Minireview: A plethora of estrogen receptors in the brain: where will it end?

Until 1996, when estrogen receptor (ER)-beta was discovered, life seemed simple. The gonadal steroid hormone 17 beta-estradiol had one receptor, the ER, a ligand-inducible nuclear transcription factor. ER variants, the result of base pair 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 ERs, in the brain as well as in the extraneural targets of estrogen. The end is unlikely to be in sight. Some of these putative receptors have been localized to plasma or nuclear membranes, and others to the cytoplasm and/or nucleus. The molecular characteristics of membrane ERs 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 ERs in the brain, including G protein-coupled receptors; a novel, developmentally regulated, membrane-associated ER, ER-X; a functional, truncated ER-alpha variant, ER-46; and a putative ER that is immunochemically, structurally, and functionally completely distinct from ER-alpha and ER-beta.