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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
X
Anti-secretory action of Estrogen
O’Mahony & Harvey Mol Endo 2008Condliffe, Doolan & Harvey J Physiol 2001
O’Mahony & Harvey JBC 2007 O’Mahony et al. Mol Endo 2009
PKC
Estrogen Inhibits Secretion in Colonic Epithelia
Condliffe, Doolan, Harvey J Physiol, 2001.
E2
control
E21nM
Estrogen Rapidly Inhibits KCNQ1
Currents in Single Isolated Crypts
1nM
O’Mahony & Harvey J Biol Chem, 2007.
Estrogen Phosphorylation of the KCNQ1 Channel
is PKC and PKA dependent
-PKC -PKA
E2E2
E2
O’Mahony & Harvey J Biol Chem, 2007.
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
Is the estrogen receptor involved?
Is the response female-specific?
Questions
A plasmamembrane-associated 66kDa mER
transduces E2 activation of PKC
O’Mahony et al. Mol Endo 2009.
Anti-secretory E2 response is female
sex-specific and estrus cycle dependent
Cl- secretion
rate
O’Mahony et al. Mol Endo 2009.
% Isc
Sex differences in ion transporter expression
O’Mahony and Harvey. Steroids, 2008.
Na/K pumpCFTR
NKCC1 KCNE3
Male Female Male Female
PKC E2PKCAI
Endocytosis
Intracellular
pool
Exocytosis
Cl-
K+
Apical
P
MAPK
PKCAI
CREB
Short term anti-
secretory effect
Transcriptional
priming
Long term anti-
secretory effect
Basolateral
Rapid and Genomic Ion transporter Responses to E2
PKC
NKCC1
KCNQ1
Na/K
ATPase
CFTR
2Cl-
Na+
K+
Na+
K+
mER
O’Mahony & Harvey. J Physiol 2009.
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
Summary
mER
mERrole in ion transport and cell proliferation
KCNQ1
K+Ion transport
response
Cell proliferation
response
mER
O’Mahony & Harvey. Steroids 2008.
CREB is Phosphorylated in the nucleus in Response to E2
And is MAPK and PKA Dependent
O’Mahony et al. Mol Endo 2009.
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
MAPKMAPK
CREBCREB
PKC mRNA mRNA
PK
A
PKC
mER
The molecular mechanisms for estrogen anti-secretory responses
are similar in colon and bronchus
Dehydration of mucus layer
Estrogen in CF, asthma ??
Respiratory function in Asthma and Cystic Fibrosis
is exacerbated in females at puberty - role for E2?
0
5
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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
AS
L H
igh
mm
CuFi_1
NHBE
1H 4H 12H 24H
CuFi_1
ASL stabilized
A
CuFi control
CuFi + E2
Estrogen reduces ASL in CF bronchus
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 ….