Endocrinology Vol. 139, No. 6 2988-2993
Copyright © 1998 by The Endocrine Society
Effects of Cellular Interactions on Calcium Dynamics in Prolactin-Secreting Cells1
Elizabeth J. Abraham,
Carlos Villalobos and
L. Stephen Frawley
Laboratory of Molecular Dynamics, Department of Cell Biology and
Anatomy, Medical University of South Carolina, Charleston, South
Carolina 29425
Address all correspondence and requests for reprints to: Dr. L. Stephen Frawley, Laboratory of Molecular Dynamics, Department of Cell Biology and Anatomy, Medical University of South Carolina, Charleston, South Carolina 29425. E-mail: frawleys{at}musc.edu
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Abstract
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Signals derived from other pituitary cells can have a dramatic effect
on PRL gene expression and secretion by mammotropes. However, the
intracellular mechanisms by which these effects are manifested on the
target cell remain unexplored. Inasmuch as calcium is a key modulator
of both gene expression and hormone export in mammotropes, we evaluated
the effects of cell to cell contact vs. specific
cellular interactions on calcium dynamics within these cells. This was
accomplished by digital-imaging fluorescence microscopy of fura-2 in
pituitary cells that were isolated in culture (singles) or adjoining
one other cell (doublets). After calcium imaging, we then subjected
cells to immunocytochemistry for PRL. Doublets were further categorized
into mammotropes attached to another mammotrope (M-M) or to a
nonmammotrope (M-nonM). We then calculated and compared Mean
[Ca2+]i values as well as Oscillation Indices
(which reflect the oscillatory behavior of cells) in singles and
doublets and found that they were not different (P
> 0.05). However, the phenotype of the adjoining cell had a profound
influence on both of these calcium parameters, such that the presence
of one mammotrope could consistently decrease (P <
0.05) the Mean [Ca2+]i value (39.17 ±
3.83 vs. 56.24 ± 5.56 in M-nonM) and Oscillation
Index (10.19 ± 1.76 vs. 21.21 ± 3.73 in
M-nonM) of its neighboring counterpart. A more detailed analysis of
oscillatory patterns in these cells revealed that nonoscillators were
more abundant in M-M (23%) than in M-nonM (12%) doublets. Taken
together, our results indicate that PRL-secreting cells convey a
signal that dampens the oscillatory behavior of
neighboring mammotropes. Thus, it appears that it is the phenotype
rather than the physical presence of a neighbor that controls
intercellular regulation of calcium dynamics among mammotropes.
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Introduction
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THERE IS NOW overwhelming experimental
evidence to support the existence and importance of intercellular
communication among cells of the anterior pituitary gland, and the
PRL-secreting mammotrope has been a model of choice for studies of this
phenomenon. Evidence in support of this view derives from studies
demonstrating that secretion of a hormone, such as PRL, is influenced
by the addition or elimination of other secretory cell types of the
pituitary (see Refs. 1–3 for reviews). Moreover, cell
density-dependent modulation of hormone secretion within pituitary
cultures also suggests the existence of cell-cell interactions (4, 5).
Indeed, mammotropes exist in a three-dimensional configuration of a
tissue. Here, they are in intimate contact with other cells from which
they receive a variety of signals that have the potential to regulate
both gene expression and hormone release. Yet, despite the wealth of
information favoring intercellular control of mammotrope function,
surprisingly little is known about how these effects are transduced
within the target cell. One particularly strong candidate to function
as an intermediary in this process is calcium. Clearly, calcium plays a
pivotal role in cell to cell adhesion of many cell types, including
those of the pituitary, and cell-cell or cell-matrix adhesions have
been shown to dramatically influence the expression of a number of
hormonal genes (6, 7, 8, 9). Like most pituitary cells, mammotropes exhibit
spontaneous oscillations of intracellular free calcium
([Ca2+]i) that are driven by electrical
activity (10, 11, 12) and are positively correlated with basal hormone
release (13, 14). In addition, pharmacological manipulation of
[Ca2+]i with agonists or antagonists evokes
predictable changes of PRL release and messenger RNA accumulation (15, 16). Thus, calcium is a pivotal regulator of the PRL biosynthetic
pathway from the point of gene transcription to that of hormone export,
but the effects of cell to cell signaling on
[Ca2+]i dynamics remain unexplored.
In a recent study on intercellular communication and gene expression,
we attempted to partition the effects upon a mammotrope of having a
neighbor (cell to cell contact) as opposed to the nature (phenotype) of
that neighbor, and found that the latter consideration was far more
important for PRL gene expression than the former (17). Our strategy
for that investigation was to make "real-time" measurements of PRL
gene expression in living, primary pituitary cells and to follow this
with immunocytochemistry (for post facto identification of
the phenotype of a given cell or its neighbor). The paradigm for the
present study was conceptually identical to this, with the only major
departure being that digital-imaging fluorescence microscopy of a
calcium-sensitive dye was substituted for analysis of gene expression.
In this manner, we could attempt to determine whether the internal
calcium dynamics of a mammotrope were also modulated by the presence
and/or secretory nature of a neighbor.
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Materials and Methods
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Animals and cell culture
Anterior pituitary glands from primiparous lactating rats (days
5–12 postpartum) were collected after decapitation and enzymatically
dispersed into single cells as described previously (18). Cells were
allowed to attach onto poly-lysine coated, gridded, glass coverslips at
a density of 250,000 cells/90 µl defined medium [equal volumes of
phenol-free M-199 with Nutrient mix F-12 (Life Technologies, Grand
Island, NY), supplemented with 0.1% BSA, insulin-transferrin-selenium
Premix, and antibiotics] and then placed into 35-mm plastic Petri
dishes. After a 1-h attachment period, defined medium containing 5%
FBS was added, and the cells were cultured at 37 C in 95% air: 5%
CO2 for 2 days until they were used for
[Ca2+]i imaging or gap-junction coupling
experiments.
Digital-imaging fluorescence microscopy of fura-2
Loading of cells. On day 2 of culture, cells were washed and
loaded with 2 µM of the calcium-sensitive dye fura-2/AM
(Molecular Probes, Eugene, OR) in phenol-free DMEM (Life
Technologies) supplemented with 5 mM D-glucose,
2 mM L-glutamine, 1 mM sodium
pyruvate, 5 mM sodium bicarbonate, 10 mM HEPES,
and 34 mM sodium chloride (pH 7.4). After 1.5 h, cells
were washed 3 times with the same medium and placed on the heated stage
(at 37 C) of an inverted microscope equipped with a 40x objective.
Cells were alternately epi-illuminated with a UV-light at 340 and 380
nm excitation wavelength. Light emitted above 520 nm was recorded for
20 min and analyzed using an Attofluor Ratio Vision System (Atto
Instruments, Rockville, MD). For every raw image, a total of 4
videoframes (2 frames per wavelength) were acquired. Then, a ratio of
the mean fluorescence intensity at 340/380 was calculated with an
overall time resolution of 4 sec. Calibration of fluorescence ratios
[R] was performed according to the formula described by Grynkiewicz
et al. (19). Fura-2 standards were used to construct a
calibration curve. This curve was then used to convert ratios [R]
into [Ca2+]i (20, 21).
Analysis of [Ca2+]i. In the
current study, we calculated two functional parameters of
Ca2+ dynamics: the Mean [Ca2+]i
value and the Oscillation Index. As described elsewhere, these
parameters reflect distinctly different ways of evaluating the same
data set (22, 23). The Mean [Ca2+]i was
obtained by integrating values collected at 4-sec intervals and
dividing them by time of measurement. The Oscillation Index, on the
other hand, denotes the relative change in
[Ca2+]i during the collection period. We
achieved this by calculating the difference in
[Ca2+]i values between consecutive intervals
of measurement over the duration of sampling. Thus, it is possible that
a given cell could have a high Oscillation Index (because of high
frequency oscillations) even though its Mean
[Ca2+]i value is low, or
vice-versa.
Immunocytochemistry. After [Ca2+]i
imaging, cells were washed and fixed with B-5 buffered formalin for 45
min. They were then subjected to immunocytochemical detection for PRL
as controlled and described previously (18). PRL-positive cells were
revealed after exposure to diaminobenzidine (Sigma, St. Louis, MO)
solution for 6 min, and the same field previously used for
[Ca2+]i imaging was reidentified by its
position on the coverslip, which was photoengraved with a
numbered/lettered grid pattern.
Gap-junctions
The possible existence of functional gap-junctions between
anterior pituitary cells was determined by comicroinjecting Lucifer
yellow (4%) and dextran-rhodamine (0.1%) into one of a pair of
adjoining cells. Microinjection was achieved through finely pulled,
glass capillaries in series with an Eppendorf semiautomated
microinjection system (17). Ten minutes post injection, coverslips were
assembled into Sykes-Moore chambers that were filled with serum-free
DMEM. This assembly was then transferred to the stage of an Axiophot
microscope equipped with a UV light source and appropriate
excitation-emission filters for fluorescent visualization of Lucifer
yellow and rhodamine. As a positive control, we also coinjected
confluent cultures of GT1–1 neurons (a clonal GnRH cell line) with the
same ratio of fluorescent dyes used for pituitary cells. Previous
reports by other investigators confirmed the presence of functional
gap-junctions in the majority of these neurons (24).
Statistical analysis
Comparisons between any two treatment groups were made with a
two-tailed, Student’s t test and results were expressed as
mean + SEM. Data reported in Table 1
were analyzed using a two-way ANOVA
followed by a multiple comparisons test (Fisher’s least significant
difference). Differences were considered significant at
P < 0.05.
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Results
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Our initial aim was to evaluate the effect of cell to cell contact
on [Ca2+]i oscillations in mammotropes. To
this end, we combined digital-imaging fluorescence microscopy of fura-2
with immunocytochemistry for PRL (Fig. 1, A and B). Identified mammotropes that were cultured in isolation
(singles) or in physical contact with just one other cell (doublets)
were then compared in terms of the aforementioned
[Ca2+]i parameters. As shown in Fig. 2, Oscillation Index values for single
mammotropes and those in the doublet configuration were virtually
identical (P > 0.05). Likewise, the Mean
[Ca2+]i values for singles and doublets were
also indistinguishable (P > 0.05). These results
demonstrate that cell to cell contact per se does not
influence Ca2+ dynamics in mammotropes cultured under basal
conditions.
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Figure 1. Experimental protocol employed in this
study. A, Anterior pituitary cells (one doublet shown) were subjected
to [Ca2+]i measurements by digital-imaging
fluorescence microscopy of fura-2. The perimeter of each
box demarcates the area in which all fluorescence
measurements were recorded in that cell. Note that each
box corresponds to individual cell and does not overlap
with the adjacent one. Relative [Ca2+]i is
indicated in panel A by the warmer colors on the
ascending pseudocolor scale to the right. B, After
[Ca2+]i measurements, the same cells were
fixed and subjected to immunocytochemistry for PRL. In this particular
instance, the doublet shown is comprised of two mammotropes. C,
[Ca2+]i transients of the same cells are
illustrated. Note that the spontaneous oscillations were
asynchronous.
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After determining that the mere presence of another cell had
no measurable effect on [Ca2+]i in
mammotropes, we next assessed whether the nature (phenotype) of the
neighbor might have an influence. Accordingly, we performed
[Ca2+]i imaging on only those cells in the
doublet configuration and followed this with immunocytochemical
detection for PRL as before. Identified mammotropes in the doublet
configuration were subsequently categorized on the basis of whether
they were attached to another mammotrope (M-M) or to a nonmammotrope
(M-nonM; in these cells [Ca2+]i values of
mammotropes and not those of nonmammotropes were analyzed).
Interestingly, we found that both Oscillation Index and the Mean
[Ca2+]i values were significantly lower
(P < 0.05) for the M-M doublets when compared with
their M-nonM counterparts (Fig. 3).
Inasmuch as "averaged" responses do not reflect the oscillatory
behavior of individual mammotropes in the M-M or M-nonM categories, we
plotted the Mean [Ca2+]i value for each
mammotrope against its corresponding Oscillation Index value. As shown
in Fig. 4, doublets in the M-nonM
configuration and singles displayed a discrete subpopulation with a
relatively high Oscillation Index and Mean
[Ca2+]i value. A corresponding group of
highly active mammotropes was virtually absent for doublets in the M-M
category. Thus, the inhibitory effect of one mammotrope upon another
appears to be manifested preferentially upon those cells that are most
active in terms of Ca2+ dynamics.
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Figure 3. Spontaneous [Ca2+]i
oscillations are influenced by the phenotype of a neighboring cell.
Bars (mean + SEM) in panels A and B
represent Oscillation Indices and Mean
[Ca2+]i values, respectively, for mammotropes
in contact with another mammotrope (M-M; n = 52 cells) or a
nonmammotrope (M-nonM; n = 89 cells). Cells obtained from nine
different dispersions were used. *, P < 0.05
vs. M-nonM.
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Having established that the average oscillatory activity of M-M cells
is lower than for M-nonM cells, we then set out to determine the basis
for these differences. This was accomplished by analyzing the pattern
of spontaneous [Ca2+]i oscillations in M-M
and M-nonM doublets. Previous studies conducted in our laboratory
successfully characterized spontaneous
[Ca2+]i oscillations of mammotropes into the
following major patterns: (A) nonoscillating or "silent"; (B) high
frequency, low amplitude oscillations; and (C) high frequency, high
amplitude oscillations (20). In the present study, we found that
although M-M and M-nonM cells displayed similar types of oscillatory
profiles (Fig. 5), the relative
proportions exhibiting patterns A and C as well as the corresponding
Oscillation Indices and Mean [Ca2+]i values
of the latter profile were strikingly different (Table 1
).
Specifically, nonoscillators were 2-fold more abundant for M-M (23%)
than for M-nonM (12%) cells. More importantly, the Oscillation Index
and Mean [Ca2+]i of "C" type oscillators
were 2-fold higher in M-nonM than in M-M cells. Thus, the higher
frequency and amplitude of spontaneous
[Ca2+]i oscillations seen in those
mammotropes associated with nonmammotropes appear to contribute, at
least in part, to the increased oscillatory activity observed in this
subset of PRL secretors. Conversely, decreased oscillatory activity in
neighboring mammotropes may in part be due to an increase in the
proportion of nonoscillators in this configuration.
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Figure 5. Patterns of spontaneous
[Ca2+]i oscillations in M-M and M-nonM
doublets. All identified mammotropes were subgrouped based on their
oscillatory patterns into (A) nonoscillating, (B) high frequency, low
amplitude oscillations, and (C) high frequency, high amplitude
oscillations. Representative traces of each profile are depicted for
M-M and M-nonM cells. Note that there were no differences between A and
B type oscillators, but that the amplitude of "C" type oscillators
tended to be higher in M-nonM than in M-M cells.
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Although our results showed clearly that Ca2+ dynamics of
mammotropes were influenced by the neighboring cell, they did not
provide any insights as to whether the communication was paracrine or
juxtacrine. In an attempt to distinguish between these possibilities,
we coinjected Lucifer yellow and dextran-rhodamine into cells
maintained as doublets. The former fluorescent dye passes readily
through gap-junctions, whereas the cell membrane is impermeable to the
latter. Thus, the rhodamine complex served both as a means for
identifying the injected cell and as a control for membrane integrity.
Of 137 doublets studied in this manner, only three exhibited functional
gap-junctions, whereas the remainder showed no dye-transfer between
adjoining cells. Inasmuch as 60–65% of the cells in our pituitary
cultures were PRL-secretors, these data demonstrate clearly that
juxtacrine signaling mediated by gap-junction coupling cannot account
for the interactions we observed between mammotropes and their
neighbors. In contrast, gap-junction coupling was observed in the
majority of GT1–1 neurons coinjected with the same mix of dyes. A
final point worthy of mention is that we found no evidence to suggest
that adjacent cells were electrically coupled. As illustrated by the
representative example in Fig. 1C, cells in the M-M configuration (or
M-nonM, for that matter) were just as likely to exhibit dissimilar as
similar patterns of [Ca2+]i oscillations.
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Discussion
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Our results provide compelling evidence that cell to cell
communication has a dramatic influence on
[Ca2+]i dynamics within living mammotropes.
To be more specific, we found that the physical presence of a
neighboring cell per se had no influence on the
Ca2+ activity of a given mammotrope but that the secretory
nature of the neighbor was of paramount importance. Indeed, when one
mammotrope was in close physical apposition with another, there was a
striking reduction of the Oscillation Index (51.9%), and, to a lesser
extent, an attenuation of the Mean [Ca2+]i
value (30.3%). Inasmuch as the former parameter is a more direct and
reliable indicator of frequency/amplitude changes than the latter, it
seems reasonable to propose that most of this inhibitory effect was
attributable to a diminution of oscillatory activity as opposed to
modulation of the average amount of Ca2+ present. Moreover,
analysis of spontaneous [Ca2+]i oscillations
indicate that inhibition of such activity in M-M cells is not
attributable to the presence or absence of discrete oscillatory
phenotypes exhibited by M-nonM doublets. Instead, it is due to a
different distribution of mammotropes exhibiting each pattern. To be
more specific, there was a much higher proportion of nonoscillatory
cells in the M-M group than in the M-nonM category, and this increment
was achieved largely at the expense of the high frequency, high
amplitude oscillators. It appears, then, that PRL-secreting cells
convey a signal that dampens the oscillatory behavior of
neighboring mammotropes. Of course, an alternative interpretation that
deserves consideration is that nonmammotropes emit a signal that
stimulates [Ca2+]i oscillations in
adjoining mammotropes. If this were the case, one would expect to see a
preponderance of cells with both high Oscillation Indices and
[Ca2+]i values when mammotropes were attached
to nonmammotropes. In reality, this was not the case at all: the
scatter plots for M-nonM doublets and singles (Fig. 4) were extremely
similar. Thus, although we cannot completely exclude the possibility of
a stimulatory signaling mechanism to explain this phenomenon, our data
are more consonant with an inhibitory one.
Results conceptually similar to these were obtained in our
previous study in which we found that M-M doublets displayed a greatly
reduced level of PRL gene expression compared with their M-nonM
counterparts (17). The striking similarities of these responses raise
the possibility that inhibitory interactions between mammotropes on PRL
gene expression are mediated by changes of
[Ca2+]i oscillations. In support of this
possibility are observations that pharmacologic diminution of
[Ca2+]i leads to a decrease of PRL gene
expression, whereas an increase of [Ca2+]i
has an opposite effect (25, 26, 27).
How might such signals be transmitted from one mammotrope to
another? One can envision at least three possible mechanisms. The first
of these, gap-junctions, is rendered implausible by our direct
observation that this form of communication was exceedingly rare under
the present experimental conditions. A second possibility is electrical
coupling of adjacent cells. This scenario also seems highly unlikely
because electrically coupled cells typically display synchronized
oscillations, and we did not find any evidence for this in the present
study, even in M-M doublets. A final possibility entirely consistent
with our results is paracrine communication. Indeed, there is a wealth
of information supportive of paracrine actions on mammotropes (1, 2, 3, 28), and our efforts are currently focused on isolating and identifying
this putative signal.
Although the physiologic relevance of inhibitory interactions among
mammotropes remain to be unequivocally established, they may serve to
hold PRL gene expression and secretion in check until the mammotrope is
presented with a challenge from other regulatory (hypophysiotropic)
signals. This may be particularly relevant in areas where there is a
concentration of mammotropes such as near the poles of the anterior
pituitary (29).
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Acknowledgments
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The authors thank Dr. R. I. Weiner for providing the GT1–1
cells and Dr. L. Nuñez for sharing her cultures with us. We would
also like to thank W. J. Faught for assistance with microinjection
studies and J. Nicholson for access to the Attofluor Vision system. We
also thank Drs. S. T. Willard, M. D. Amstutz, and L.
Nuñez and Ms. A. Gore for expert critique of the manuscript.
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Footnotes
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1 This study was supported by funds from NIH \E
Grant DK-38215 and a USDA-Competitive Research Grant
(95-37206-2438). 
Received December 22, 1997.
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Top
Abstract
Introduction
