The neuroprotective effects of estrogen, along with its role related to gender and reproduction, have been believed to act through two estrogen receptors called ER- and ER-ß. Both receptors are located in the nucleus, where they bind estrogen and activate estrogen-regulated genes.

But some effects of estrogen, including neuron growth, happen too quickly to be explained by gene activation processes in the nucleus that take hours to kick in. These faster activities probably occur through activation of genes not regulated by the nuclear receptors.

Now, new research by Dr. Dominique Toran-Allerand, professor of anatomy and cell biology in the Center for Reproductive Sciences, the Center for Neurobiology and Behavior, and in neurology, describes the discovery of a previously unknown estrogen receptor, ER-X, on the surface of the cell membrane that may explain the speedier cellular behaviors. The new receptor may be behind estrogen's protective effect in the brain and lead to new drugs to reduce the risk of stroke or lessen the loss of neurons in Alzheimer's disease.

Almost 30 years ago, Dr. Toran-Allerand found estrogen was not just controlling sexual differentiation and reproduction, but also was stimulating the growth of axons and dendrites with other growth factors.

Since then, others also have found estrogen has non-traditional effects in adults. It prevents the death of neurons in mature rats when the brain is injured by stroke. Epidemiological studies also show women taking hormone replacement therapy have less chance of getting Alzheimer's than women not taking estrogen, suggesting the hormone may protect neurons from disease.

But how estrogen elicits its neural developmental and injury-prevention effects is unknown. Dr. Toran-Allerand previously found evidence estrogen sometimes works through an unknown receptor on the neuron's cell membrane. But others thought the receptor was a version of ER-, because antibodies to ER- bind to something on the cell membrane.

In new research published in the October Journal of Neuroscience, Dr. Toran-Allerand isolated the estrogen receptor from the membrane of mouse neurons. It turned out to be an unknown protein that binds ER- antibodies but has a completely different molecular weight than the nuclear receptor. The new estrogen receptor—called ER-X—also shows up in knockout mice that are missing the ER- receptor, providing further evidence the protein is not ER-.

To learn what ER-X does, Dr. Toran-Allerand analyzed fetal and adult tissues from mice to determine where and when the receptor is expressed. During development, she found the receptor appears in the brain and the uterus and seems to bind 17ß-estradiol, the estrogen that binds to the two nuclear receptors.

She also found the new receptor mediates activation of a biochemical pathway that induces the growth of axons and dendrites. The receptor appears to activate the growth pathway after it binds 17-estradiol (the mirror image of 17ß-estradiol), which was previously believed to be inactive. "Many of the growth-enhancing effects of estrogen in the developing brain are probably due to ER-X, not ER-," Dr. Toran-Allerand says. "ER-X also binds and responds to 17ß-estradiol with the same affinity as 17-estradiol, but only when ER-, which inhibits the growth pathway, is absent."

Tracking ER-X expression also showed the receptor disappears from the brain after the first month of life but can reappear, like ER-, in injured regions of adult brains after a stroke.

"One possible reason estrogen is beneficial in cognitive disorders like stroke and Alzheimer's is because it's binding to ER-X," she says.

If ER-X is responsible for protecting neurons, she adds, one outcome could be therapeutics to prevent neuron death from stroke or Alzheimer's.

Forms of estrogen that work via the two nuclear receptors can't be used for neuroprotection because they have unacceptable feminizing side effects on men.

A form of estrogen that only binds to ER-X, as she found 17-estradiol does, may protect neurons but leave ER- and ER-ß alone.

Dr. Toran-Allerand says she still needs to clone the ER-X gene to ultimately prove the membrane receptor is unique and to study its structure and function in more detail.

"Years ago I showed estrogen stimulates the growth of axons and dendrites," she says, "and I have been trying to figure out how ever since. ER-X may be part of the answer."

Dr. Toran-Allerand's research was funded by the National Institute on Aging, National Institute of Mental Health, National Science Foundation, Alzheimer's Association, and a Research Scientist Award from the Alcohol, Drug Abuse, and Mental Health Administration.