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Department of Physiology, University of Texas Southwestern Medical Center (Q.G., R.L.M.), Dallas, Texas 75235; Laboratories for Reproductive Biology, University of North Carolina (K.S.K.), Chapel Hill, North Carolina 27599
Address all correspondence and requests for reprints to: Dr. Robert L. Moss, Department of Physiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235-9049. E-mail: rmoss{at}mednet.swmed.edu
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and ERß), the role of ERs in the rapid action of
17ß-estradiol remains elusive. Here we report that the rapid action
of 17ß-estradiol is independent from the classical ER activation in
the modulation of membrane excitability. Under whole cell voltage clamp
recording configuration, 17ß-estradiol-induced potentiation was
observed in both wild-type and the ER gene knockout mice. The
perfusion or incubation of ICI 182,780, which blocks both ER and
ERß, did not affect estrogen potentiation in either group. Further
study showed that adenosine 3',5'-cyclic-monophosphothioate
Rp-isomer, a specific inhibitor of protein kinase A, completely
blocked the potentiation observed with the application of
17ß-estradiol in ER gene knockout mice. Our results provide
evidence that a distinct estrogen-binding site exists, which appears to
be coupled to -amino-3-hydroxyl-5-methyl-4-isoxazole proprionic
acid/kainate receptors by a cAMP-dependent phosphorylation
process. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and ERß, that differ in the C-terminal ligand-binding
domain and in the N-terminal trans-activation domain (1, 4, 5, 6). The interaction of the estrogen receptor complex with the
hormone response elements in the genome enhances or suppresses
transcription and protein synthesis. Studies have shown that the
genomic effect of estrogen is of long latency and that it takes more
than 30 min (usually hours to days) to occur. A novel pathway for the
action of gonadal steroids on the central nervous system is indicated
by studies demonstrating rapid (within 2–3 min) and reversible changes
in membrane excitability after steroid application (7, 8). Although
little is known about the molecular identity of the binding site of the
rapid action, there is evidence that some rapid action may involve
membrane or intracellular receptors that are coupled to ion channels
and transmitter receptors by second messengers (9, 10, 11, 12). Some results
also suggest synergistic or opposing interactions of rapid and genomic
pathways in estrogen affecting membrane excitability (13, 14).
In the hippocampus, 17ß-estradiol has been shown to potentiate
kainate-induced currents in dissociated CA1 neurons with a short
latency (15). The action of estrogen is steroid and stereospecific
(i.e. testosterone and 17-estradiol are inactive) and
reversible upon the removal of the steroid. The current-voltage plot
and the dose-response curves of kainate-induced currents show that the
application of 17ß-estradiol increases the conductance rather than
affects the kinetics of the kainate-induced current. These data suggest
that there is no direct allosteric interaction of estrogen with
-amino-3-hydroxyl-5-methyl-4-isoxazole proprionic acid
(AMPA)/kainate receptors. As 8-bromo-cAMP, a membrane-permeable
cAMP analog, can mimic the effect of 17ß-estradiol on the
kainate-induced current, 17ß-estradiol may bind to distinct membrane
or intracellular sites that are coupled to a cAMP-dependent
phosphorylation process.
Previous studies have demonstrated that hippocampal neurons contain
ERs. A comparative study of ER distribution indicated that messenger
RNA (mRNA) for both forms of the ER ( and ß) was expressed in the
hippocampus, where small numbers of cells have been shown to contain
ER mRNA, whereas a relatively large number of CA1 cells express
ERß mRNA (16). An immocytochemical study has shown that there are
ER-immunoreactive cells located in CA1 region and that there are no sex
differences in either the number or the immunostaining intensity of
ER-immunoreactive cells in the hippocampus (17). The presence of ERs in
the hippocampus leaves open the possibility that the potentiation of
kainate-induced currents by 17ß-estradiol involves ERs. The present
study was designed to explore this possibility as well as to examine
the possibility of interactions between rapid and genomic pathways in
17ß-estradiol potentiation. We examined the action of 17ß-estradiol
on isolated CA1 neurons from mice in which ER has been genetically
knocked out (ERKO). The development of the ERKO mouse was accomplished
by inserting a neomycin-encoding sequence into exon 2 of the mouse
ER gene. The neomycin insert inhibits proper transcription and
translocation of the ER gene by its premature stop codons and
polyadenylation sequence and functionally inhibits expression (4). To
investigate the involvement of ERß in the action of 17ß-estradiol
on kainate-induced currents, ICI 182,780 (ICI) was employed in some
experiments. ICI exerts its pure antagonism by blocking both ER and
ERß transcriptional activity (18).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Preparation of acutely dissociated neurons
CA1 hippocampal neurons were acutely dissociated using a
modification of procedures reported by Kay and Wong (19). Mice were
decapitated via a guillotine. Hippocampi were removed from the brain,
quickly blocked, and placed in cold PIPES-saline solution: NaCl, 120
mM; KCl, 5.0 mM; CaCl2, 1.0
mM; MgCl2, 1.0 mM;
D-glucose, 25 mM; and
piperazine-N-N'-bis(2-ethane sulfonic acid)
(PIPES), 20 mM; pH 7.4. The blocked tissue was
cut on a Vibratome (Technical Products International, Inc., St. Louis,
MO) into sections approximately 450 µm thick while being
bathed in a 4 C oxygenated PIPES-saline solution. The slices were
placed in a petri dish on a black surface, and punches were made in the
CA1 area with a capillary tube. The punches were incubated at room
temperature (20–22 C) in PIPES-saline solution with 1.5 mg/ml protease
(Sigma Chemical Co., St. Louis, MO). The incubation medium
was stirred slowly and smoothly with 95% O2-5%
CO2 blown at its surface. After 30–45 min of enzymatic
digestion, punches were rinsed three times with oxygenated PIPES-saline
and triturated with a fire-polished Pasteur pipette for mechanical
dissociation. The cell suspension was then plated into the central
concave area of a slide containing the standard extracellular solution:
NaCl, 140 mM; KCl, 3.0 mM; CaCl2,
2.0 mM; and HEPES, 10 mM; pH 7.3. All chemicals
were obtained from Sigma Chemical Co.
Whole cell patch clamp recordings
Whole cell recordings were performed under the voltage clamp
mode according to standard technique (20). Both conventional as well as
perforated whole cell patch clamp recordings were employed in isolated
CA1 hippocampal neurons. The dissociated neurons were approximately
30–40 µM in diameter and were visualized with a
Nikon inverted, phase contrast microscope
(Nikon, Melville, NY) equipped with Nomarski optics. The
electrode resistance was typically 2–5 M
in bath solution. The
standard internal solution for the recording electrode consisted of the
following: CsCl, 140 mM; NaCl, 4.0 mM; EGTA, 10
mM; HEPES, 10 mM; and CaCl2, 1
mM. The internal solution was adjusted to pH 7.3 with CsOH.
The holding potential was -60 mV. In studying the current-voltage
relations, the holding potential was varied from -70 to +50 mV. Access
resistance was compensated (80%) electronically and monitored
periodically.
Puffer electrode and chemical application
A multiple barrel pipette with a total diameter of 10
µM was used to puff individual substances on the dendrite
of the recorded dissociated CA1 hippocampal neuron. Ejection of each
chemical could be made separately with a picosprizer unit (General
Valve Corp., Fairfield, NJ). Kainate, 17ß-estradiol,
17ß-estradiol, and ICI 182,780 were assigned randomly to one of the
barrels. Adenosine 3',5'-cyclic-monophosphothioate Rp-isomer
(Rp-cAMPS), a specific inhibitor of protein kinase A (PKA), was
obtained from L. C. Laboratories (Woburn, MA), and ICI
182,780 was obtained from Tocris (Baldwin, MO). Kainate currents
were induced by pulses of ejection (20 msec; 0.1–1.0 psi) of kainate
at the dendrite of the CA1 neuron. The application was repeated once
every 30 s and commenced immediately after the patch was ruptured.
The effects of the different drugs on the kainate-induced currents were
tested by extracellularly perfusing the cell for 3 min.
Data analysis
Whole cell currents were recorded under voltage clamp
configuration with an Adams/List EPC-9 amplifier (ALA, Great
Neck, NY), sampled at 2 kHz, and filtered at 2.3 kHz. Data were
digitized and stored on an Atari Mega 4 computer (Atari Corp.,
Sunnyvale, CA). Analysis of whole cell current records was
performed with an Atari data analysis program. Peak currents were
normalized as I/I0, where I represents the amplitude of
kainate-induced currents at any testing time point, and I0
is the initial value at the beginning of the recording. The percent
change in the amplitude of kainate-induced currents was determined
according to the formula (Idrug/Io - 1)100%,
where Idrug represents the peak amplitude of the kainate
current in the presence of the test drug. Current-voltage data were
obtained by subtraction of leak currents from currents recorded in the
presence of agonists at each potential. All quantitative data are
expressed as the mean ± SEM; n indicates the number
of cells tested. Statistical analysis was performed using paired or
unpaired Student’s t test. Results were considered
significant only for P < 0.05.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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gene is
disrupted, whereas the ERß is apparently still present (18, 22). Both
sexes of these animals from the ERKO group are infertile and
demonstrate a variety of phenotypic changes (4, 5, 23).
The role of ER in the potentiation of kainate-induced currents by
17ß-estradiol in ERKO and WT mice was examined under whole cell,
voltage clamp recording configuration. Application of kainate (100
µM; 20 msec) elicited inward currents in dissociated
hippocampal CA1 neurons from both WT and ERKO mice. The kainate-induced
current showed similar characteristics in the time course and amplitude
of the response in the WT group (306 ± 118 pA; n = 43) and
the ERKO group (281 ± 107 pA; n = 58). 17ß-Estradiol
application (50 nM; 3 min) increased the amplitude of
kainate-induced currents in the WT mice (by 32.0 ± 4.0% in 6 of
18 neurons tested) and in ERKO mice (by 30.0 ± 7.2% in 8 of 22).
The potentiation occurred within 3 min of application of
17ß-estradiol and was gradually reversed after removal of the
chemical. This potentiation is similar to that previously observed in
rats (15, 24). No significant differences were observed in the
17ß-estradiol potentiation of kainate-induced currents between
the WT and ERKO mice (Fig. 1
).
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0 mV) and linearity in the
absence and presence of 17ß-estradiol (n = 3). However, the
slope of the I-V curve was significantly increased in the neurons
exposed to 17ß-estradiol (P < 0.05; Fig. 2A). Similar findings were observed in
hippocampal neurons from WT mice (Fig. 2B).
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. To
confirm and extend these findings, experiments were conducted by
applying the compound ICI to the neurons from ERKO or WT mice.
As illustrated in Fig. 3, coapplication
of ICI (100 nM; 5 min) with 17ß-estradiol did not
abolish the potentiation of kainate- induced currents by
17ß-estradiol in the cells from the ERKO group. Similar potentiated
amplitudes were observed in the absence (32 ± 8%) and presence
(30 ± 5%) of ICI (n = 10). In the presence of ICI,
17ß-estradiol potentiation exhibited no significant difference
between the ERKO and WT groups in terms of the short latency,
amplitude, and reversibility. In another set of experiments, neurons
from ERKO mice were preincubated with ICI (100 nM; 30
min) before testing the effect of 17ß-estradiol. The results are
summarized in Table 1. Kainate-induced
currents displayed no obvious differences in amplitude between the
preincubated and control groups. 17ß-Estradiol potentiated
kainate-induced currents in the presence of the ICI compound in the
same pattern as that observed in the control experiments. Collectively,
these findings indicate that pharmacological blockage of ERß and
ER had no observable effect on the potentiation of kainate-induced
currents by 17ß-estradiol.
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or ERß. In rat hippocampal
neurons, 17ß-estradiol potentiation can be mimicked by a cAMP analog
and can be modulated by a phosphodiesterase inhibitor
(isobutylmethylxanthine). By application of Rp-cAMPS
(50 µM), a specific inhibitor of PKA, the potentiation of
kainate-induced currents could be blocked (15). These previous findings
strongly argue that these distinct binding sites were coupled to a
cAMP-dependent phosphorylation process. This hypothesis was verified to
some extent in the present experiment using ERKO mice. The
administration of Rp-cAMPS (50 µM) completely blocked the
potentiation observed with application of 17ß-estradiol (Fig. 4). Thus, the mechanism involved in
17ß-estradiol potentiation of kainate-induced currents is the same in
ERKO mice.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-aminobutyric acidB
and µ-opioid receptors from a K+ channel. This results in
more inhibition in the presynaptic cell and decreased excitability in
the postsynaptic GnRH cell. Rather than through the genomic pathway, in
this case estrogen acts rapidly via the intracellular ER to
phosphorylate a component of the coupling of the transmitter receptor
to the ion channel (27). On the other hand, an interaction between
genomic and nongenomic mechanisms contributes to lactotroph excitation.
In this case, estrogen decreases the efficacy of tonic inhibitory
dopaminergic input to the cell by a rapid decoupling of the dopamine
receptor from its channels and by a long term down-regulation of the
number of dopamine receptors (13, 14). The expression of both isoforms
of ER in hippocampal neurons raised the question as to whether
intracellular ERs play a role in the rapid action, or whether the
genomic mechanism has an impact on the nongenomic action of
17ß-estradiol.
One of the feasible approaches in testing these possibilities is to use
the mutant mouse line without functional ER. As the expression of
the ER gene has been suppressed, the pathways activated by the ER
are presumably blocked. In addition, the response of a organ to
estrogen depends not only on its activation of the receptors, but also
its effects during early development (28). The strength of using ERKO
mice over other approaches is that the ERKO mice are deprived of
estrogen’s action on brain both developmentally and in adulthood.
Studies have shown that female ERKO mice have ovaries containing
immature and atrophic follicles, immature reproductive tracts, and an
inability to display sexual receptivity (22, 23). As elevated
circulating levels of estradiol and androgen in plasma hormones have
been found in the ERKO mice, the cell dissociation procedure used in
the present study eliminated this condition.
In the present study, kainate-induced currents exhibited no observable
differences in neurons from ERKO and WT mice. In the presence of
17ß-estradiol, the amplitude of kainate- induced currents in
the ERKO group increased to about 30%, which is similar to that
observed in the WT mice. Similarities were also found in terms of the
short latency and reversibility of the potentiation and in the
percentage of the cells responsive to 17ß-estradiol. It suggests that
suppression of ER expression does not alter the signaling pathway by
which 17ß-estradiol enhances kainate-induced currents.
By employing ICI compounds in the genetically deficit ER mouse line,
ERß can be pharmacologically blocked. ICI 182,780 and ICI 164,384
belong to a series of 7-alkylamide analogues of 17ß-estradiol.
Studies have shown that ICI compounds are pure antiestrogens by
directly binding to the estrogen receptor. The kinetic parameters of
this interaction are similar to those for the binding of estradiol. The
binding of estradiol results in a steroid-receptor complex that can be
transformed to a form with increased affinity for DNA. However, the
complex formed with the ICI compound suppresses the transformation
process. Therefore, the application of ICI compounds should induce a
complete blockage of the transcriptional effect of estrogen (29, 30).
The specificity and potency of the ICI compounds have also been
evaluated by several studies. ICI 182,780 and ICI 164,384 block both
functional domains (AF-1 and AF-2) of the receptor or ß. ICI
182,780 is more potent than ICI 164,384. When added at 10
nM and above, ICI 182,780 can lower estrogen-induced ERß
activity even below its basal level (18). A recent study in our
laboratory has shown that incubation of vomeronasal tissue with
17ß-estradiol for 15 min caused an increase in c-fos mRNA
expression measured at 60 min. The effect of 17ß-estradiol was
evident as low as 10 pM. Western blot analysis revealed the
presence of ERs in the tissue. The response to 17ß-estradiol remained
the same in vomeronasal tissue from ERKO mice. If the tissue was
preincubated with ICI 182,780 for 15 min, however, administration of
17ß-estradiol induced no increase in c-fos mRNA expression
(our unpublished observations). The data indicate that ERß or
other ER variants play a role in the modulation of vomeronasal organ
function. Based on the accumulated evidence, the concentration and
duration of ICI 182,780 used in the present experiment were effective
in blocking the actions of estrogen through ERß. Application of ICI
in the present study, however, resulted in no observable differences in
the potentiation of kainate- induced currents by 17ß-estradiol.
This suggests that the binding site for estrogen potentiation of
kainate-induced currents in hippocampal neurons is distinct from those
for either of the two genomic ER isoforms.
The reversal potentials of the current-voltage curves suggest the involvement of nonspecific cationic channels. The application of 17ß-estradiol did not change the reversal potential or the linearity of the curves. The conductance of AMPA/kainate receptor channels, however, was significantly increased by 17ß-estradiol in both ERKO and WT groups. There was no statistically significant difference in the increase in conductance between the two groups. Wong and Moss have shown that 17ß-estradiol did not affect the parameters of the kainate receptor channels in excised patch from hippocampal neurons, suggesting that there was no direct allosteric interaction between estrogen with the AMPA/kainate receptors (31). This hypothesis was supported by the data from a kainate dose-response study performed under whole cell recording configuration. Here, 17ß-estradiol, without altering their kinetics, increased the amplitude of kainate-induced currents (15).
As the time course of 17ß-estradiol potentiation of kainate-induced currents in hippocampal neurons is too rapid to be explained by the classical genomic pathway for steroid action, a nongenomic binding site, especially a membrane binding site, might be responsible for this event. The fact that Rp-cAMPs blocks the effect of 17ß-estradiol implies possible involvement of PKA-dependent phosphorylation downstream in the signal processing.
To date, binding studies have not identified specific estrogen membrane receptors. However, a number of studies using immunocytochemical techniques have indicated the presence of estrogen-binding sites in the plasma membrane (32, 33, 34, 35). Watson’s laboratory has demonstrated a subpopulation of binding sites in the plasma membrane by using antibodies directed against a peptide representing the hinge region of intracellular ER. The membrane binding sites mediate a rapid release of PRL in GH3/B6 rat pituitary tumor cells. The confocal scanning laser microscopy of cells labeled live with the antipeptide antibody further supports a membrane localization of ER. The monoclonal antibodies H226 and H222 and the polyclonal antibody, ER21, immunohistochemically label membrane proteins in immunoselected GH3/B6 cells. Each of these antibodies recognizes a unique epitope on intracellular ER: NH2-terminal to the DNA-binding region, within the steroid-binding region, and NH2-terminal end, respectively. The results suggest that the membrane binding sites bear structural similarities to the intracellular ER. Coincubation of cells with anti-ER antibody and the fluorescent estrogen-BSA conjugate reveals that these labels colocalize on the cell surface. Although our present results also suggest distinct sites, especially membrane binding sites, for 17ß-estradiol action on hippocampal neurons from the ERKO mice, the site of action appears to be genetically and pharmacologically different from that of the classic intracellular ER. Further study is required to characterize the site to which 17ß-estradiol initially binds in modulation of membrane excitability.
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Acknowledgments |
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Footnotes |
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Received August 14, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and ß form heterodimers on DNA. J Biol
Chem 272:19858–19862 (ER) and estrogen receptor-ß (ERß) messenger
ribonucleic acid in the wild-type and ER-knockout mouse.
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G. E. Stoica, T. F. Franke, A. Wellstein, F. Czubayko, H.-J. List, R. Reiter, E. Morgan, M. B. Martin, and A. Stoica Estradiol Rapidly Activates Akt via the ErbB2 Signaling Pathway Mol. Endocrinol., May 1, 2003; 17(5): 818 - 830. [Abstract] [Full Text] [PDF]
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Y. Zhu, C. D. Rice, Y. Pang, M. Pace, and P. Thomas From the Cover: Cloning, expression, and characterization of a membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fish oocytes PNAS, March 4, 2003; 100(5): 2231 - 2236. [Abstract] [Full Text] [PDF]
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C. D. Toran-Allerand, X. Guan, N. J. MacLusky, T. L. Horvath, S. Diano, M. Singh, E. S. Connolly Jr, I. S. Nethrapalli, and A. A. Tinnikov ER-X: A Novel, Plasma Membrane-Associated, Putative Estrogen Receptor That Is Regulated during Development and after Ischemic Brain Injury J. Neurosci., October 1, 2002; 22(19): 8391 - 8401. [Abstract] [Full Text] [PDF]
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 Y.-H. Suh and F. Checler Amyloid Precursor Protein, Presenilins, and alpha -Synuclein: Molecular Pathogenesis and Pharmacological Applications in Alzheimer's Disease Pharmacol. Rev., September 1, 2002; 54(3): 469 - 525. [Abstract] [Full Text] [PDF]
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H. F. Figueiredo, C. M. Dolgas, and J. P. Herman Stress Activation of Cortex and Hippocampus Is Modulated by Sex and Stage of Estrus Endocrinology, July 1, 2002; 143(7): 2534 - 2540. [Abstract] [Full Text] [PDF]
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C. S. Nunemaker, R. A. DeFazio, and S. M. Moenter Estradiol-Sensitive Afferents Modulate Long-Term Episodic Firing Patterns of GnRH Neurons Endocrinology, June 1, 2002; 143(6): 2284 - 2292. [Abstract] [Full Text] [PDF]
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E. F. Rissman, A. L. Heck, J. E. Leonard, M. A. Shupnik, and J.-A. Gustafsson Disruption of estrogen receptor beta gene impairs spatial learning in female mice PNAS, March 19, 2002; 99(6): 3996 - 4001. [Abstract] [Full Text] [PDF]
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A. B. Ropero, B. Soria, and A. Nadal A Nonclassical Estrogen Membrane Receptor Triggers Rapid Differential Actions in the Endocrine Pancreas Mol. Endocrinol., March 1, 2002; 16(3): 497 - 505. [Abstract] [Full Text] [PDF]
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 B. McEwen Estrogen Actions Throughout the Brain Recent Prog. Horm. Res., January 1, 2002; 57(1): 357 - 384. [Abstract] [Full Text] [PDF]
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 B. S. McEwen Genome and Hormones: Gender Differences in Physiology: Invited Review: Estrogens effects on the brain: multiple sites and molecular mechanisms J Appl Physiol, December 1, 2001; 91(6): 2785 - 2801. [Abstract] [Full Text] [PDF]
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 A. Nadal, M. Diaz, and M. A. Valverde The Estrogen Trinity: Membrane, Cytosolic, and Nuclear Effects Physiology, December 1, 2001; 16(6): 251 - 255. [Abstract] [Full Text] [PDF]
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 L. O'Donnell, K. M. Robertson, M. E. Jones, and E. R. Simpson Estrogen and Spermatogenesis Endocr. Rev., June 1, 2001; 22(3): 289 - 318. [Abstract] [Full Text] [PDF]
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S. F. Palter, A. B. Tavares, A. Hourvitz, J. D. Veldhuis, and E. Y. Adashi Are Estrogens of Import to Primate/Human Ovarian Folliculogenesis? Endocr. Rev., June 1, 2001; 22(3): 389 - 424. [Abstract] [Full Text] [PDF]
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R. Clarke, F. Leonessa, J. N. Welch, and T. C. Skaar Cellular and Molecular Pharmacology of Antiestrogen Action and Resistance Pharmacol. Rev., March 1, 2001; 53(1): 25 - 72. [Abstract] [Full Text] [PDF]
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P. Thomas, J. Pinter, and S. Das Upregulation of the Maturation-Inducing Steroid Membrane Receptor in Spotted Seatrout Ovaries by Gonadotropin During Oocyte Maturation and Its Physiological Significance Biol Reprod, January 1, 2001; 64(1): 21 - 29. [Abstract] [Full Text]
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E. Falkenstein, H.-C. Tillmann, M. Christ, M. Feuring, and M. Wehling Multiple Actions of Steroid Hormones---A Focus on Rapid, Nongenomic Effects Pharmacol. Rev., December 1, 2000; 52(4): 513 - 556. [Abstract] [Full Text] [PDF]
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A. Nadal, A. B. Ropero, O. Laribi, M. Maillet, E. Fuentes, and B. Soria Nongenomic actions of estrogens and xenoestrogens by binding at a plasma membrane receptor unrelated to estrogen receptor alpha and estrogen receptor beta PNAS, October 10, 2000; 97(21): 11603 - 11608. [Abstract] [Full Text] [PDF]
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 M. R. Zamani, N. L Desmond, and W. B Levy Estradiol Modulates Long-Term Synaptic Depression in Female Rat Hippocampus J Neurophysiol, October 1, 2000; 84(4): 1800 - 1808. [Abstract] [Full Text] [PDF]
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 G. Khetawat, N. Faraday, M. L. Nealen, K. V. Vijayan, E. Bolton, S. J. Noga, and P. F. Bray Human megakaryocytes and platelets contain the estrogen receptor beta and androgen receptor (AR): testosterone regulates AR expression Blood, April 1, 2000; 95(7): 2289 - 2296. [Abstract] [Full Text] [PDF]
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M. Singh, G. Setalo Jr, X. Guan, D. E. Frail, and C. D. Toran-Allerand Estrogen-Induced Activation of the Mitogen-Activated Protein Kinase Cascade in the Cerebral Cortex of Estrogen Receptor-alpha Knock-Out Mice J. Neurosci., March 1, 2000; 20(5): 1694 - 1700. [Abstract] [Full Text] [PDF]
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 A. B Ropero, E. Fuentes, J. M Rovira, C. Ripoll, B. Soria, and A. Nadal Non-genomic actions of 17{beta}-oestradiol in mouse pancreatic {beta}-cells are mediated by a cGMP-dependent protein kinase J. Physiol., December 1, 1999; 521(2): 397 - 407. [Abstract] [Full Text] [PDF]
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B. Moosmann and C. Behl The antioxidant neuroprotective effects of estrogens and phenolic compounds are independent from their estrogenic properties PNAS, August 3, 1999; 96(16): 8867 - 8872. [Abstract] [Full Text] [PDF]
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B. S. McEwen and S. E. Alves Estrogen Actions in the Central Nervous System Endocr. Rev., June 1, 1999; 20(3): 279 - 307. [Abstract] [Full Text]
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J. F. Couse and K. S. Korach Estrogen Receptor Null Mice: What Have We Learned and Where Will They Lead Us? Endocr. Rev., June 1, 1999; 20(3): 358 - 417. [Abstract] [Full Text]
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 B. S. McEwen The Molecular and Neuroanatomical Basis for Estrogen Effects in the Central Nervous System J. Clin. Endocrinol. Metab., June 1, 1999; 84(6): 1790 - 1797. [Full Text]
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 J. M. Hall, J. F. Couse, and K. S. Korach The Multifaceted Mechanisms of Estradiol and Estrogen Receptor Signaling J. Biol. Chem., September 28, 2001; 276(40): 36869 - 36872. [Full Text] [PDF]
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). Actual current traces selected
from the records at specific time points (arrows) are
displayed in the upper portion of the graph.
