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Department of Physiology and Program in Neuroscience, University of Maryland, Baltimore, Baltimore, Maryland 21201
Address all correspondence and requests for reprints to: Margaret M. McCarthy, Department of Physiology and Program in Neuroscience, University of Maryland, Baltimore, 655 West Baltimore Street, Baltimore, Maryland 21201. E-mail: mmccarth{at}umaryland.edu.
A long-standing apartheid between peptide and steroid hormone action was generally tolerated for decades, with segregation along lines of membrane vs. nuclear addresses. Persistent revolutionary rumblings of steroid hormones crossing over into the neighborhood of membrane actions were easy to dismiss due to lack of clear evidence for a bona fide membrane receptor for steroids, in particular estradiol. But in a process that one would like to see happen more frequently in the geopolitical world, the truth eventually won out, and it is now the norm to accept that steroid hormones have multiple effects, with actions at the membrane complementing and perhaps being a requisite precursor to those at the nucleus. Nonetheless, the cellular basis for membrane-mediated effects is often unknown and is at times downright controversial. Not ones to shrink from controversy, the collaborators and colleagues of A. E. Herbison have taken a new look at this old question in the article titled "Critical in Vivo Roles for Classical Estrogen Receptors in Rapid Estrogen Actions on Intracellular Signaling in Mouse Brain" (1).
With any new world order, old terms require redefining so that a common language can once again emerge. Previous descriptors focused on whether steroid effects were genomic or nongenomic, with the implicit corollary that genomic effects involved binding of estradiol to its receptor (ER), which was parked in the cytoplasm in anticipation of a ride into the nucleus once its passenger was aboard. After arriving in the nucleus, the receptor reveals its identity as a transcription factor, settles down on the appropriate palindrome, and commences transcribing, resulting in the synthesis of new protein. The many steps in the process—receptor binding, translocation, transcription, translation, and posttranslational processing—necessitated that hormonal action was slow in onset and long in duration (2, 3). An additional wrinkle was the discovery that ER could interact directly with other transcription factors such as fos or jun and could thereby influence transcription at activator protein-1 sites, eliminating the need for an estrogen response element (4), but we were still safely ensconced within the nucleus. If physiological effects of estradiol were apparent with a very rapid time course (milliseconds to seconds), this was considered diagnostic of a membrane effect and presumed to be due to a novel receptor with distinct binding properties and mysterious ways. Much effort was expended in an attempt to find and characterize the putative membrane receptor for estradiol, and some successes were achieved (5, 6, 7). Other effects of estradiol occur extremely rapidly and are clearly at the membrane but appear to involve direct modulation of heterotypic proteins such as amino acid neurotransmitter receptors, voltage-gated calcium channels, or G protein-coupled receptors (8, 9, 10, 11).
In the mellowing that so often accompanies age, there has been a gradual creep in the length of time considered indicative of "rapid" effects of estradiol, combined with an unambiguous marker of estradiol action that is likely not a transcriptional event and is of clear physiological relevance—phosphorylation. Two endpoints in particular have been notable, phosphorylation of the transcription factor cAMP response element binding protein (CREB), which is required for its activation, and phosphorylation of MAPK. Estradiol can increase or induce the phosphorylation of both of these within 15 min, a time course we now call rapid. Estradiol also increases phosphorylation of Akt via kinase B in a process that requires about an hour (12). The discovery of a novel effect of estradiol leads naturally into the search for a novel mechanism, one that might involve, perhaps, a novel receptor? ER-X is a clear candidate for said novel receptor, particularly in the developing cerebral cortex (13, 14), and other as-yet-undiscovered receptors could be involved as well. But the data presented by Ábrahám et al. (1) definitively establish that rapid effects of estradiol on the phosphorylation of CREB and MAPK in steroid-concentrating regions of the adult mouse brain require the presence of at least one of the classical ERs, ER
or ERß. Brain areas lacking classical ER do not show a change in phosphorylation state of either protein in response to estradiol and, more definitively, brains from mice with a null mutation for either or both receptors show no changes in CREB or MAPK phosphorylation in what is for the most part a highly lawful manner.
The qualifier regarding estradiol action comes from the unusual observation in the medial preoptic area, where either receptor alone is sufficient for phosphorylation of CREB and the response eliminated only in a double knockout mouse that is incapable of expressing either ER. The preoptic area is notable for being one of the few brain areas that appears to contain both isoforms of ER in abundance, including in the same cell (15). This apparent substitutability in receptor action is not true for the phosphorylation of MAPK in the preoptic area, which requires that both receptors be present.
When a finding is truly definitive, it often raises a host of new and interesting questions. The current piece of elegant work has no shortcomings on that score. One of the first questions raised is why have two receptors if they are both achieving the same endpoint, phosphorylation of CREB? Of course, there are many other potential effects of ER vs. ERß than the phosphorylation of CREB, but that only dodges the question—why are they doing the same thing in this instance? Why do some brain regions express ER and some ERß, and why does the preoptic area have both when one is clearly enough for other brain regions? Is it just for safety in case one malfunctions? A lack of phenotype in mice with null mutations of critical genes is often dismissed as being due to compensation. Is it possible the preoptic area evolved endogenous compensation due to its critical role in reproductive processes? Of course, there are likely other distinct roles for these two receptors that we have not yet discovered, and other steroid receptor-concentrating brain regions are as critically important to reproduction, but this brain area remains distinctive nonetheless. A comparative analysis of the expression of these ancient proteins placed in the context of phylogeny and brain development could provide useful insight into the why and where of ER expression.
Another question of interest is why is it that in every area in the brain that has been looked at so far that contains ER, including a limited number of GnRH neurons (16), the pyramidal neurons of the hippocampus (17), anteroventral periventricular nucleus (18), and those examined in the current study, does estradiol always have the same effect, an increase in the phosphorylation of CREB? Where is the specificity? Is phosphorylated CREB just the obligatory first step to any estradiol action? And how exactly does activation of ER result in the phosphorylation of CREB or MAPK? Is the signal transduction pathway activated the same way in each brain region? Questions of how a cytoplasmic/nuclear transcription factor could exert rapid effects on phosphorylation events are at least in part answered by the observation that the classical receptor actually intercalates into the membrane (19), upping the ante on the range of potential signaling events in which it could be involved. It is also a delightful turnaround in which an old dog reveals it has more tricks than we knew. These are just some of the myriad questions raised by this interesting report. The key is going to be deciding which questions are most relevant and tractable, and the fun is going to be in watching the answers emerge.
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Received March 15, 2004.
Accepted for publication March 22, 2004.
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and progestin receptor proteins in the female rat forebrain: effects of estradiol treatment. Endocrinology 142:5172–5181 and ERß expressed in chinese hamster ovary cells. Mol Endocrinol 13:307–319This article has been cited by other articles:
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  M. I. Boulware, H. Kordasiewicz, and P. G. Mermelstein Caveolin Proteins Are Essential for Distinct Effects of Membrane Estrogen Receptors in Neurons J. Neurosci., September 12, 2007; 27(37): 9941 - 9950. [Abstract] [Full Text] [PDF]
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