore, ET-1 significantly stimulated adenosine 3′,5′-cyclic monophosphate (cAMP) production and increased cytosolic calcium concentration in these preparations. Both ET-1-induced calcium influx and ANP release were decreased by the cAMP antagonist Rp-cAMPS, the Rp diastereoisomer of cAMP. Moreover, ET-1-induced ANP secretion was strongly inhibited in the presence of nifedipine as well as in the absence of extracellular calcium. Thus our results suggest that ET-1 stimulates ANP release in ventricular cardiomyocytes via an ETAreceptor-mediated pathway involving cAMP formation and activation of a nifedipine-sensitive calcium channel.

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