Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.


Logo for

J. Neurosci. 23 (29): 9529-9540

Copyright © 2003 by the Society for Neuroscience.


Rapid Signaling of Estrogen in Hypothalamic Neurons Involves a Novel G-Protein-Coupled Estrogen Receptor that Activates Protein Kinase C

Jian Qiu,1 Martha A. Bosch,1 Sandra C. Tobias,2 David K. Grandy,1 Thomas S. Scanlan,2 Oline K. Rønnekleiv,1 , and Martin J. Kelly1

1Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon 97239, and 2Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, California 94143

Abstract: Classically, 17{beta}-estradiol (E2) is thought to control homeostatic functions such as reproduction, stress responses, feeding, sleep cycles, temperature regulation, and motivated behaviors through transcriptional events. Although it is increasingly evident that E2 can also rapidly activate kinase pathways to have multiple downstream actions in CNS neurons, the receptor(s) and the signal transduction pathways involved have not been identified. We discovered that E2 can alter µ-opioid and GABA neurotransmission rapidly through nontranscriptional events in hypothalamic GABA, proopiomelanocortin (POMC), and dopamine neurons. Therefore, we examined the effects of E2 in these neurons using whole-cell recording techniques in ovariectomized female guinea pigs. E2 reduced rapidly the potency of the GABAB receptor agonist baclofen to activate G-protein-coupled, inwardly rectifying K+ channels in hypothalamic neurons. These effects were mimicked by the membrane impermeant E2-BSA and selective estrogen receptor modulators, including a new diphenylacrylamide compound, STX, that does not bind to intracellular estrogen receptors {alpha} or {beta}, suggesting that E2 acts through a unique membrane receptor. We characterized the coupling of this estrogen receptor to a G{alpha}q-mediated activation of phospholipase C, leading to the upregulation of protein kinase C{delta} and protein kinase A activity in these neurons. Moreover, using single-cell reverse transcription-PCR, we identified the critical transcripts, PKC{delta} and its downstream target adenylyl cyclase VII, for rapid, novel signaling of E2 in GABA, POMC, and dopamine neurons. Therefore, this unique Gq-coupled estrogen receptor may be involved in rapid signaling in hypothalamic neurons that are critical for normal homeostatic functions.

Key Words: GABAB receptorGIRKdopamineGADPOMCSERMs

Received for publication June 13, 2003. Revision received August 1, 2003. Accepted for publication August 22, 2003.

The Memory-Enhancing Effects of Hippocampal Estrogen Receptor Activation Involve Metabotropic Glutamate Receptor Signaling.
M. I. Boulware, J. D. Heisler, and K. M. Frick (2013)
J. Neurosci. 33, 15184-15194
   Abstract »    Full Text »    PDF »
The membrane estrogen receptor ligand STX rapidly enhances GABAergic signaling in NPY/AgRP neurons: role in mediating the anorexigenic effects of 17{beta}-estradiol.
A. W. Smith, M. A. Bosch, E. J. Wagner, O. K. Ronnekleiv, and M. J. Kelly (2013)
Am J Physiol Endocrinol Metab 305, E632-E640
   Abstract »    Full Text »    PDF »
Neuroestrogens Rapidly Regulate Sexual Motivation But Not Performance.
A. L. Seredynski, J. Balthazart, V. J. Christophe, G. F. Ball, and C. A. Cornil (2013)
J. Neurosci. 33, 164-174
   Abstract »    Full Text »    PDF »
Estrogen Facilitates Spinal Cord Synaptic Transmission via Membrane-bound Estrogen Receptors: IMPLICATIONS FOR PAIN HYPERSENSITIVITY.
Y. Zhang, X. Xiao, X.-M. Zhang, Z.-Q. Zhao, and Y.-Q. Zhang (2012)
J. Biol. Chem. 287, 33268-33281
   Abstract »    Full Text »    PDF »
Serotonin 5-HT2C receptor-mediated inhibition of the M-current in hypothalamic POMC neurons.
T. A. Roepke, A. W. Smith, O. K. Ronnekleiv, and M. J. Kelly (2012)
Am J Physiol Endocrinol Metab 302, E1399-E1406
   Abstract »    Full Text »    PDF »
Rapid Estrogen Signaling in the Brain: Implications for the Fine-Tuning of Neuronal Circuitry.
D. P. Srivastava, E. M. Waters, P. G. Mermelstein, E. A. Kramar, T. J. Shors, and F. Liu (2011)
J. Neurosci. 31, 16056-16063
   Abstract »    Full Text »    PDF »
Fasting and 17{beta}-Estradiol Differentially Modulate the M-Current in Neuropeptide Y Neurons.
T. A. Roepke, J. Qiu, A. W. Smith, O. K. Ronnekleiv, and M. J. Kelly (2011)
J. Neurosci. 31, 11825-11835
   Abstract »    Full Text »    PDF »
Membrane Estrogen Receptors Stimulate Intracellular Calcium Release and Progesterone Synthesis in Hypothalamic Astrocytes.
J. Kuo, N. Hamid, G. Bondar, E. R. Prossnitz, and P. Micevych (2010)
J. Neurosci. 30, 12950-12957
   Abstract »    Full Text »    PDF »
Estradiol Rapidly Regulates Membrane Estrogen Receptor {alpha} Levels in Hypothalamic Neurons.
R. Dominguez and P. Micevych (2010)
J. Neurosci. 30, 12589-12596
   Abstract »    Full Text »    PDF »
Position Paper: Rapid responses to steroids: current status and future prospects.
A. Wendler, E. Baldi, B. J. Harvey, A. Nadal, A. Norman, and M. Wehling (2010)
Eur. J. Endocrinol. 162, 825-830
   Abstract »    Full Text »    PDF »
Estradiol and G1 Reduce Infarct Size and Improve Immunosuppression after Experimental Stroke.
B. Zhang, S. Subramanian, S. Dziennis, J. Jia, M. Uchida, K. Akiyoshi, E. Migliati, A. D. Lewis, A. A. Vandenbark, H. Offner, et al. (2010)
J. Immunol. 184, 4087-4094
   Abstract »    Full Text »    PDF »
17{beta}-Estradiol Mediates the Sex Difference in Capsaicin-Induced Nociception in Rats.
Y.-C. Lu, C.-W. Chen, S.-Y. Wang, and F.-S. Wu (2009)
J. Pharmacol. Exp. Ther. 331, 1104-1110
   Abstract »    Full Text »    PDF »
17{beta}-Estradiol Regulation of T-Type Calcium Channels in Gonadotropin-Releasing Hormone Neurons.
C. Zhang, M. A. Bosch, E. A. Rick, M. J. Kelly, and O. K. Ronnekleiv (2009)
J. Neurosci. 29, 10552-10562
   Abstract »    Full Text »    PDF »
Long-Term Potentiation in the Rat Medial Vestibular Nuclei Depends on Locally Synthesized 17{beta}-Estradiol.
S. Grassi, A. Frondaroli, C. Dieni, M. Scarduzio, and V. E. Pettorossi (2009)
J. Neurosci. 29, 10779-10783
   Abstract »    Full Text »    PDF »
Expression of ER-{alpha}36, a Novel Variant of Estrogen Receptor {alpha}, and Resistance to Tamoxifen Treatment in Breast Cancer.
L. Shi, B. Dong, Z. Li, Y. Lu, T. Ouyang, J. Li, T. Wang, Z. Fan, T. Fan, B. Lin, et al. (2009)
J. Clin. Oncol. 27, 3423-3429
   Abstract »    Full Text »    PDF »
Sprouty2 Interacts with Protein Kinase C{delta} and Disrupts Phosphorylation of Protein Kinase D1.
S. Y. Chow, C. Y. Yu, and G. R. Guy (2009)
J. Biol. Chem. 284, 19623-19636
   Abstract »    Full Text »    PDF »
Stimulating the GPR30 Estrogen Receptor with a Novel Tamoxifen Analogue Activates SF-1 and Promotes Endometrial Cell Proliferation.
B. C. Lin, M. Suzawa, R. D. Blind, S. C. Tobias, S. E. Bulun, T. S. Scanlan, and H. A. Ingraham (2009)
Cancer Res. 69, 5415-5423
   Abstract »    Full Text »    PDF »
Differential Regulation of Gonadotropin-Releasing Hormone Neuron Activity and Membrane Properties by Acutely Applied Estradiol: Dependence on Dose and Estrogen Receptor Subtype.
Z. Chu, J. Andrade, M. A. Shupnik, and S. M. Moenter (2009)
J. Neurosci. 29, 5616-5627
   Abstract »    Full Text »    PDF »
p21-Activated kinase mediates rapid estradiol-negative feedback actions in the reproductive axis.
Z. Zhao, C. Park, M. A. McDevitt, C. Glidewell-Kenney, P. Chambon, J. Weiss, J. L. Jameson, and J. E. Levine (2009)
PNAS 106, 7221-7226
   Abstract »    Full Text »    PDF »
Rapid signaling by steroid receptors.
E. R. Levin (2008)
Am J Physiol Regulatory Integrative Comp Physiol 295, R1425-R1430
   Abstract »    Full Text »    PDF »
Kisspeptin Depolarizes Gonadotropin-Releasing Hormone Neurons through Activation of TRPC-Like Cationic Channels.
C. Zhang, T. A. Roepke, M. J. Kelly, and O. K. Ronnekleiv (2008)
J. Neurosci. 28, 4423-4434
   Abstract »    Full Text »    PDF »
Hormonal regulation of G{alpha}i2 and mPR{alpha} in immortalized human oviductal cell line OE-E6/E7.
K. S. Monkkonen, R. Aflatoonian, K.-F. Lee, W. S.B. Yeung, S.-W. Tsao, J. T. Laitinen, and A. Fazeli (2007)
Mol. Hum. Reprod. 13, 845-851
   Abstract »    Full Text »    PDF »
Serotonin 5-Hydroxytryptamine2C Receptor Signaling in Hypothalamic Proopiomelanocortin Neurons: Role in Energy Homeostasis in Females.
J. Qiu, C. Xue, M. A. Bosch, J. G. Murphy, W. Fan, O. K. Ronnekleiv, and M. J. Kelly (2007)
Mol. Pharmacol. 72, 885-896
   Abstract »    Full Text »    PDF »
Gonadotropin-Releasing Hormone Neurons Express KATP Channels That Are Regulated by Estrogen and Responsive to Glucose and Metabolic Inhibition.
C. Zhang, M. A. Bosch, J. E. Levine, O. K. Ronnekleiv, and M. J. Kelly (2007)
J. Neurosci. 27, 10153-10164
   Abstract »    Full Text »    PDF »
Caveolin Proteins Are Essential for Distinct Effects of Membrane Estrogen Receptors in Neurons.
M. I. Boulware, H. Kordasiewicz, and P. G. Mermelstein (2007)
J. Neurosci. 27, 9941-9950
   Abstract »    Full Text »    PDF »
Membrane Estrogen Receptor-{alpha} Interactions with Metabotropic Glutamate Receptor 1a Modulate Female Sexual Receptivity in Rats.
P. Dewing, M. I. Boulware, K. Sinchak, A. Christensen, P. G. Mermelstein, and P. Micevych (2007)
J. Neurosci. 27, 9294-9300
   Abstract »    Full Text »    PDF »
Distribution and characterization of estrogen receptor G protein-coupled receptor 30 in the rat central nervous system.
E. Brailoiu, S. L Dun, G C. Brailoiu, K. Mizuo, L. A Sklar, T. I Oprea, E. R Prossnitz, and N. J Dun (2007)
J. Endocrinol. 193, 311-321
   Abstract »    Full Text »    PDF »
Estrogen Upregulates T-Type Calcium Channels in the Hypothalamus and Pituitary.
J. Qiu, M. A. Bosch, K. Jamali, C. Xue, M. J. Kelly, and O. K. Ronnekleiv (2006)
J. Neurosci. 26, 11072-11082
   Abstract »    Full Text »    PDF »
Estradiol-Induced Increase in the Magnitude of Long-Term Potentiation Is Prevented by Blocking NR2B-Containing Receptors..
C. C. Smith and L. L. McMahon (2006)
J. Neurosci. 26, 8517-8522
   Abstract »    Full Text »    PDF »
Estrogen synthesis in the spinal dorsal horn: a new central mechanism for the hormonal regulation of pain..
H. C. Evrard (2006)
Am J Physiol Regulatory Integrative Comp Physiol 291, R291-R299
   Abstract »    Full Text »    PDF »
Sex differences in morphine-induced analgesia of visceral pain are supraspinally and peripherally mediated.
Y. Ji, A. Z. Murphy, and R. J. Traub (2006)
Am J Physiol Regulatory Integrative Comp Physiol 291, R307-R314
   Abstract »    Full Text »    PDF »
A G-Protein-Coupled Estrogen Receptor Is Involved in Hypothalamic Control of Energy Homeostasis.
J. Qiu, M. A. Bosch, S. C. Tobias, A. Krust, S. M. Graham, S. J. Murphy, K. S. Korach, P. Chambon, T. S. Scanlan, O. K. Ronnekleiv, et al. (2006)
J. Neurosci. 26, 5649-5655
   Abstract »    Full Text »    PDF »
Inositol triphosphate participates in an oestradiol nongenomic signalling pathway involved in accelerated oviductal transport in cycling rats..
P. A Orihuela, A. Parada-Bustamante, L. M Zuniga, and H. B Croxatto (2006)
J. Endocrinol. 188, 579-588
   Abstract »    Full Text »    PDF »
Cybernetic principles in the systematic concept of hypothalamic feeding control.
O. Fricke, G. Lehmkuhl, and D. W Pfaff (2006)
Eur. J. Endocrinol. 154, 167-173
   Abstract »    Full Text »    PDF »
Sex differences in estrogenic regulation of neuronal activity in neonatal cultures of ventromedial nucleus of the hypothalamus.
J. Zhou, D. W. Pfaff, and G. Chen (2005)
PNAS 102, 14907-14912
   Abstract »    Full Text »    PDF »
Sex and estrogenic effects on coexpression of mRNAs in single ventromedial hypothalamic neurons.
N. Devidze, J. A. Mong, A. M. Jasnow, L.-M. Kow, and D. W. Pfaff (2005)
PNAS 102, 14446-14451
   Abstract »    Full Text »    PDF »
Estrogen-Induced Increase in the Magnitude of Long-Term Potentiation Occurs Only When the Ratio of NMDA Transmission to AMPA Transmission Is Increased.
C. C. Smith and L. L. McMahon (2005)
J. Neurosci. 25, 7780-7791
   Abstract »    Full Text »    PDF »
Estradiol Activates Group I and II Metabotropic Glutamate Receptor Signaling, Leading to Opposing Influences on cAMP Response Element-Binding Protein.
M. I. Boulware, J. P. Weick, B. R. Becklund, S. P. Kuo, R. D. Groth, and P. G. Mermelstein (2005)
J. Neurosci. 25, 5066-5078
   Abstract »    Full Text »    PDF »
Uterine blood flow responses to ICI 182 780 in ovariectomized oestradiol-17{beta}-treated, intact follicular and pregnant sheep.
R. R. Magness, T. M. Phernetton, T. C. Gibson, and D.-b. Chen (2005)
J. Physiol. 565, 71-83
   Abstract »    Full Text »    PDF »
Rapid Regulation of Pain by Estrogens Synthesized in Spinal Dorsal Horn Neurons.
H. C. Evrard and J. Balthazart (2004)
J. Neurosci. 24, 7225-7229
   Abstract »    Full Text »    PDF »
The membrane actions of estrogens can potentiate their lordosis behavior-facilitating genomic actions.
L.-M. Kow and D. W. Pfaff (2004)
PNAS 101, 12354-12357
   Abstract »    Full Text »    PDF »
Direct Action of Estradiol on Gonadotropin-Releasing Hormone-1 Neuronal Activity via a Transcription-Dependent Mechanism.
J. L. Temple, E. Laing, A. Sunder, and S. Wray (2004)
J. Neurosci. 24, 6326-6333
   Abstract »    Full Text »    PDF »
Rapid, Hierarchical Modulation of Vocal Patterning by Steroid Hormones.
L. Remage-Healey and A. H. Bass (2004)
J. Neurosci. 24, 5892-5900
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882