(The FASEB Journal. 1999;13:S209-S215.)
© 1999 FASEB
Imaging structured space-time patterns of Ca2+ signals: essential information for decisions in cell division
ROBERT B. SILVER1
Marine Biological Laboratory, Woods Hole, Massachusetts 02543, USA
1Correspondence: Marine Biological Laboratory, Woods Hole, MA 02543, USA. E-mail: rsilver{at}mbl.edu
 |
INTRODUCTION
|
|---|
STRUCTUREAND FUNCTION are interwoven within the fabric of essential
cellular processes. The history of cell biology, especially throughout
the past half century, has relied on integrated morphological and
biochemical characterizations of specific processes. Many pioneers,
Keith Porter being especially notable, have demonstrated that
structures revealed through light and electron microscopy provided both
a physical and conceptual scaffold on which biochemical and biophysical
processes are conducted—a biochemical and biophysical cytology.
Consideration of structure, however, is often limited to consideration
of spatial dimensions of multi-molecular physical assemblies whose
actions are rapid with respect to developmental processes. In this vein
we can ask, "Is there is space-time structure to the regulatory
biochemistry and transductions of dynamical cellular processes?" If
such a space-time structure exists, then knowledge of its scale and
bounds will be essential in establishing an understanding of
fundamental biological processes.
To better understand the dynamics of these processes and their
facilitating scaffold, we need to consider cellular processes in one
temporal dimension as well as two or more spatial dimensions (i.e.,
observations along one temporal and two spatial dimensions of an
optical section of a cell). Extending this notion of space-time
structure to cellular signaling, we can apply mathematical approaches
to learn if there is information content in those signals. If the
cellular chemistry and physics of dynamical cellular processes does
exists as a nonrandom structure, and there is inherent, nonrandom
space-time structure to signals of dynamical cellular processes, then
we may discover that it can lead to a more detailed understanding of
that, and other related, processes.
|
CALCIUM SIGNALS IN MITOSIS: WHAT IS THE NATURE OF THE MESSAGE?
|
|---|
Calcium signals that control cell function present us with a
conundrum. Calcium signals are used in a large proportion of regulatory
pathways and are thus considered ubiquitous in cell biology, yet they
are also selective or specific in the control exerted among myriad
functions within a common cytoplasm. How this complex messaging is
achieved through a single ion, calcium, remains unsolved. Considering
cell signals in the light of Communication Theory (e.g., ref
27
) teaches us that such signals acting in a system as
complex as living cells must have information content well beyond one
bit (i.e., ‘on’ and ‘off’, or ‘start’ and ‘stop’. Within this
paradigm applicable, then, we should find affirmative answers and
supporting quantitative evidence to the questions: Is there evidence
for such structure, and thus information content, in a calcium signal?
Are there discernable biochemical and structural bases for such
space-time structures signals?
Among the fundamental cellular processes, a calcium signal precedes,
and is required for, nuclear envelope breakdown (NEB)
(1
2
3
4
5
6
7
8
9
10
11
12
13
14)
. Across cell and tissue biology, an increasing
body of evidence indicates that temporally patterned
Ca2+ signals, whose durations range from
milliseconds through tens of seconds, are essential for regulation of
cell function (6
, 9
10
11
12
, 14
15
16
17
18
19
20
21
22
23)
. Various mechanisms for
calcium release, which rely on various agonists, have been described
and modeled, including: wholesale release (12
, 16)
, waves
(17
, 22
, 24)
, oscillations (6
, 12
, 16
, 17
, 20
, 24
25
26)
, and fine-structured space-time patterns of very limited
spatial and temporal scope (6
, 9
, 27
28
29
30
31)
. Some calcium
signals appear to involve diffusion of Ca2+ over
relatively large distances, while others appear to remain localized to
the site of release (8
, 9
, 14
, 24
, 28
, 31
, 32)
.
Studies from this laboratory have shown that the pre-NEB
Ca2+ signal occurs as structured, nonrandom
space-time patterns of several thousand quantum emission domains (QEDs)
that are generated, and act, within 1 µM of the site of calcium
release within perinuclear microdomains (14
, 33
34
35
; see
Fig. 1
Based, in part, on our quantitative analyses we have hypothesized that
the pre-NEB Ca2+ signals, which do not spread
beyond their microdomain, are evoked by a mechanism using reduced
leukotriene B4 (LtB4) as
the agonist. Consistent with that hypothesis, phospholipase
A2 (PLA2) and other enzymes
needed to produce LtB4, should be present, and
phospholipase C (PLC) should be absent from the calcium regulatory
endomembranes of (prophase) mitotic apparatus (MA), while both should
be present in whole cells; indeed, that is the case.
View larger version (88K):
[in this window]
[in a new window]
|
Figure 1. A) A multispectral video image of 10 s of the
pre-nuclear envelope breakdown calcium signal in a second cell cycle
sand dollar (Echinaracnius parma) embryo. Note that the
calcium-dependent aequorin luminescence signal is found around the
centrally located nucleus. The cell on the left was injected with
hcp-r-aequorin, the cell on the right was uninjected.
Experimental conditions are described in refs 8
, 14
, and 34
. Bar = 20 µM. B) A transmission
electron micrograph showing calcium regulatory endomembranes, derived from endoplasmic
reticulum, associated with microtubules in the mitotic apparatus.
Experiential conditions are described in ref 38
. Bar = 200 nm. C) A scanning electron micrograph of a
prophase mitotic apparatus isolated from a first cell cycle sea urchin
embryo, showing the nucleus flanked by the asters. Note the
preponderance of discrete membrane vesicles in the asters. Experimental
conditions are described in ref 38
. Bar = 5 µM.
D) A sketch showing the proposed model for regulation of
the prenuclear envelope breakdown calcium signal through controlled
synthesis of leukotriene B4 (e.g., refs
46
, 47
, 56
), including integration of the pentose
phosphate pathway (e.g., ref 47
), and regeneration of ATP
through creatine kinase (e.g., ref 57
).
|
|
|
ENDOMEMBRANE CONTROL OF CALCIUM IN MITOTIC APPARATUS
|
|---|
An important empirical step the study of mitosis came with methods
for isolating and characterizing the MA. The first successful isolation
of MA was that of Mazia and Dan (36)
and the later work of
Kane (37)
(reviewed in ref 38
). Several
workers, notably Harris, Paweletz, and Hepler, promoted the notion that
calcium regulation through MA-associated endomembranes (e.g.,
endoplasmic reticulum amid spindle and astral microtubules); those
studies were based on morphological and histochemical methods and were
therefore limited to inference. Silver et al. provided the first direct
demonstration of calcium regulation by endomembranes within the MA
came with the isolation of native MA whose osmotically active
endomembranes exhibited ATP-dependent calcium uptake activity
(38)
. Subsequent work from Silver’s lab showed that the
MA-associated calcium pump, which shared epitopic homology with the
calcium pump of smooth muscle, was required for mitosis (38
, 39)
. Independently, Wolniak (40)
and Silver
(39
, 41)
, using calcium-7-chlortetracycline and
immunofluorescence labeling methods, showed that discrete (punctate)
MA-associated endomembrane stores of calcium were associated with the
spindle and astral fibers of plant and animal cells, respectively.
The essential relationship between a specifically timed calcium signal
from endomembranes and NEB and subsequent DNA synthesis, and the
interaction of that signal with a mitotic clock mechanism, was
established by Silver (8
, 41)
. Furthermore, several labs
reported calcium transients arising in the vicinity of the nucleus
using calcium reporters ranging from quin II (e.g., refs 40
, 42
) to fura2 (e.g., refs 43
, 44
) and aequorin
(e.g., ref 14
).
It was with aequorin that the discrete nature of the pre-NEB calcium
signal was most evident; the pre-NEB calcium signal was found to occur
within microdomains (Fig. 1A
) and that the signals had
inherent and decipherable structure in space and time. The first
notable point from these studies was that the calcium pump and ion
channels involved in generating the calcium signals were juxtaposed
with the structure whose assembly was controlled—a situation similar
to the intimate spatial arrangement of the sarcoplasmic reticulum and
the sarcomere revealed in part through the studies of, and discussed
by, Franzini-Armstrong in this volume. The concept of calcium
microdomains was also seen to occur at the synaptic preterminal, where
calcium influx across plasma membrane ion channels triggers secretion
of chemical neurotransmitter at multiple sites along a synapse
(10
, 11
, 29
, 30
, 45)
.
|
WHAT IS THE SPATIAL NATURE OF REGULATION OF PRE-NEB CALCIUM SIGNALS?
|
|---|
Quantitative analysis of the space-time structure of the pre-NEB
calcium signal revealed another interesting clue to the regulation of
calcium signals and mitosis, namely that neither the calcium nor the
agonist that evoked the calcium release from endomembranes did not
spread over distances <1 µM. That analysis ruled out a freely
diffusible agonist such as 1,4,5-inositol trisphosphate
(IP3), which is typically found to be generated
at the plasma membrane in response to a stimulus interacting with
receptors at the cell surface—a condition well established to not be
required for mitosis reviewed in refs 8
, 14
).
Those analyses, viewed in light of the earlier studies of fine
structure of the size and distribution of endomembranes in mitotic
cells, and especially in the vicinity of the nucleus, it was proposed
that the calcium signals were generated locally and acted locally in
relation to the site of their release (8
, 14)
.
Furthermore, it was proposed that the enzymatic machinery, and probably
substrate, that produces the pre-NEB calcium signal agonist were also
present on those same endomembranes (14)
.
Recent findings demonstrate that that proposal is the organization that
provides an accurate window on the cell; LtB4 can
serve as the agonist for pre-NEB calcium signals, and the enzymes
needed to produce LtB4 are, in fact, present and
enriched on the calcium regulatory endomembranes recruited into
prophase MA (46
, 47)
. Enzymological and immunoblot methods
have shown that PLA2, 5-lipoxygenase, leukotriene
A4 hydrolase, glutathione S-transferase, and
glutathione reductase are all present on the calcium regulatory
endomembrane subfractions of whole cells and prophase MA. Indeed, these
enzymes are enriched within the prophase MA. That provides the
enzymatic activities to produce LtB4 from
endomembrane phospholipid, and thus evoke Ca2+
release and also a shunt mechanism—production of leukotriene
C4 (LtC4) in the presence
of adequate levels of reduced glutathione (GSH), thus preventing
inopportune LtB4-mediated calcium release. In
contrast, phospholipase C activity, needed to produce
IP3, although present in whole cells, is absent
from the prophase MA. [This scheme is consistent with and analogous to
the compartmentalized arrangement of cytochromes on the inner
mitochondrial membrane first seen as ‘globular structural units’
(48
49
50
51)
, which were consistent with the chemi-osmotic
theory of Mitchell (52
, 53)
.]
In this paradigm (see ref 47
and Fig. 1D
), a
localized presence of reduced glutathione (GSH) is required (e.g.,
through action of glutathione S-transferase), which catalyzes the
reaction:
and glutathione reductase, which provides the GSH from oxidized
glutathione (GSSG) through the reaction:
The principal source for NADPH in animal cells is the oxidative
branch of the pentose phosphate pathway (PPP); in plant cells, NADPH is
also produced by chloroplasts. In oxidative PPP, NADPH is produced
through the action of glucose-6-phosphate dehydrogenase on
glucose-6-phosphate in the reaction:
In a subsequent reaction step following action of lactonase on
6-phospho-glucono-gamma-lactone to yield 6-phosphogluconate, a second
NADPH can be produced by the action of 6-phosphogluconate
dehydrogenase:
In other studies, (46
, 47)
we have established that
glucose–phosphate dehydrogenase is present on the calcium regulatory
endomembranes of prophase MA. Thus, the calcium regulatory
endomembranes of the prophase MA have each of the enzymes needed to
1) evoke calcium signals through localized generation of
leukotriene B4; 2) prevent precocious
calcium release using a shunt of leukotriene A4
to leukotriene C4 by action of glutathione
S-transferase with GSH; and, 3) produce NADPH, by way of
glucose-6-phosphate dehydrogenase (and possibly 6-phosphogluconate
dehydrogenase) proximal to glutathione reductase production of GSH.
This paradigm in which the enzymes necessary to generate a calcium
signal whose agonist does not diffuse beyond 1 µM, in effect
remaining localized to the site where calcium signals arise and act,
has led to developing the following reaction scheme for the regulation
of pre-NEB calcium signals through LtB4 (Fig. 1D
). In this scheme, based on components that we have
established to be present as part of the calcium regulatory
endomembranes, one can trace activities from initial formation of
arachidonic acid by action of PLA2 to the switch
at LtA4 to yield either
LtC4 and no calcium release or, in the absence of
available GSH, evocation of calcium release by
LtB4, which then spontaneously oxidizes to an
inactive form. This scheme is supported by a compartmentalized
metabolic model under development by Wastney and Silver (Wastney and
Silver, preliminary results) and is supported by recent work of
Pearson, Ponce-Dawson, and Keizer (personal communication from J. E. Pearson), which finds through purely numerical means that calcium
release events must be localized (i.e., near to the sites of
calcium-stimulated action; e.g., within microdomains).
|
OVER WHAT TEMPORAL AND SPATIAL SCALE ARE THE PRE-NEB CALCIUM SIGNALS LIKELY TO ACT?
|
|---|
Invoking the concept of microdomains provides us a means of
setting useful bounds within which we can establish the scale for
temporal and spatial regulation and effects of the signal. The unity
event in these signals is the release of calcium [i.e., the
agonist-induced flow of calcium through the endomembrane calcium
channel, for example, 1 ms (e.g., refs 29
, 30
, 45
)]. As
all of the events within the microdomain either lead to or from the
calcium release event, all kinetic assessments must be performed with 1
ms as the incremental unit for temporal analysis (e.g., for
reaction-diffusion systems analysis). Such analyses might even have to
be conducted at times steps of 0.2–0.3 ms to account for Nyquist
sampling considerations.
The evident colocalization of enzymes needed for generation of an
agonist that evokes a calcium signal on the same membranes that are the
source of calcium, and juxtaposed to the site of the calcium regulated
process (e.g., NEB), is fully consistent with the concept of calcium
microdomains, for example, as used in analysis of calcium signals at
synaptic preterminals (11)
. Morphological surveys of the
calcium-regulatory vesicles in prophase through anaphase MA yields an
average vesicle diameter of 0.2–0.25 µM and a mean distance between
vesicle centers of 0.5 µM (e.g., ref 14
; Fig. 1B
). Thus, the spatial scale for analysis of the mechanism
for calcium release should be performed over that spatial scale (i.e.,
the gird size for quantitative analyses of the mechanism for regulation
of calcium signals and of calcium regulated processes should then be
bounded between the minimum of 0.2 and a maximum of 1 µM (based on
the diffusion limit for the calcium signal or its agonist
(14)
. One other important point to consider is that
microdomains within a given MA do not exhibit coherence in their
calcium release activities (i.e., actions within one microdomain are
not directly linked with activities in another microdomain). This is
evident when comparing microdomain patterns from successive temporal
intervals (e.g., fig. 8 of ref 14
) and the discontinuous
nature of disruption of the nuclear envelope at NEB.
Accretion of calcium regulatory endomembranes within asters provides
another clue to the structure/function relationships required for these
signals. In assembling the aster and the polarized microtubule arrays,
vesicles are collected through saltatory movement into an
ever-increasingly thick shell around the centrosome (e.g., refs
54
, 55
; Fig. 1C
). Those vesicles create
localized environments conducive to microtubule assembly and stability.
If the metabolic reactions catalyzed by endomembrane components are
entrainable, then coordinated activities can be achieved within a
volume limited by the diffusion of reactants and the
KD of the component enzymes and receptors for the
various substrates and ligands; the reaction-diffusion limits for which
would define the size of a given microdomain.
Thus, analyses of regulatory processes over excessively large
increments of temporal or spatial scales are unnecessary coarse and
will lead to inappropriate interpretations of mechanisms attendant to
observed events. This can be seen in two examples: one on the temporal
scale and the second illustrated on a spatial scale. Temporal
integrations over time scales typically used for ratiometric
fluorescence-based measurements of intracellular calcium concentrations
yield artifactual ‘waves’ where no such propagations were observed or
occurred (e.g., refs 14
, 33
34
35
). By the same token, too
coarse a spatial scale can obscure necessary detail and is a useful
caution to heed in image processing (deconvolution and reconstruction).
By the same token, overly fine grid scales are unnecessary and can
actually lead to failure of quantitative analyses through comprehensive
mathematical models.
|
IMPACTS OF QUANTITATIVE ANALYSIS IN CELL BIOLOGY—LOOKING FORWARD
|
|---|
The biological sciences, and cell biology in particular, have
undergone remarkable advancement over the past five decades. This
growth has resulted from the use of ever-more sophisticated means of
addressing fundamental biological questions with ever-increasing
accuracy and precision across a broadening spectrum of questions.
Indeed, our ability to develop an understanding on a quantitative
foundation, and to more readily identify cross-cutting ideas, concepts,
and mechanisms, places us at the horizon of what was imaginable only a
decade ago. Two decades ago such developments were the dreams of only a
few. That forward progress has had enormous impact on science and,
consequently, on society.
As computers have become more readily usable and accessible (largely
through the visionary efforts of the NSF and NIH), scientists have
found new means of analyzing and understanding the data they obtain and
revealing newly-appreciated relationships among data—accelerating our
acquisition of knowledge and understanding. Quantitative analysis and
allied computational methods are ‘the looking glass’ for the most
complex questions we face today and, like the word processor, are
becoming more widely used for an ever-increasing number of complex
tasks. Some recent examples of advances in biology and medicine
fostered through computational processing and quantitative analysis
include: 1) new understandings of the mechanism of
generation and propagation of chemical and electrical signals essential
for cell and tissue function (e.g., cardiac muscle contraction and
rhythmicity); 2) 3-dimensional reconstruction of cell and
tissue structures from light and electron micrographs (e.g., work
reported by Aebi, McIntosh, and Satir) and dynamical cell processes
(e.g., work reported by Larabell, Lippincott-Schwartz, Salmon, and
Silver) through the use of image processing and tomographic once
reserved for airborne and satellite imaging and medical applications;
and, 3) modeling of metabolism, including interactions among
substrates and enzymes, sequences of reactions, and the impact of
various pharmacological agents on those pathways.
In this scenario, 2.5-dimensional renderings (what are now colloquially
called 3-dimensional reconstructions) are giving rise to true
3-dimensional reconstructions. Similarly, many existing issues will
need to be readdressed, such as development and use of accurate
deconvolution algorithms for microscopes and cells/tissues/specimens;
it is simply no longer sufficient to erode image to get sharp lines
that match preconceived notions. In addition to the computational
methods, new forms of imaging using polarized light (circular,
interference contrast) will find increasing importance.
If we take clues from our past, we can see a bright future for cell
biology—especially with the advent of analysis, modeling, and
simulations of cellular processes. Such modeling efforts, and the
understanding and new knowledge they afford, will bring together the
vastness of the interplay of morphology, cytology, biochemistry, and
quantitative methods from mathematics, chemistry, and physics. As the
problems become tractable, and computing resources in the 100 teraflop
range and beyond become available to those with the actual need for
such capabilities (such as through the DOE ASCI and Next Generation
programs and new multiagency research initiatives being launched by
NSF, NIH, and DOE) we will enter a new era in cell biology that draws
together more of the fundamental principles into our analyses and
understanding. With proper nurturing, it is likely that 50 years hence,
at the time of the 100th anniversary of Porter’s publication of the
first electron micrographs of a cell, we will see a new face for cell
biology that embraces a norm of interdisciplinary collaborations among
biologists, physicists, chemists, mathematicians, and engineers; the
information, insights, and view across that horizon should be
spectacular.
|
ACKNOWLEDGMENTS
|
|---|
Thanks are extended to Drs. Shimomura (Marine Biological
Laboratory), Kishi and Inouye for their gifts of the coelenterazine
derivatives used to prepare the semisynthetic aequorin preparations
used in this study, and Drs. Shinya Inoué, Rodolfo Llinás,
Daniel Mazia, John E. Pearson, Howard Rasmussen, Raoul F. Reiser, Roger
D. Sloboda, Mitsuyuki Sugimori, Meryl E. Wastney, Stephen M. Wolniak,
and John F. Wootton for their support and helpful comments and
discussions. The work described here was supported by grants from the
Molecular and Cellular Biosciences Program of the National Science
Foundation, and that support is gratefully acknowledged.
|
REFERENCES
|
|---|
-
Mazia, D. (1961) Mitosis and the physiology of cell division. Brachet, J. Mirsky, A. E. eds. The Cell Vol. 3,77-412 Academic New York.
-
Mitchison, J. M. (1971) The Biology of the Cell Cycle Cambridge University Press Cambridge, U.K..
-
Baker, P. F., Hodgkin, A. L., Ridgeway, E. B. (1971) Depolarization and calcium entry in squid giant axon. J. Physiol. (Lond.) 218,709-755[Abstract/Free Full Text]
-
Brown, J. E., Blinks, J. R. (1974) Changes in intracellular free calcium concentration during illumination of invertebrate photoreceptors. J. Gen. Physiol. 64,643-665[Abstract/Free Full Text]
-
Brown, J. E., Rubin, L. J., Ghalayini, A. J., Tarver, A. P., Irvine, R. F., Berridge, M. J., Anderson, R. E. (1984) Myo-inositol polyphosphate may be a messenger for visual excitation in Limulus photoreceptors. Nature (London) 312,315-321[Medline]
-
Rasmussen, H. (1985) Rubin, R. P. Weiss, G. B. Putney, J. W., Jr. eds. Calcium in Biological Systems ,13-22 Plenum New York.
-
Wolniak, S. M., Bart, K. M. (1986) Nifedipine reversibly arrests mitosis in stamen hair cells of Tradiscantia. Eur. J. Cell Biol. 39,273-277[Medline]
-
Silver, R. B. (1989) Nuclear envelope breakdown and mitosis in sand dollar embryos is inhibited by microinjection of calcium buffers in a calcium-reversible fashion, and by antagonists of intracellular Ca2+ channels. Develop. Biol. 131,11-26[Medline]
-
Alkon, D. L., Rasmussen, H. (1989) A spatial-temporal model for cell activation. Science 239,998-1005
-
Llinás, R., Sugimori, M., Silver, R. B. (1991) Imaging calcium concentration microdomains in the squid giant synapse. Biol. Bull. 181,316-317
-
Llinás, R., Sugimori, M., Silver, R. B. (1992) Microdomains of high calcium concentration in a presynaptic terminal. Science (Washington, D.C.). 256,677-679[Abstract/Free Full Text]
-
Clapham, D. E. (1995) Calcium signaling. Cell 80,259-268[Medline]
-
Bootman, M. D., Berridge, M. J. (1995) The elemental principles of calcium signaling. Cell 83,675-678[Medline]
-
Silver, R. B. (1996) Calcium, BOBs, QEDs, microdomains and a cellular decision: control of mitotic cell division in sand dollar blastomeres. Cell Calcium 20,161-179[Medline]
-
Heilbrunn, L.V. (1956) The Dynamics of Living Cytoplasm Academic New York.
-
Woods, N. M., Cuthbertson, K. S., Cobbold, P. H. (1986) Repetitive transient rises in cytoplasmic free calcium in hormone-stimulated hepatocytes. Nature (London) 319,600-602[Medline]
-
Yoshimoto, Y., Iwamtsu, T., Hirano, K.-I., Hiramoto, Y. (1986) The wave pattern of free calcium release upon fertilization in medaka and sand dollar eggs. Develop. Growth Differ. 28,583-596
-
Hepler, P. K., Callaham, D. A. (1987) Free calcium increases during anaphase in stamen hair cells of Tradescantia. J. Cell Biol. 105,2137-2144[Abstract/Free Full Text]
-
Goldbeter, A., DuPont, G., Berridge, M. J. (1990) Minimal model for signal-induced Ca2+ oscillations and for their frequency encoding through protein phosphorylation. Proc. Natl. Acad. Sci. USA 87,1461-1465[Abstract/Free Full Text]
-
Tse, A., Hille, B. (1991) GnRH-induced Ca2+ oscillations and rhythmic hyperpolarizations of pituitary gonadotropes. Science 255,462-464
-
Allbritton, N. L., Meyer, T., Stryer, L. (1992) Range of messenger action of calcium ion and inositol 1,4,5-trisphosphate. Science 258,1812-1815[Abstract/Free Full Text]
-
Jaffe, L. F. (1993) Classes and mechanisms of calcium waves. Cell Calcium 14,736-745[Medline]
-
Stricker, S. A. (1995) Time-lapse confocal imaging of calcium dynamics in starfish embryos. Develop. Biol. 170,496-518[Medline]
-
Gilkey, J. C., Jaffe, L. F., Ridgway, E. B., Reynolds, G. T. (1978) A free calcium wave traverses the activating egg of the medaka. Oryzias latipes. J. Cell Biol. 76,448-466
-
Cheng, H., Lederer, W. J., Cannell, M. B. (1993) Calcium sparks: elementary events underlying excitation-contraction coupling in heart muscle. Science 262,741-744
-
Putney, J. W., Jr (1998) Calcium signaling: up, down, up, down What’s the point?. Science 279,191-192[Free Full Text]
-
Shannon, C. E., Weaver, W. (1964) The Mathematical Theory of Communication University of Illinois Press Urbana.
-
Simon, S. M., Llinás, R. R. (1985) Compartmentalization of the submembrane calcium activity during calcium influx and its significance in transmitter release. Biophys. J. 48,485-498[Abstract/Free Full Text]
-
Silver, R. B., Sugimori, M., Lang, E. J., Llinás, R. (1994) Time resolved imaging of Ca2+-dependent aequorin luminescence of microdomains and QEDs in synaptic preterminals. Biol. Bull. 187,293-299[Abstract]
-
Sugimori, M., Lang, E. J., Silver, R. B., Llinás, R. (1994) High resolution measurement of the time course of calcium-concentration microdomains at squid presynaptic terminals. Biol. Bull. 187,300-303[Abstract]
-
Thomas, A. P., Bird, G. S. J., Hajnóczky, G., Robb-Gaspers, L. D., Putney, J. W. (1996) Spatial and temporal aspects of cellular calcium signaling. FASEB J 10,1505-1517[Abstract]
-
Keizer, J., DeYoung, G. (1992) Two roles for Ca2+ in agonist stimulated Ca2+ oscillations. Biophys. J. 61,649-660[Abstract/Free Full Text]
-
Silver, R. B., Reeves, A. P., Whitman, M., Kelley, B. (1994) Analysis of spatial and temporal patterns in the Ca2+ signal that signals nuclear envelope breakdown in sand dollar (Echinaracnius parma) cells. Biol. Bull. 187,237-238[Medline]
-
Silver, R. B. (1994) Video light microscopic imaging of the calcium signal that initiates nuclear envelope breakdown in sand dollar (Echinaracnius parma) cells. Biol. Bull. 187,235-237[Medline]
-
Silver, R. B., Reeves, A. P., Kelley, B. P., Fripp, W. J. (1996) Inherent nonrandom structure of the pre-nuclear envelope breakdown calcium signal in sand dollar (Echinaracnius parma) embryos. Biol. Bull. 191,278-279
-
Mazia, D., Dan, K. (1952) The isolation and biochemical characterization of the mitotic apparatus of dividing cells. Proc. Natl. Acad. Sci. USA 38,826-838[Free Full Text]
-
Kane, R. E. (1962) The mitotic apparatus: isolation by controlled pH. J. Cell Biol. 12,47-55[Abstract/Free Full Text]
-
Silver, R. B., Cole, R. D., Cande, W. Z. (1980) Isolation of mitotic apparatus containing vesicles with calcium sequestration activity. Cell 19,505-519[Medline]
-
Silver, R. B. (1986) Mitosis in sand dollar embryos is inhibited by antibodies directed against the calcium transport enzyme of muscle. Proc. Natl. Acad. Sci. USA 83,4302-4306[Abstract/Free Full Text]
-
Wolniak, S. M., Hepler, P. K., Jackson, W. T. (1983) Ionic changes in the mitotic apparatus and the metaphase/anaphase transition. J. Cell Biol. 96,598-605[Abstract/Free Full Text]
-
Silver, R. B. (1990) Calcium and cellular clocks orchestrate cell division. Ann. NY Acad. Sci. 582,207-221[Medline]
-
Wolniak, S. M., Bart, K. M. (1985) The buffering of calcium with Quin 2 reversibly forestalls anaphase onset in stamen hair cells of Tradescantia. Eur. J. Cell Biol. 39,33-40[Medline]
-
Poenie, M., Alderton, J., Tsien, R. Y., Steinhardt, R. A. (1985) Changes in free calcium levels with stages of the cell division cycle. Nature (London) 315,147-149[Medline]
-
Keith, C. H., Ratan, R., Maxfield, F. R., Bajer, A., Shelanski, M. L. (1985) Nature (London) 316,848-850[Medline]
-
Llinás, R., Sugimori, M., Silver, R. B. (1995) Time resolved calcium microdomains and synaptic transmission. J. Physiol. (Paris) 89,77-81[Medline]
-
Silver, R. B., King, L. A., Wise, A. F. (1998) Calcium regulatory endomembranes of prophase mitotic apparatus of sand dollar cells contain enzyme activities that produce leukotriene B4 but lack phospholipase C activity. Biol. Bull. 195,209-210
-
Silver, R. B. (1999) Leukotriene B4
evokes space-time patterned intracellular Ca2+
signals of mitosis. (submitted)
-
Sjostrand, F. (1963) A new ultrastructural element of the membranes in mitochondria and of some cytoplasmic membranes. J. Ultrastruct. Res. 9,340-361
-
Sjostrand, F., Barajas, L. (1968) Effects of modifications in conformation of protein molecules on structure of mitochondrial membranes. J. Ultrastruct. Res. 25,121-155[Medline]
-
Sjostrand, F. (1978) The structure of mitochondrial membranes: a new concept. J. Ultrastruct. Res. 64,217-245[Medline]
-
Sjostrand, F., Barajas, L. (1970) A new model for mitochondrial membranes based on structural and on biochemical information. J. Ultrastruct. Res. 32,293-306[Medline]
-
Mitchell, P. (1961) Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature (London) 191,144-148[Medline]
-
Mitchell, P. (1967) Protein-translocation phosphorylation in mitochondria, chloroplasts and bacteria: natural fuel cells and solar cells. Fed. Proc. 26,1370-1379[Medline]
-
Rebhun, L. I. (1967) Structural aspects of saltatory movement. J. Gen. Physiol. 50,233-239
-
Rebhun, L. I. (1972) Polarized intracellular particle transport: saltatory movements and cytoplasmic streaming. Int. Rev. Cytol. 32,93-117[Medline]
-
Silver, R. B. (1995) Leukotriene B4 induces release of calcium from endomembrane stores in eggs and mitotic cells of the sand dollar Echinaracnius parma. Biol. Bull. 189,203-204
-
Silver, R. B., Saft, M. S., Taylor, A. R., Cole, R. D. (1983) Identification of non-mitochondrial creatine phosphokinase activity in isolated sea urchin mitotic apparatus. J. Biol. Chem. 258,13287-13291[Abstract/Free Full Text]
TOP
INTRODUCTION
CALCIUM SIGNALS IN MITOSIS:...
