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This version published online on December 11, 2003
Endocrinology, doi:10.1210/en.2003-1462
A more recent version of this article appeared on March 1, 2004
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Submitted on October 29, 2003
Accepted on November 25, 2003

Mini-Review: A PLETHORA OF ESTROGEN RECEPTORS in the brain: WHERE WILL IT END?

C. Dominique Toran-Allerand1*

1 Departments of Anatomy & Cell Biology, and Neurology, and Centers for Neurobiology & Behavior and Reproductive Sciences, Columbia University College of Physicians & Surgeons, New York, NY 10032, USA.

* To whom correspondence should be addressed. E-mail: cdt2{at}columbia.edu.

Until 1996, when estrogen receptor-{beta} (ER-{beta}) was discovered, life seemed simple. The gonadal steroid hormone 17{beta}-estradiol had one receptor, the estrogen receptor, a ligand-inducible nuclear transcription factor. Estrogen receptor variants, the result of bp insertions, transitions, and deletions as well as alternative splicing, were considered abnormal and a prominent feature of breast cancer. Since then, like many other scientific beliefs, this concept has increased dramatically in complexity, and we are now faced with an ever-increasing array of estrogen-binding proteins, putative estrogen receptors, in the brain as well as in the extra-neural targets of estrogen. The end is unlikely to be in sight. Some of these putative receptors have been localized to plasma or nuclear membranes; others to the cytoplasm and/or nucleus. The molecular characteristics of membrane estrogen receptors are still in question, and, in most instances, the proteins have not been sequenced or cloned. However, based on transfection and immunohistochemistry, the generally held view, if not dogma, maintains that both nuclear and plasma-membrane-associated ERs probably originate from the same gene and transcript that produce the classical intranuclear receptors, ER-{alpha} and ER-{beta}. However, the physiological relatedness of this observation remains open to question. This review addresses evidence that, in addition to ER-{alpha} and ER-{beta}, there exist a variety of non-ER-{alpha}/non-ER-{beta} nuclear, cytoplasmic and plasma membrane estrogen receptors in the brain, including G protein-coupled receptors, a novel, developmentally regulated, membrane-associated estrogen receptor "ER-X", a functional, truncated ER-{alpha} variant ER-46 and a putative estrogen receptor (pER) that is immunochemically, structurally, and functionally completely distinct from ER-{alpha} and ER-{beta}.
Key words: estrogen receptors • plasma membrane • ER-{alpha} • ER-{beta} • "ER-X" • G-protein-coupled receptors • brain • caveolae • caveolar-like membranes




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