Estrogen Receptors on the Membrane

For this article, Eugene Russo interviewed Ellis R. Levin, chief of endocrinology and metabolism at the Long Beach Veterans Affairs Medical Center and vice chairman for research in the department of medicine at the University of California, Irvine. Data from the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. M. Razandi, A. Pedram, G.L. Greene, E.R. Levin, "Cell membrane and nuclear estrogen receptors (ERs) originate from a single transcript: Studies of ER alpha and ER beta expressed in Chinese hamster ovary cells," Molecular Endocrinology, 13:307-19, February 1999. (Cited in 110 papers) For years, endocrinologists believed that the actions of estrogen and other steroids were confined to the cell's nucleus. By presenting evidence for a plasma membrane estrogen receptor (ER), this paper made the rather unorthodox claim that estrogen also had cell biologic effects that originate in the plasma membrane. Courtesy of Long Beach Vetrans Affairs Mediclal CenterEllis R. LevinThe results presented continue to be divisive. "There's been a tremendous turn-around by a number of prominent people in the field who are now looking at this concept very seriously," says senior author Ellis R. Levin, chief of endocrinology and metabolism at the Long Beach Veterans Affairs Medical Center and vice chairman for research in the department of medicine at the University of California, Irvine. Levin's group first suspected membrane effects when observing cellular events that, they believed, were far to rapid to occur via nuclear ERs--that is, via gene activation and protein product production in the nucleus. Many laboratories in the 1970s, 80s, and 90s had presented data suggesting the existence of membrane steroid receptors. "This kind of work didn't really get a lot of support," says Levin. "The people in that area had trouble getting their grants and their papers published." Levin's group set out to devise a model in which they could isolate the cell membrane to look for signs of a putative estrogen membrane receptor. They turned to Chinese hamster ovary (CHO) cells precisely because those cells do not express the receptor. Levin and colleagues produced both nuclear and membrane receptors in CHO cells in vitro by transfecting a single cDNA. "You don't need to postulate a second gene for the membrane receptor," explains Levin. "You don't have to postulate an alternately expressed transcript. It all can happen from a single mRNA making a single protein." Some of that protein moves to the membrane; a lot more of it moves to the nucleus. According the Levin, nuclear and membrane receptors appear to be nearly biochemically identical. As the 1999 paper and subsequent papers suggest, the two receptors work in concert. If a cell needs to rapidly modulate function of a given protein, it employs the membrane receptor. Long-term, chronic effects are primarily modulated through transcription and protein synthesis via the nuclear receptor. The paper also reported the first direct evidence that the membrane ER belongs to an important class of signaling molecules called G-protein coupled receptors, a finding that explains previous observations of estrogen's downstream effects on calcium flux and cyclic AMP generation. Follow-up work on non-nuclear ERs has implicated them in an array of cellular functions in humans. Last September, a Harvard group showed that estrogen could rescue mice from ischemia and reperfusion injury via a non-nuclear estrogen signaling pathway.1 That same month, Levin's group showed that estradiol, a type of estrogen made in the ovaries, can signal from the cell membrane and serve as a survival factor for breast cancer cells, thus making them resistant to chemotherapy and radiation therapy.2 Last December, Levin's group also showed that estrogen, via a signal transduction pathway governed by membrane receptors, could both rescue endothelial cells from a hypoxia-induced death and promote new blood vessel formation.3 He even cites continuing research into the role of membrane-mediated estrogen signaling in the central nervous system. Levin points out that ongoing studies suggest the presence of other forms of rapidly signaling steroid receptors in the membrane including vitamin D, progesterone, glucocorticoid, and mineralocorticoid. "This may change the way we think about steroid hormone action quite dramatically," he says. "People are embracing the idea that there is a bona fide estrogen receptor in the membrane, that it can signal, and that the signaling pathways are well-known in other models known to be important for cell biology." Eugene Russo can be contacted at erusso@the-scientist.com References 1. T. Simoncini et al., "Interaction of oestrogen receptor with the regulatory subunit of phosphatidylinositol-3-OH kinase," Nature, 407: 538-41, September 28, 2000. 2. M. Razandi et al., "Plasma membrane estrogen receptors signal to antiapoptosis in breast cancer," Molecular Endocrinology, 14:1434-47, September 2000. 3. E.R. Levin et al., "Estrogen signals to the preservation of endothelial cell form and function," Journal of Biological Chemistry, 49:38540-6, December 8, 2000.

Estrogen Receptors on the Membrane

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