Estradiol and 3β-diol protect female cortical astrocytes by regulating connexin 43 Gap Junctions.

Publisher: North Holland Publishing Country of Publication: Ireland NLM ID: 7500844 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-8057 (Electronic) Linking ISSN: 03037207 NLM ISO Abbreviation: Mol Cell Endocrinol Subsets: MEDLINE

Publication: Limerick : North Holland Publishing
Original Publication: Amsterdam, North-Holland.

Connexin 43*/metabolism ; Connexin 43*/genetics ; Astrocytes*/metabolism ; Astrocytes*/drug effects ; Estradiol*/pharmacology ; Gap Junctions*/metabolism ; Gap Junctions*/drug effects ; Cerebral Cortex*/metabolism ; Cerebral Cortex*/cytology ; Cerebral Cortex*/drug effects; Animals ; Female ; Cells, Cultured ; Dihydrotestosterone/pharmacology ; Oxidative Stress/drug effects

While estrogens have been described to protect or preserve neuronal function in the face of insults such as oxidative stress, the prevailing mechanistic model would suggest that these steroids exert direct effects on the neurons. However, there is growing evidence that glial cells, such as astrocytes, are key cellular mediators of protection. Noting that connexin 43 (Cx43), a protein highly expressed in astrocytes, plays a key role in mediating inter-cellular communication, we hypothesized that Cx43 is a target of estradiol (E2), and the estrogenic metabolite of DHT, 3β-diol. Additionally, we sought to determine if either or both of these hormones attenuate oxidative stress-induced cytotoxicity by eliciting a reduction in Cx43 expression or inhibition of Cx43 channel permeability. Using primary cortical astrocytes, we found that E2 and 3β-diol were each protective against the mixed metabolic/oxidative insult, iodoacetic acid (IAA). Moreover, these effects were blocked by estrogen receptor antagonists. However, E2 and 3β-diol did not alter Cx43 mRNA levels in astrocytes but did inhibit IAA-induced Cx43 gap junction opening/permeability. Taken together, these data implicate astrocyte Cx43 gap junction as an understudied mediator of the cytoprotective effects of estrogens in the brain. Given the wide breadth of disease states associated with Cx43 function/dysfunction, further understanding the relationship between gonadal steroids and Cx43 channels may contribute to a better understanding of the biological basis for sex differences in various diseases.
Competing Interests: Declaration of competing interest None of the contributing authors of this manuscript have a conflict of interest relevant to the subject matter or materials included in this Work.
(Copyright © 2023 Elsevier B.V. All rights reserved.)

Nature. 1981 Jul 2;292(5818):17-21. (PMID: 6168915)
Fertil Steril. 2010 Dec;94(7):2938-41. (PMID: 20684953)
Front Mol Neurosci. 2017 Dec 15;10:418. (PMID: 29326548)
J Biol Chem. 1999 Jan 1;274(1):236-40. (PMID: 9867835)
J Neurosci. 1999 Feb 15;19(4):1179-88. (PMID: 9952396)
J Neurochem. 2013 Nov;127(4):487-95. (PMID: 24033289)
J Steroids Horm Sci. 2012;S2:. (PMID: 22860237)
Biochim Biophys Acta Biomembr. 2018 Jan;1860(1):96-101. (PMID: 28690048)
Endocrinology. 2012 Dec;153(12):5949-60. (PMID: 23117931)
Physiol Rev. 2011 Oct;91(4):1393-445. (PMID: 22013215)
J Neurosci. 2006 May 17;26(20):5438-47. (PMID: 16707796)
J Neurochem. 1994 Feb;62(2):489-95. (PMID: 7905024)
Acta Pharmacol Sin. 2015 Aug;36(8):928-38. (PMID: 26095039)
Oncogene. 2019 Jun;38(23):4429-4451. (PMID: 30814684)
Neuron. 1991 Jan;6(1):133-43. (PMID: 1702648)
Neurotox Res. 2019 Apr;35(3):654-667. (PMID: 30402773)
Neurochem Res. 2018 Jan;43(1):59-65. (PMID: 28589517)
Trends Neurosci. 2008 Oct;31(10):529-37. (PMID: 18774188)
Pharmacol Ther. 2015 Sep;153:90-106. (PMID: 26073311)
Cardiovasc Res. 2012 Apr 1;94(1):58-65. (PMID: 22287588)
Endocrinology. 2015 Jun;156(6):2150-61. (PMID: 25849728)
PLoS One. 2012;7(10):e47311. (PMID: 23110066)
J Biol Chem. 2014 Jan 17;289(3):1345-54. (PMID: 24302722)
Neurochem Res. 2010 Aug;35(8):1231-8. (PMID: 20437093)
Cell Calcium. 2003 Jan;33(1):37-48. (PMID: 12526886)
Cardiovasc Res. 2004 Jul 1;63(1):109-17. (PMID: 15194467)
J Neuroinflammation. 2018 Mar 27;15(1):97. (PMID: 29587860)
Biochem Biophys Res Commun. 1987 Aug 14;146(3):1502-8. (PMID: 3304294)
J Mol Endocrinol. 2001 Feb;26(1):1-10. (PMID: 11174849)
Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14602-7. (PMID: 16984997)
NeuroRx. 2005 Jul;2(3):396-409. (PMID: 16389304)
In Vitro Cell Dev Biol Anim. 2000 Jul-Aug;36(7):447-64. (PMID: 11039495)
Curr Neuropharmacol. 2016;14(7):759-71. (PMID: 27262601)
Endocrinology. 2016 May;157(5):2067-79. (PMID: 26990062)
Front Endocrinol (Lausanne). 2011 Nov 10;2:65. (PMID: 22649380)
Neuroscience. 2016 May 26;323:183-94. (PMID: 25711938)
J Steroid Biochem Mol Biol. 1993 Dec;47(1-6):195-205. (PMID: 8274436)
Front Cell Neurosci. 2013 Oct 01;7:159. (PMID: 24101894)
Neurochem Int. 2017 Sep;108:481-493. (PMID: 28652220)
Eur J Neurosci. 2003 Jul;18(2):267-74. (PMID: 12887408)
Endocrinology. 2013 May;154(5):1802-12. (PMID: 23515287)
Mol Endocrinol. 2012 Nov;26(11):1798-807. (PMID: 22935924)
Brain Res. 2012 Dec 3;1487:88-98. (PMID: 22789907)
Br J Pharmacol. 2005 Mar;144(5):617-27. (PMID: 15678088)
Proc Natl Acad Sci U S A. 2001 May 22;98(11):6330-5. (PMID: 11371645)
Cell Mol Life Sci. 2015 Aug;72(15):2899-910. (PMID: 26100515)
J Pharmacol Exp Ther. 2010 Sep 1;334(3):1031-41. (PMID: 20551294)
Trends Cell Biol. 2016 Dec;26(12):944-955. (PMID: 27339936)
Neurology. 2000 Feb 22;54(4):833-7. (PMID: 10690972)
Endocrinology. 2007 May;148(5):2458-64. (PMID: 17303658)
Proc Natl Acad Sci U S A. 2018 Oct 9;115(41):E9668-E9677. (PMID: 30237284)
Endocrinology. 2016 Jul;157(7):2824-35. (PMID: 27167771)
J Cereb Blood Flow Metab. 2016 Jul;36(7):1202-11. (PMID: 26661210)
Proc Natl Acad Sci U S A. 2012 May 22;109(21):8280-5. (PMID: 22566616)
Nat Rev Cancer. 2016 Dec;16(12):775-788. (PMID: 27782134)
J Mol Cell Cardiol. 2004 Nov;37(5):1013-22. (PMID: 15522278)
Biochem J. 2006 Jul 1;397(1):1-14. (PMID: 16761954)
Brain Res. 2005 May 31;1045(1-2):107-15. (PMID: 15910768)
Proc Natl Acad Sci U S A. 2002 Jan 8;99(1):495-500. (PMID: 11756680)
Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11741-6. (PMID: 14504383)
Cell Metab. 2017 Aug 1;26(2):353-360.e3. (PMID: 28768174)
Bone. 2013 Apr;53(2):587-96. (PMID: 23247057)
J Neurosci. 2011 Mar 30;31(13):4962-77. (PMID: 21451035)
Neurosci Res. 1996 Dec;26(4):369-76. (PMID: 9004275)
Glia. 2010 Feb;58(3):329-43. (PMID: 19705457)
Methods. 2001 Dec;25(4):402-8. (PMID: 11846609)
Biophys J. 2016 Jan 5;110(1):127-40. (PMID: 26745416)
Neuron. 2017 Sep 13;95(6):1365-1380.e5. (PMID: 28867552)
Pharmacol Rev. 1999 Mar;51(1):63-81. (PMID: 10049998)
Proc Natl Acad Sci U S A. 2002 Oct 15;99(21):13589-94. (PMID: 12370428)
PLoS One. 2015 Apr 07;10(4):e0123096. (PMID: 25848957)
Endocrinology. 2012 May;153(5):2353-61. (PMID: 22434086)
J Neurosci. 2014 Aug 20;34(34):11228-32. (PMID: 25143604)
Biochim Biophys Acta. 2004 Mar 23;1662(1-2):102-12. (PMID: 15033582)
Reprod Biol Endocrinol. 2014 Sep 20;12:90. (PMID: 25239217)
Glia. 2015 Dec;63(12):2208-19. (PMID: 26200696)

P01 AG027956 United States AG NIA NIH HHS

Keywords: Androgen; Astrocyte; Connexin 43; Estrogen; Gap junctions; Oxidative stress

0 (Connexin 43)
4TI98Z838E (Estradiol)
08J2K08A3Y (Dihydrotestosterone)

Date Created: 20230818 Date Completed: 20241202 Latest Revision: 20241202

20241204

PMC10592012

10.1016/j.mce.2023.112045

37595662