It is now generally accepted that in common with other steroid hormones aldosterone has rapid nongenomic effects, in addition to those mediated via DNA-directed, RNAmediated protein synthesis. The currently accepted physiology of aldosterone was primarily charted by nephrologists, who understandably focused on the epithelial (and genomic) effects of aldosterone on urinary electrolytes, and the homeostatic changes in aldosterone secretion in response to sodium deficiency or potassium loading. The most acute physiological stimulus to aldosterone secretion, however, is assumption of the upright posture. Given this, it is not inappropriate to seek responses, similarly acute, to this rapid change in plasma aldosterone levels. In the paper by Gros et al,1 the authors conclusively show that aldosterone at low picomolar concentrations can act rapidly via both GPR30 (originally an “orphan” G protein– coupled receptor, subsequently an erstwhile membrane estrogen receptor) and classic mineralocorticoid receptors (MR) over a range of parameters. These include extracellular signal-regulated kinase (ERK) 1/2 activation and myosin light chain phosphorylation in rat aortic vascular smooth muscle cells (VSMC) in vitro; for ERK activation, aldosterone has equivalent action via both receptors at low picomolar concentrations. The effects on GPR30 appear mineralocorticoid specific: in rat aortic endothelial cells, with MR expression below detection levels by Western blotting, aldosterone increased ERK activation with an EC50 10 pM, an action abrogated by the GPR30 antagonist G15. In contrast, the effect of estradiol on inhibition of ERK activation was unaffected by G15 but blocked by the estrogen receptor (ER ) antagonist ICI-182780. The first point to be made is that these studies firmly establish GPR30 as a bona fide receptor for aldosterone, given the low picomolar concentrations used (except for myosin light chain phosphorylation, where inexplicably 10 nmol/L aldosterone was used, and Figures 8 and 9 point in quite different directions). Although GPR30 was also known as GPER, the latter designation was always on shaky ground: the concentrations of estradiol needed for its effect on ERK, for example, were orders of magnitudes higher than peak circulating levels. The second salient finding of the studies presented is that both spironolactone and eplerenone, classical MR antagonists, lowered but did not abolish the GPR30-mediated effects of aldosterone on VSMC. The authors term them partial antagonists, a term usually reserved for molecules that are also partial agonists. Eplerenone appears to be a full antagonist under some circumstances (eg, Figures 1B and 3B), as does spironolactone (Figure 3B), but a weaker antagonist under others (Figures 2, 5B, and 7B), with the reason for this discrepancy not apparent. Under no circumstances, however, is there any suggestion that eplerenone or spironolactone has any GPR30 agonist activity, as clearly shown in Figures 3B and 9B. Partial antagonist is therefore a misnomer, and the MR antagonists are thus putatively GPR30 antagonists per se, with the expectation that at higher concentrations the effect will be closer to more complete. In terms of potential (patho)physiological roles, there are a number of fascinating findings, and one item of unfinished business. First, in a demonstration of the perils of cell culture, the authors clearly demonstrate that GPR30 expression diminishes relatively rapidly with cell passage, necessitating the use of freshly dissociated or transfected cells. Second, they show that whereas MR levels remain relatively constant in passaged cells, in cells transfected to express (probably overexpress) GPR30, MR expression is downregulated. What determines GPR30 levels in vivo, or in freshly isolated aortic VSMCs, is understandably not addressed in the paper, but may be a factor in regulating MR expression in vivo. If this is the case, then GPR30 levels would have a (ligandindependent) flow-on effect on both acute and genomic actions of aldosterone via classical MR, a level of complexity not previously suggested. Finally, given the opposing effects of aldosterone (via GPR30) and estradiol (via ER , albeit at relatively high concentrations [see Figure 4C]), it is tempting to speculate that these two hormone-receptor systems act as ying and yang in terms of vascular smooth muscle ERK activation, and the consequences thereof. The unfinished business, which bears heavily on the possible physiological roles of GPR30 as a membrane MR, are the data presented in supplemental Figure 2. Supplemental Figure 2B shows that corticosterone, the physiological glucocorticoid in rats, appears to be a weak agonist in terms of ERK phosphorylation but that the significant increase seen at 100 pM is unaffected by the GPR30 antagonist G15. This is unfinished business because while it shows corticosterone not to be a GPR30 agonist in terms of ERK phosphorylation, it throws no light on whether it might be a GPR30 antagonist (as it is for MR in the kidney when 11 -hydroxysteroid The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From Prince Henry’s Institute, Clayton, Victoria, Australia. Correspondence to John W. Funder, Prince Henry’s Institute, PO Box 5152, Clayton, Victoria 3168, Australia. E-mail email@example.com (Hypertension. 2011;57:370-372.) © 2011 American Heart Association, Inc.