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Harvey Newcastle Upon Tyne Phys Soc 8 Sept 2009


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presentation to the Physiological Society Symposium on Epithelial Membrane Transport, Newcastle-upon-Tyne, September 2009

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Harvey Newcastle Upon Tyne Phys Soc 8 Sept 2009

  1. 1. Anti-secretory Action of Estrogen in the Intestine Brian Harvey Department of Molecular Medicine Royal College of Surgeons in Ireland The Physiological Society Membrane and Epithelial Transport Symposium Newcastle-upon-Tyne 2009
  2. 2. RCSI Molecular Medicine Estrogen rapid responses Rodrigo Alzamora Fiona O’Mahony Warren Thomas
  3. 3. Estrogen and Fluid Retention O’Mahony & Harvey J Physiol 2009
  4. 4. Anti-secretory action of Estrogen X PKC Condliffe, Doolan & Harvey J Physiol 2001 O’Mahony & Harvey Mol Endo 2008 O’Mahony & Harvey JBC 2007 O’Mahony et al. Mol Endo 2009
  5. 5. Estrogen Inhibits Secretion in Colonic Epithelia control E2 1nM E2 Condliffe, Doolan, Harvey J Physiol, 2001.
  6. 6. Estrogen Inhibits Secretion via PKC Rottlerin E2 -PKC E2 Condliffe, Doolan, Harvey J Physiol 2001.
  7. 7. Estrogen Rapidly Inhibits KCNQ1 Currents in Single Isolated Crypts 1nM O’Mahony & Harvey J Biol Chem, 2007.
  8. 8. Estrogen Phosphorylation of the KCNQ1 Channel is PKC and PKA dependent -PKC -PKA E2 E2 E2 O’Mahony & Harvey J Biol Chem, 2007.
  9. 9. Summary Estrogen causes a rapid and sustained inhibition of both Ca2+ and cAMP driven chloride ion secretion via PKC - PKA phosphorylation of KCNQ1 channels causing closure and retrieval of the channel Estrogen inhibits basal secretion and secretion activated by cholera toxin and heat-stable enterotoxin Questions  Is the estrogen receptor involved?  Is the response female-specific?
  10. 10. A plasmamembrane-associated 66kDa mER transduces E2 activation of PKC O’Mahony et al. Mol Endo 2009.
  11. 11. Anti-secretory E2 response is female sex-specific and estrus cycle dependent Cl- secretion rate % Isc O’Mahony et al. Mol Endo 2009.
  12. 12. Sex differences in ion transporter expression NKCC1 KCNE3 Male Female Male Female CFTR Na/K pump O’Mahony and Harvey. Steroids, 2008.
  13. 13. Female sex-specific activation of PKC by E2 Male Female O’Mahony et al. Mol Endo 2009.
  14. 14. Rapid and Genomic Ion transporter Responses to E2 Apical Basolateral Short term anti- Na+ secretory effect NKCC1 K+ 2Cl- CREB MAPK Transcriptional PKCAI mER priming PKC  PKCAI E2 P Intracellular Long term anti- PKC  pool KCNQ1 K+ secretory effect Endocytosis Cl- CFTR K+ Exocytosis Na/K ATPase Na+ O’Mahony & Harvey. J Physiol 2009.
  15. 15. Summary  Estrogen regulates Cl- secretion via PKC inhibition of KCNQ1 channels  The anti-secretory response is female sex-specific and estrus cycle dependent  Estrogen regulates the expression of protein kinases and ion transporters to effect sustained inhibition of secretion  A membrane-bound 66KDa mER mediates the rapid kinase responses to estrogen and genomic priming of the anti-secretory response
  16. 16. mERrole in ion transport and cell proliferation mER KCNQ1 Ion transport K+ response Cell proliferation response mER O’Mahony & Harvey. Steroids 2008.
  17. 17. MAPK Expression is Gender Regulated Male Female Male Female O’Mahony et al. Mol Endo 2009.
  18. 18. CREB is Phosphorylated in the nucleus in Response to E2 And is MAPK and PKA Dependent O’Mahony et al. Mol Endo 2009.
  19. 19. Rapid mER-estrogen regulated transcriptional responses O’Mahony et al. Mol Endo 2009.
  20. 20. Conclusions • Estrogen inhibits epithelial ion and fluid secretion in females only • The anti-secretory response to estrogen has both beneficial and pathological effects in intestine and lung, respectively • The KCNQ1:KCNE3 channel is differentially regulated by estrogen in females • The mER receptor transduces rapid anti-secretory responses to estrogen and primes the genomic phase of expression of protein kinases, ion channels and receptors, and cell proliferation
  21. 21. The molecular mechanisms for estrogen anti-secretory responses are similar in colon and bronchus mER PKC PK  A MAPK CREB PKC mRNA Dehydration of mucus layer Estrogen in CF, asthma ??
  22. 22. Estrogen and KCNQ1 channels in CF and Asthma?
  23. 23. Respiratory function in Asthma and Cystic Fibrosis is exacerbated in females at puberty - role for E2?
  24. 24. A Estrogen reduces ASL in CF bronchus CuFi_1 55 1H 4H 12H 24H 50 45 40 CuFi control 35 ASL High m m CuFi_1 30 CuFi + E2 NHBE 25 20 15 10 5 ASL stabilized 0 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Hours
  25. 25. Summary  The estrous cycle differences in the anti-secretory response to estrogen may be important for fluid retention and volume expansion required for implantation of the embryo  The anti-secretory effects of estrogen are observed in other epithelia such as endometrium, sweat gland, renal CCD and bronchus.  Estrogen modulation of KCNQ1 channel activity has important physiological implications for female-specific responses in secretory diarrhoea, Cystic Fibrosis, Asthma ….