Axogenic effect of estrogen in male rat hypothalamic neurons involves Ca2+, PKC and ERK signaling

GOROSITO, SV, CAMBIASSO MJ

JOURNAL OF NEUROSCIENCE RESEARCH

Wiley Interscience

Lugar: United States; Año: 2008 p. 145 - 157

0360-4012

17-beta-Estradiol (E2) stimulates the growth of axons in male-derivedhypothalamic neurons in vitro. This effect is not exerted through the classicalintracellular estrogen receptor (ER) but depends on a membrane mechanisminvolving TrkB. In the present study, we investigate the intracellular signaling cascade that mediates the axogenic effect of E2. Treatment with an intracellular Ca(2+) chelator, a Ca(2+)-dependent protein kinase C (PKC) inhibitor, or twospecific inhibitors of extracellular signal-regulated kinases (ERK)mitogen-activated protein kinases (MAPK) completely inhibited the E2-inducedaxogenesis. E2 and the membrane-impermeant construct E2BSA rapidly inducedphosphorylation of ERK, which was blocked by the specific inhibitor of the ERKpathway UO126 but not by the ER antagonist ICI 182,780. Decrease of intracellularfree Ca(2+) or disruption of PKC activation by Ro 32-0432 attenuated ERKactivation, indicating the confluence of signals in the MAPK pathway. Subcellularanalysis of ERK demonstrated that the phospho-ERK signal is augmented in thenucleus after 15 min of E2 stimulation. We have also shown that E2 increasedphosphorylation of CREB via ERK signaling. In summary, this study demonstratesthat E2, probably via a membrane-associated receptor, induces axonal growth byactivating CREB phosphorylation through ERK signaling by a mechanism involvingCa(2+) and PKC activation.