Abstract
In 1968, Bruce McEwen discovered that 3H-corticosterone administered to adrenalectomised rats is retained in neurons of hippocampus rather than those of hypothalamus. This discovery signalled the expansion of endocrinology into the science of higher brain regions. With this in mind, our contribution highlights the saga of the brain mineralocorticoid receptor (MR) in three episodes. First, the precloning era dominated by the conundrum of two types of corticosterone-binding receptors in the brain, which led to the identification of the high-affinity corticosterone receptor as the 'promiscuous' MR cloned in 1987 by Jeff Arriza and Ron Evans in addition to the classical glucocorticoid receptor (GR). Then, the post-cloning period aimed to disentangle the function of the brain MR from that of the closely related GR on different levels of biological complexity. Finally, the synthesis section that highlights the two faces of brain MR: Salt and Stress. 'Salt' refers to the regulation of salt appetite, and reciprocal arousal, motivation and reward, by a network of aldosterone-selective MR-expressing neurons projecting from nucleus tractus solitarii (NTS) and circumventricular organs. 'Stress' is about the limbic-forebrain nuclear and membrane MRs, which act as a switch in the selection of the best response to cope with a stressor. For this purpose, activation of the limbic MR promotes selective attention, memory retrieval and the appraisal process, while driving emotional expressions of fear and aggression. Subsequently, rising glucocorticoid concentrations activate GRs in limbic-forebrain circuitry underlying executive functions and memory storage, which contribute in balance with MR-mediated actions to homeostasis, excitability and behavioural adaptation.
Highlights
On Tuesday April 14, 1987, while visiting Ron Evans and Jeff Arriza, we learned that they had cloned the mineralocorticoid receptor (NR3C2 or MR)
About 20 years later, we discovered one of the two reasons: in contrast to corticosterone, the dexamethasone tracer poorly penetrates the brain because it is a substrate for multidrug resistance P-glycoproteins encoded by the ABCB1 gene in the blood–brain barrier (Meijer et al 1998)
We found that i.c.v. administration of the MR antagonist RU28318 caused a slow and long-lasting suppression of the stress-induced pressor response
Summary
On Tuesday April 14, 1987, while visiting Ron Evans and Jeff Arriza, we learned that they had cloned the mineralocorticoid receptor (NR3C2 or MR). The San Diego visit in March 1987 gave us (E R de Kloet) a head start in combining new methods to measure MR with the knowledge gained from pharmacological and endocrine studies. In this tribute to the 30 years anniversary of the cloning of the MR, we will try to capture the special feeling that MR scientists of this world share. This is because many card-carrying MR aficionados are old enough to remember the attempts to piece together what the peculiar aldosterone- and corticosterone receptor-binding profiles meant and still young enough to appreciate the technological breakthroughs for the sake of better MR understanding. We will start with a brief account of the pre-MR cloning era, highlight the excitement during the first 5 post-cloning years and conclude with a synthesis that is beginning to reveal the plot of an unfolding brain MR story
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