Is GPR30 the membrane aldosterone receptor postulated 20 years ago?

Letters to the Editor will be published, if suitable, as space permits. They should not exceed 1000 words (typed double-spaced) in length and may be subject to editing or abridgment. Gros et al 1 describe the involvement of GPR30 in rapid actions of aldosterone. The hypothesis that a structure other than the mineralocorticoid receptor (MR) may mediate rapid actions of aldosterone was postulated many years ago. Wehling et al 2 showed in 1991 that the rapid effect of aldosterone on the sodium-proton exchanger in human mononuclear leukocytes and vascular smooth muscle cells was independent of classic aldo-sterone antagonists like canrenoate or canrenone. 3 Grossmann et al 4 showed almost 15 years later that cytosolic Ca 2ϩ was increased by aldosterone in mock-and in human MR-transfected cells to the same extent, and spironolactone did not block this effect, pointing to MR-independent mechanisms. Most recently, aldosterone binding sites were detected at the membrane of human endothelial cells using atomic force microscopy. Aldo-sterone binding to these sites was spironolactone and dexameth-asone insensitive. 5 These examples are just a few of those pointing to MR-independent rapid aldosterone actions, and this interpretation is mainly based on their insensitivity to MR antagonists. The functions of GPR30, especially with respect to estrogen actions, are a matter of ongoing debate, and the new findings on its involvement in rapid aldosterone actions add an important facet to this discussion. Gros et al 1 postulate that eplerenone and spironolactone are partial antagonists of GPR30. This needs further clarification. Analyzing Figure 2 of the article by Gros et al 1 in detail, it is tempting to assume that, in vascular smooth muscle cells which have been transfected with the control construct (green fluorescent protein), extracellular signal–regulated kinase phosphoryla-tion by aldosterone reflects basic MR expression, because it is completely inhibited by eplerenone. When MR is overexpressed in those cells, the effect of aldosterone is roughly doubled, but it remains completely (ϭ100%) eplerenone sensitive. In GPR30-transfected cells, extracellular signal–regulated kinase phosphor-ylation by aldosterone is also roughly doubled. However, the added effect is not eplerenone sensitive, because eplerenone decreases extracellular signal–regulated kinase phosphorylation only by exactly the same amount seen in cells transfected with the control construct (green fluorescent protein). Therefore, the effect of eplerenone in the GPR30-transfected cells seems to be fully explained by the inhibition of the assumed endogenous MR activity. This is underlined by numerically identical results in Figure 7A through …