Female gender and estrous cycle‐dependent estrogen regulation of intestinal secretion and KCNQ1 channel function via membrane estrogen receptors

ABSTRACT The secretion of Cl− across distal colonic crypt cells provides the driving force for the movement of fluid into the luminal space. 17β-Estradiol (E2) produces a rapid and sustained reduction in secretion in females, which is dependent on the novel protein kinase Cδ (PKCδ) isozyme and PKA isoform I targeting of KCNQ1 channels. This sexual dimorphism in the E2 response is associated with a higher expression level of PKCδ in female compared with the male tissue. The present study revealed the antisecretory response is regulated throughout the female reproductive (estrous) cycle and is primed by genomic regulation of the kinases. E2 (1-10 nm) decreased cAMP-dependent secretion in colonic epithelia during the estrous, metestrous, and diestrous stages. A weak inhibition of secretion was demonstrated in the proestrous stage. The expression levels of PKCδ and PKA fluctuated throughout the estrous cycle and correlated with the potency of the antisecretory effect of E2. The expression of PKCδ and PKA were up-regulated by estrogen at a transcriptional level via a PKCδ-MAPK-cAMP response element-binding protein-regulated pathway indicating a genomic priming of the antisecretory response. PKCδ was activated by the membrane-impermeant E2-BSA, and this response was inhibited by the estrogen receptor antagonist ICI 182,780. The 66-kDa estrogen receptor-α isoform was present at the plasma membrane of female colonic crypt cells with a lower abundance found in male colonic crypts. The study demonstrates estrogen regulation of intestinal secretion both at a rapid and transcriptional level, demonstrating an interdependent relationship between both nongenomic and genomic hormone responses.

Download Full-text

Genomic Priming of the Antisecretory Response to Estrogen in Rat Distal Colon throughout the Estrous Cycle

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jcem.94.11.9991 ◽

2009 ◽

Vol 94 (11) ◽

pp. 4627-4628

Author(s):

Fiona O'Mahony ◽

Rodrigo Alzamora ◽

Ho-Lam Chung ◽

Warren Thomas ◽

Brian J. Harvey

Keyword(s):

Estrogen Receptor ◽

Estrous Cycle ◽

Intestinal Secretion ◽

Distal Colon ◽

Estrogen Receptor Α ◽

Transcriptional Level ◽

Colonic Crypt ◽

Estrogen Regulation ◽

Antisecretory Effect ◽

Crypt Cells

Abstract The secretion of Cl− across distal colonic crypt cells provides the driving force for the movement of fluid into the luminal space. 17β-Estradiol (E2) produces a rapid and sustained reduction in secretion in females, which is dependent on the novel protein kinase Cδ (PKCδ) isozyme and PKA isoform I targeting of KCNQ1 channels. This sexual dimorphism in the E2 response is associated with a higher expression level of PKCδ in female compared with the male tissue. The present study revealed the antisecretory response is regulated throughout the female reproductive (estrous) cycle and is primed by genomic regulation of the kinases. E2 (1–10 nm) decreased cAMP-dependent secretion in colonic epithelia during the estrous, metestrous, and diestrous stages. A weak inhibition of secretion was demonstrated in the proestrous stage. The expression levels of PKCδ and PKA fluctuated throughout the estrous cycle and correlated with the potency of the antisecretory effect of E2. The expression of PKCδ and PKA were up-regulated by estrogen at a transcriptional level via a PKCδ-MAPK-cAMP response element-binding protein-regulated pathway indicating a genomic priming of the antisecretory response. PKCδ was activated by the membrane-impermeant E2-BSA, and this response was inhibited by the estrogen receptor antagonist ICI 182,780. The 66-kDa estrogen receptor-α isoform was present at the plasma membrane of female colonic crypt cells with a lower abundance found in male colonic crypts. The study demonstrates estrogen regulation of intestinal secretion both at a rapid and transcriptional level, demonstrating an interdependent relationship between both nongenomic and genomic hormone responses.

Download Full-text

Differential expression of cyclooxygenase 1 and cyclooxygenase 2 in the bovine oviduct

Journal of Endocrinology ◽

10.1677/joe.1.06761 ◽

2006 ◽

Vol 191 (1) ◽

pp. 263-274 ◽

Cited By ~ 29

Author(s):

Simone Odau ◽

Christoph Gabler ◽

Christoph Holder ◽

Ralf Einspanier

Keyword(s):

Mrna Expression ◽

Estrous Cycle ◽

Luteal Phase ◽

Cellular Level ◽

Differential Distribution ◽

Cyclooxygenase 1 ◽

Epithelial Cell Layer ◽

Cox 2 ◽

Cycle Dependent ◽

Cox 1

The aim of the present study was to investigate the enzymes for the local prostaglandin (PG) biosynthesis present in the bovine oviduct during the estrous cycle to influence early reproductive events. Bovine oviducts were classified into four phases: pre-ovulatory, post-ovulatory, early-to-mid luteal, and late luteal phase, subdivided further into ipsi- or contralateral site and separated into ampulla or isthmus. Oviductal cells were gained by flushing the oviductal regions. Quantitative real-time reverse transcriptase-PCR was performed for the secretory and cytosolic phospholipases A2 (sPLA2IB, cPLA2α, and cPLA2β) and cyclooxygenases (COX-1 and COX-2) as the first step enzymes of PG synthesis. COX-1 and cPLA2β showed significant highest mRNA expression around and before ovulation compared with the luteal phase respectively. sPLA2IB and cPLA2α mRNA expression was unregulated during the estrous cycle. Regional differences in mRNA content were found for sPLA2IB with higher mRNA expression in the ampulla than in the isthmus. Western blot analysis revealed the highest COX-1 protein content in the early-to-mid luteal phase. Immunohistochemistry demonstrated that COX-1 was localized in epithelial and smooth muscle cells, whereas COX-2 was only localized in epithelial cells. COX-2 showed a differential distribution within the epithelial cell layer suggesting a regulation on a cellular level, although the COX-2 mRNA and protein amounts did not vary throughout the estrous cycle. A COX activity assay of oviductal cells revealed that COX activity originated predominantly from COX-1 than from COX-2. Treatment of primary oviductal cells with 10 pg/ml 17β-estradiol or 10 ng/ml progesterone resulted in a higher expression of COX-2 and cPLA2α, but not of the other enzymes. The expression pattern of these enzymes suggests that an estrous-cycle dependent and region-specific PG synthesis in the bovine oviduct may be required for a successful reproduction.

Download Full-text

Circadian and estrous cycle-dependent variations in blood pressure and heart rate in female rats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1994.267.5.r1250 ◽

1994 ◽

Vol 267 (5) ◽

pp. R1250-R1256 ◽

Cited By ~ 8

Author(s):

H. Takezawa ◽

H. Hayashi ◽

H. Sano ◽

H. Saito ◽

S. Ebihara

Keyword(s):

Heart Rate ◽

Estrous Cycle ◽

Female Rats ◽

Constant Darkness ◽

Dark Phase ◽

Daily Rhythms ◽

Abrupt Decrease ◽

Internal Phase ◽

Free Running ◽

Cycle Dependent

To determine whether cardiovascular functions are controlled by the endogenous circadian system and whether they change with the estrous cycle in female rats, we measured mean arterial pressure (MAP), heart rate (HR), and spontaneous activity (ACT) of female rats using an implantable radiotelemetry device and a computerized data-collecting system. Under a 12:12-h light-dark (LD) cycle, these parameters exhibited daily rhythms that were entrained to the photic cycle. The patterns of the daily rhythms varied with estrous cycles, and variations were particularly marked in the proestrous stage. During the dark period of this stage, ACT levels were significantly higher, but HR was significantly lower than in other stages. Although the peak MAP occurred within 2 h after the onset of the dark phase in three of the estrous stages, it occurred around midnight in the proestrous stage. Such estrous cycle-dependent variations were eliminated by ovariectomy. The implantation of 17 beta-estradiol produced a gradual increase in MAP and an abrupt decrease in HR. During constant darkness, all three parameters were free running, maintaining the same internal phase relationships with each other as during LD cycles. These results indicate that daily variations in these parameters were controlled by the endogenous circadian oscillating system, that they vary with the estrous cycle in female rats, and that estrogen may be responsible for these estrous cycle-dependent variations.

Download Full-text

Estrous cycle variation of TRPV1-mediated cross-organ sensitization between uterus and NMDA-dependent pelvic-urethra reflex activity

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90289.2008 ◽

2008 ◽

Vol 295 (3) ◽

pp. E559-E568 ◽

Cited By ~ 30

Author(s):

Hsien-Yu Peng ◽

Pei-Chen Huang ◽

Jiuan-Miaw Liao ◽

Kwong-Chung Tung ◽

Shin-Da Lee ◽

...

Keyword(s):

Estrous Cycle ◽

Pelvic Pain ◽

Intrathecal Injection ◽

Pain Syndrome ◽

Reflex Activity ◽

Pelvic Pain Syndrome ◽

Dependent Manner ◽

The Cross ◽

Cycle Dependent

Cross-organ sensitization between the uterus and the lower urinary tract (LUT) underlies the high concurrence of pelvic pain syndrome and LUT dysfunctions, and yet the role of gonadal steroids is still unknown. We tested the hypothesis that cross-organ sensitization on pelvic-urethra reflex activity caused by uterine capsaicin instillation is estrous cycle dependent. When compared with the baseline reflex activity (1.00 ± 0.00 spikes/stimulation), uterine capsaicin instillation significantly increased reflex activity (45.42 ± 9.13 spikes/stimulation, P < 0.01, n = 7) that was corroborated by an increase in phosphorylated NMDA NR2B ( P < 0.05, n = 4) but not NR2A subunit ( P > 0.05, n = 4) expression. Both intrauterine pretreatment with capsazepine (5.02 ± 2.11 spikes/stimulation, P < 0.01, n = 7) and an intrathecal injection of AP5 (3.21 ± 0.83 spikes/stimulation, P < 0.01, n = 7) abolished the capsaicin-induced cross-organ sensitization and the increment in the phosphorylated NR2B level ( P < 0.05, n = 4). The degrees of the cross-organ sensitization increased in a dose-dependent manner with the concentration of instilled capsaicin from 100 to 300 μM in both the proestrus and metestrus stages, whereas they weakened when the concentrations were higher than 1,000 μM. Moreover, the cross-organ sensitization caused by the uterine capsaicin instillation increased significantly in the rats during the proestrus stage when compared with the metestrus stage ( P < 0.01, n = 7). These results suggest that estrogen levels might modulate the cross-organ sensitization between the uterus and the urethra and underlie the high concurrence of pelvic pain syndrome and LUT dysfunctions.

Download Full-text

Estrous Cycle-Dependent Phasic Changes in the Stoichiometry of Hippocampal Synaptic AMPA Receptors in Rats

PLoS ONE ◽

10.1371/journal.pone.0131359 ◽

2015 ◽

Vol 10 (6) ◽

pp. e0131359 ◽

Cited By ~ 11

Author(s):

Hirobumi Tada ◽

Mayu Koide ◽

Wakana Ara ◽

Yusuke Shibata ◽

Toshiya Funabashi ◽

...

Keyword(s):

Estrous Cycle ◽

Ampa Receptors ◽

Cycle Dependent

Download Full-text

Differential Expression of Estrogen Receptors in Two Hippocampal Regions During the Estrous Cycle of the Rat

The Anatomical Record ◽

10.1002/ar.21247 ◽

2011 ◽

Vol 294 (11) ◽

pp. 1913-1919 ◽

Cited By ~ 23

Author(s):

Luciano Mendoza-garcés ◽

Carmen Adriana Mendoza-rodríguez ◽

Francisco Jiménez-trejo ◽

Ofir Picazo ◽

María Carmen rodríguez ◽

...

Keyword(s):

Estrogen Receptors ◽

Differential Expression ◽

Estrous Cycle

Download Full-text

Progesterone and estrogen receptors in the myometrium of the cow during the estrous cycle and pregnancy and of the sheep at the time of parturition

Animal Reproduction Science ◽

10.1016/0378-4320(92)90033-a ◽

1992 ◽

Vol 29 (3-4) ◽

pp. 195-203 ◽

Cited By ~ 10

Author(s):

M. Klauke ◽

B. Hoffmann

Keyword(s):

Estrogen Receptors ◽

Estrous Cycle

Download Full-text

Functional requirement of AgRP and NPY neurons in ovarian cycle-dependent regulation of food intake

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0904747106 ◽

2009 ◽

Vol 106 (37) ◽

pp. 15932-15937 ◽

Cited By ~ 103

Author(s):

Louise E. Olofsson ◽

Andrew A. Pierce ◽

Allison W. Xu

Keyword(s):

Food Intake ◽

Estrous Cycle ◽

Estrogen Receptor Alpha ◽

Ovarian Cycle ◽

Central Administration ◽

Related Protein ◽

17Β Estradiol ◽

Cycle Dependent ◽

Cyclic Changes ◽

Agouti Related Protein

In female mammals including rodents and humans, feeding decreases during the periovulatory period of the ovarian cycle, which coincides with a surge in circulating estrogen levels. Ovariectomy increases food intake, which can be normalized by estrogen treatment at a dose and frequency mimicking those during the estrous cycle. Furthermore, administration of estrogen to rodents potently inhibits food intake. Despite these well-known effects of estrogen, neuronal subtypes that mediate estrogen's anorexigenic effects have not been identified. In this study, we show that changes in hypothalamic expression of agouti-related protein (Agrp) and neuropeptide Y (Npy) coincide with the cyclic changes in feeding across the estrous cycle. These cyclic changes in feeding are abolished in mice with degenerated AgRP neurons even though these mice cycle normally. Central administration of 17β-estradiol (E2) decreases food intake in controls but not in mice lacking the AgRP neurons. Furthermore, E2 treatment suppresses fasting-induced c-Fos activation in AgRP and NPY neurons and blunts the refeeding response. Surprisingly, although estrogen receptor alpha (ERα) is the key mediator of estrogen's anorexigenic effects, we find that expression of ERα is completely excluded from AgRP and NPY neurons in the mouse hypothalamus, suggesting that estrogen may regulate these neurons indirectly via presynaptic neurons that express ERα. This study indicates that neurons coexpressing AgRP and NPY are functionally required for the cyclic changes in feeding across estrous cycle and that AgRP and NPY neurons are essential mediators of estrogen's anorexigenic function.

Download Full-text