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Membrane‐initiated estradiol signaling increases tyrosine hydroxylase promoter activity with ERα in PC12 cells
Author(s) -
Maharjan Shreekrishna,
Serova Lidia I.,
Sabban Esther L.
Publication year - 2010
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2009.06430.x
Subject(s) - creb , phosphorylation , cyclic amp response element binding protein , biology , protein kinase a , microbiology and biotechnology , signal transduction , tyrosine phosphorylation , tyrosine hydroxylase , transcription factor , chemistry , endocrinology , biochemistry , dopamine , gene
J. Neurochem. (2010) 112 , 42–55. Abstract Tyrosine hydroxylase (TH) promoter activity is induced by 17β‐estradiol (E 2 ) in PC12 cells expressing estradiol receptor‐alpha (ERα) requiring a cAMP/calcium response element (CRE/CaRE) at −45. To examine whether membrane‐initiated estradiol signaling is underlying this induction, cells co‐transfected with TH reporter construct and ERα expression vector were exposed to membrane‐impermeant estradiol conjugate (β‐estradiol‐6‐(O‐carboxy‐methyl) oxime‐bovine serum albumin, E 2 BSA). TH promoter activity was elevated by E 2 BSA in dose‐ and time‐dependent manner. E 2 BSA also elicited rapid phosphorylation of CRE binding protein (CREB) and increased CRE‐driven promoter activity. Over‐expression of dominant negative forms of CREB, with mutations in DNA binding or phosphorylation site, prevented TH promoter response to E 2 BSA. Pre‐treatment with protein kinase A (PKA) and MEK inhibitors reduced E 2 dependent phosphorylation of CREB and ERK, and also decreased induction of TH promoter activity by E 2 or E 2 BSA. Blocking S ‐palmitoylation of ERα with C451A mutation and/or pre‐treatment with 2‐Bromopalmitate did not prevent but instead enhanced E 2 or E 2 BSA‐elicited induction of TH promoter activity. These findings reveal, for the first time, that estradiol induction of TH gene transcription with ERα in PC12 cells involves membrane‐initiated estradiol signaling, rapid activation of dual PKA/MEK signaling pathways, leading to CREB phosphorylation, acting at CRE/CaRE. The data demonstrate possible mechanism whereby estradiol affects catecholaminergic systems in vivo .