Extracellular calcium concentration controls the frequency of intracellular calcium spiking independently of inositol 1,4,5-trisphosphate production in HeLa cells

Bootman, Martin D.; Young, Kenneth W.; Young, J. M.; Moreton, R. B.; Berridge, Michael J.

doi:10.1042/bj3140347

Cited by 73 publications

(56 citation statements)

References 53 publications

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“…It is already well known that Ca 2ϩ influx affects oscillation frequency in many cell types (10,13,(35)(36)(37). In Xenopus oocytes, which have a very small surface-to-volume ratio and thus a small ␦, Ca 2ϩ oscillations persist in the absence of external Ca 2ϩ , as found in the model.…”

Section: Discussionsupporting

confidence: 49%

Control of calcium oscillations by membrane fluxes

Sneyd

Tsaneva-Atanasova

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

126

116

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It is known that Ca 2؉ influx plays an important role in the modulation of inositol trisphosphate-generated Ca 2؉ oscillations, but controversy over the mechanisms underlying these effects exists. In addition, the effects of blocking membrane transport or reducing Ca 2؉ entry vary from one cell type to another; in some cell types oscillations persist in the absence of Ca 2؉ entry (although their frequency is affected), whereas in other cell types oscillations depend on Ca 2؉ entry. We present theoretical and experimental evidence that membrane transport can control oscillations by controlling the total amount of Ca 2؉ in the cell (the Ca 2؉ load). Our model predicts that the cell can be balanced at a point where small changes in the Ca 2؉ load can move the cell into or out of oscillatory regions, resulting in the appearance or disappearance of oscillations. Our theoretical predictions are verified by experimental results from HEK293 cells. We predict that the role of Ca 2؉ influx during an oscillation is to replenish the Ca 2؉ load of the cell. Despite this prediction, even during the peak of an oscillation the cell or the endoplasmic reticulum may not be measurably depleted of Ca 2؉ .I n response to an increased concentration of inositol trisphosphate (IP 3 ), oscillations in the concentration of free intracellular calcium (Ca 2ϩ ) occur in many cell types and are important for the control of many cellular functions (1-4). In nonexcitable cells, such as epithelial cells, these oscillations occur as the result of Ca 2ϩ flux into and out of the endoplasmic reticulum (ER). However, although the oscillations result from the cycling of Ca 2ϩ between the ER and the cytoplasm, the transport of Ca 2ϩ across the cell membrane can have a dramatic effect on these oscillations.Although Ca 2ϩ influx is known to be important, disagreement exists, first, over the mechanisms by which Ca 2ϩ influx is modulated during a Ca 2ϩ oscillation, and, second, over the role played by Ca 2ϩ influx. The capacitative entry hypothesis proposes that depletion of ER Ca 2ϩ causes enhanced entry of Ca 2ϩ across the plasma membrane (5-9). Often, although not necessarily, in this scenario, Ca 2ϩ entry is necessary for the refilling of the ER, and thus oscillation frequency is controlled by the refilling time (10, 11). Although capacitative entry is certainly an important factor during the response to a maximal stimulus, other investigators have pointed to a lack of direct evidence that it plays an important role during smaller stimuli that generate oscillatory behavior (12). They maintain that Ca 2ϩ influx, under these conditions, is controlled by a noncapacitative pathway involving arachidonic acid and that the purpose of the influx is to increase the likelihood that low levels of IP 3 will induce Ca 2ϩ release from internal stores (13). This controversy is complicated by the fact that, in some cell types, Ca 2ϩ oscillations persist in the absence of Ca 2ϩ influx (14-16), whereas in other cell types, oscillations depend absolutely on influx (17, ...

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Section: Discussionsupporting

confidence: 49%

Control of calcium oscillations by membrane fluxes

Sneyd

Tsaneva-Atanasova

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

126

116

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“…These (41). In addition to defining the parameters of receptor-mediated Ca 2ϩ oscillations observed in the HeLa cells used in this study, this analysis reveals one of the major problems in biochemically defining the coupling of Ca 2ϩ oscillations to signaling pathways.…”

Section: Resultsmentioning

confidence: 99%

The frequencies of calcium oscillations are optimized for efficient calcium-mediated activation of Ras and the ERK/MAPK cascade

Kupzig

Walker

Cullen

2005

Proc. Natl. Acad. Sci. U.S.A.

114

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Ras proteins are binary switches that, by cycling through inactive GDP-and active GTP-bound conformations, regulate multiple cellular signaling pathways, including those that control growth and differentiation. For some time, it has been known that receptormediated increases in the concentration of intracellular free calcium ( [Ca 2ϩ ] i is responsible for controlling a diverse array of cellular processes, including secretion, contraction, learning, and proliferation (3). Understanding how receptor-mediated increases in [Ca 2ϩ ] i are capable of modulating so many physiological processes is one of the major challenges in the study of Ca 2ϩ signaling. It appears that such control is achieved through a complex relationship between the amplitude and spatiotemporal patterning of the Ca 2ϩ signal and its resultant ability to couple to an extensive molecular repertoire of Ca 2ϩ -sensing proteins (3).Receptor-mediated increases in [Ca 2ϩ ] i are often observed as repetitive Ca 2ϩ spikes or oscillations that increase their frequency with the amplitude of the receptor stimuli (refs. 4 and 5; reviewed in ref. 3). These frequency-encoded signals appear to be critical for the induction of selective cellular functions (3). For example, the frequency of receptor-mediated Ca 2ϩ oscillations determines the efficiency of gene expression driven by the transcription factors NF-AT, OAP, and NF-B (6-8) and mitochondrial ATP production (9). To decode the information contained within Ca 2ϩ oscillations, cells have evolved a number of frequency-modulated decoders. Such proteins include calmodulin (10), protein kinase C (11-15), calpain (16), calmodulin-dependent protein kinase II (17,18), and the Ras GTPaseactivating protein RASAL (19).Ras proteins are binary molecular switches that regulate multiple signaling pathways, including those controlling growth and differentiation, through an ability to cycle between inactive GDP-and active GTP-bound conformations (20-23). The magnitude and duration of Ras signaling is controlled by two classes of proteins: Guanine nucleotide exchange factors modulate Ras activation by enhancing the exchange of GDP for GTP, and GTPase-activating proteins regulate inactivation by increasing the intrinsic Ras GTPase activity (20-23). Although it has been known for some time that increases in [Ca 2ϩ ] i can modulate Ras activation (for example, Ca 2ϩ influx through voltage-operated ion channels or release from internal stores can activate Ras in neuronal cells) (24), only recently have molecular entities been described that allow for this coupling (reviewed in ref. 25).Two families of Ras guanine nucleotide exchange factors (GEFs), and RasGRPs (30-36), the latter also being known as CalDAG-GEFs, are modulated by increases in [Ca 2ϩ ] i . For RasGRFs, this modulation occurs indirectly through association with Ca 2ϩ ͞calmodulin, whereas for RasGRPs, a more direct control is achieved through association of Ca 2ϩ with atypical EF hands (25). In addition to stimulating Ras activation, increases in [Ca 2ϩ ] i ...

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“…In these assays, the initial increase in [Ca 2ϩ ] i that arose from IP 3 -stimulated release of Ca 2ϩ from internal stores (38) was not significantly altered in those cells expressing YFP-GAP1 IP4BP (R601C), YFP-GAP1 IP4BP (L484A), or YFP-GAP1 IP4BP (Fig. 3).…”

Section: Gap1 Ip4bp and The Regulation Of Ca 2ϩ Signalingmentioning

confidence: 99%

Analyzing the Role of the Putative Inositol 1,3,4,5-Tetrakisphosphate Receptor GAP1IP4BP in Intracellular Ca2+ Homeostasis

Walker¹,

Kupzig²,

Lockyer³

et al. 2002

Journal of Biological Chemistry

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Despite many studies on the possible role of inositol 1,3,4,5-tetrakisphosphate (IP 4 ) 1 in cellular physiology, its function remains unclear and indeed there is still some debate over whether it has a function at all (1, 2). Formed by direct phosphorylation of inositol 1,4,5-trisphosphate (IP 3 ), a reaction catalyzed by a family of Ca 2ϩ -regulated IP 3 3-kinases (1, 3), IP 4 has been linked to a potential role in the regulation of intracellular free Ca 2ϩ concentration ([Ca 2ϩ ] i ) following cellular stimulation with agonists that activate phosphoinositide-specific phospholipase C (4 -7). Evidence for this finding has come from a number of sources. For example, in endothelial cells, there is direct evidence (8) and, in neurons, there is direct (9) and indirect evidence (10) that IP 4 can activate Ca 2ϩ influx channels in the plasma membrane. Furthermore, one of the first effects of IP 4 to be reported highlighted an ability of this compound to synergize with IP 3 to mobilize Ca 2ϩ and regulate subsequent store-operated Ca 2ϩ influx (11-13). However, the marked sensitivity of this particular system to experimental protocols (11, 14 -16) has also raised a significant degree of controversy over the role of IP 4 in intracellular Ca 2ϩ homeostasis. In recent years, we have taken the view that if IP 4 does indeed constitute a novel second messenger, one criterion that must be fulfilled is the presence within cells of protein(s) that specifically bind IP 4 , i.e. an IP 4 receptor. To this end, we have described the purification (17, 18) and cloning (19) of a highly specific IP 4 -binding protein termed GAP1IP4BP . This protein, which functions as a GTPase-activating protein for members of the Ras-like family of small GTPases, at present constitutes the most promising candidate IP 4 receptor.The Ras-like family includes H-Ras, N-Ras, and K-Ras4A and 4B, the R-Ras proteins, the Ral proteins, and the Rap proteins 1A, 1B, 2A, and 2B (20 -22). These are ubiquitously expressed, evolutionarily conserved proteins that couple extracellular signals to various cellular responses (20 -22). All of these proteins have the inherent ability to undergo conformational changes in response to the alternate binding of GDP and GTP. The GDP-bound "off" state and the GTP-bound "on" state recognize distinct effector proteins, thereby allowing these proteins to function as two-state molecular "switches." Importantly, cycling between the two forms does not occur spontaneously. Activation requires guanine nucleotide exchange factors to induce the dissociation of GDP to allow association of the more abundant GTP, and deactivation requires GTPase-activating proteins (GAPs) to bind to the GTP-bound form to enhance the rate of intrinsic GTPase activity (20 -22). GAP1 IP4BP along with the related proteins GAP1 m , RASAL, and CAPRI (23-30) is composed of tandem N-terminal C 2 domains, a C-terminal pleckstrin homology (PH) domain adjacent to a Bruton's tyrosine kinase (Btk) motif, and a central catalytic Ras GAP-related domain. Associated with th...

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Extracellular calcium concentration controls the frequency of intracellular calcium spiking independently of inositol 1,4,5-trisphosphate production in HeLa cells

Cited by 73 publications

References 53 publications

Control of calcium oscillations by membrane fluxes

Control of calcium oscillations by membrane fluxes

The frequencies of calcium oscillations are optimized for efficient calcium-mediated activation of Ras and the ERK/MAPK cascade

Analyzing the Role of the Putative Inositol 1,3,4,5-Tetrakisphosphate Receptor GAP1IP4BP in Intracellular Ca2+ Homeostasis

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