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The Brain Mineralocorticoid Receptor: a Saga in Three Episodes

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The Brain Mineralocorticoid Receptor: a Saga in Three Episodes 234 1 M JOËLS and E R DE KLOET Brain MR 234:1 T49–T66 Thematic Review 30 YEARS OF THE MINERALOCORTICOID RECEPTOR The brain mineralocorticoid receptor: a saga in three episodes Marian Joëls1,2 and E Ronald de Kloet3 1Department of Translational Neuroscience, Brain Center Rudolf Magnus, University Medical Center, Utrecht, The Netherlands Correspondence 2University of Groningen, University Medical Center, Groningen, The Netherlands should be addressed 3Division of Endocrinology, Department of Internal Medicine, Leiden University Medical Center, to E R de Kloet Leiden, The Netherlands Email [email protected] Abstract In 1968, Bruce McEwen discovered that 3H-corticosterone administered to Key Words adrenalectomised rats is retained in neurons of hippocampus rather than those of f brain hypothalamus. This discovery signalled the expansion of endocrinology into the science f stress of higher brain regions. With this in mind, our contribution highlights the saga of f behavioural adaptation the brain mineralocorticoid receptor (MR) in three episodes. First, the precloning era f neuronal circuits Endocrinology dominated by the conundrum of two types of corticosterone-binding receptors in the f mineralocorticoid of brain, which led to the identification of the high-affinity corticosterone receptor as the receptors ‘promiscuous’ MR cloned in 1987 by Jeff Arriza and Ron Evans in addition to the classical f glucocorticoid receptors glucocorticoid receptor (GR). Then, the post-cloning period aimed to disentangle the Journal 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 Journal of Endocrinology actions to homeostasis, excitability and behavioural adaptation. (2017) 234, T49–T66 Introduction On Tuesday April 14, 1987, while visiting Ron Evans and Arriza’s manuscript had just passed the Science and Jeff Arriza, we learned that they had cloned the review process and was waiting to be published on July mineralocorticoid receptor (NR3C2 or MR). At the time, 6th of the same year (Arriza et al. 1987). We were all one of us (M Joëls) was working next door, with George excited, particularly as from our studies, evidence was Siggins and Floyd Bloom at the Scripps Clinic. Evans’ mounting that there had to be an MR-like receptor http://joe.endocrinology-journals.org © 2017 Society for Endocrinology This paper is part of a thematic review section on 30 Years of the Mineralocorticoid DOI: 10.1530/JOE-16-0660 Published by Bioscientifica Ltd. Receptor. The guest editors for this section were John Funder and Printed in Great Britain Maria Christina Zennaro. Downloaded from Bioscientifica.com at 09/30/2021 06:49:57PM via free access 10.1530/JOE-16-0660 Thematic Review M JOËLS and E R DE KLOET Brain MR 234:1 T50 co-existing with the classical glucocorticoid receptors Saturday November 30, 1968, the Nature publication (GRs) in the brain. This was discovered in seminal on hippocampal corticosterone retention was published, binding studies using 3H-corticosterone in the absence and Monday December 2, I (E R de Kloet) started my or presence of the unlabeled pure glucocorticoid PhD research. In those days, there was no distracting RU28362 (Moguilewsky & Raynaud 1980). The San Internet. New research findings were read and discussed Diego visit in March 1987 gave us (E R de Kloet) a immediately after publication. Inspired by the new data, head start in combining new methods to measure MR one could do right away a cutting-edge experiment in with the knowledge gained from pharmacological and a Popperian attempt to reject a hypothesis as there endocrine studies. were no time-consuming rules and regulations. For In this tribute to the 30 years anniversary of the instance, in this corticosterone case, we assumed cloning of the MR, we will try to capture the special feeling in The Netherlands that we would get better results that MR scientists of this world share. This is because with the much more potent synthetic glucocorticoid many card-carrying MR aficionados are old enough dexamethasone. However, whatever I (E R de Kloet) tried, to remember the attempts to piece together what the dexamethasone did not mimic corticosterone binding peculiar aldosterone- and corticosterone receptor-binding in the rat brain but, rather, was retained in the pituitary profiles meant and still young enough to appreciate the (de Kloet et al. 1974). In 1975, when I (E R de Kloet) was a technological breakthroughs for the sake of better MR postdoc in Bruce McEwen’s lab, it was concluded that the understanding. Here, we will start with a brief account 3H-dexamethasone tracer was indeed poorly retained in of the pre-MR cloning era, then highlight the excitement cell nuclei of hippocampus (de Kloet et al. 1975). About during the first 5 post-cloning years and conclude with 20 years later, we discovered one of the two reasons: in a synthesis that is beginning to reveal the plot of an contrast to corticosterone, the dexamethasone tracer unfolding brain MR story. poorly penetrates the brain because it is a substrate for multidrug resistance P-glycoproteins (mdr Pgp) Precloning era encoded by the ABCB1 gene in the blood–brain barrier Endocrinology (Meijer et al. 1998). of When Bruce McEwen at Rockefeller University inspected The other reason was that if 3H-dexamethasone had the print out of the scintillation counter to learn about been able to penetrate the brain, the receptor binding 3 in the hippocampus would still have differed from Journal brain retention and uptake of H-corticosterone administered to an adrenalectomised (ADX) rat, he that reported by McEwen for 3H-corticosterone. Even was shocked. Wisdom at the time predicted that the in the mid-seventies, we were already entertaining this hormone would accumulate in the ‘hypophysiotropic’ idea, i.e., the existence of two distinct populations of hypothalamus that harboured the main regulator of the receptor sites for corticosterone and dexamethasone hypothalamic–pituitary–adrenal (HPA) axis: corticotropin- (de Kloet et al. 1975, McEwen et al. 1976). Meanwhile, releasing hormone (CRH, cloned in 1981 by the late Wylie 3H-aldosterone autoradiography and cytosol receptor Vale) and vasopressin in the paraventricular nucleus binding showed a striking similarity with the pattern of (PVN). However, it was not in the PVN that corticosterone corticosterone retention in the rat brain (Ermisch & Rühle was retained; by far the highest uptake and retention of 1978, de Nicola et al. 1981, Beaumont & Fanestil 1983). the tracer occurred in the hippocampus (McEwen et al. Moreover, inclusion of the glucocorticoid RU28362 1968, Gerlach & McEwen 1972). This observation appeared to discriminate between high- and low-affinity matched with the behavioural and neuroendocrine effects binding of corticosterone (Moguilewsky & Raynaud of glucocorticoid implants in suprahypothalamic regions 1980, Veldhuis et al. 1982). Then, it was discovered by (Bohus & Lissak 1968). The impact was large: it became the late Zig Krozowski that cytosol of brain and kidney clear that brain regions beyond the hypothalamus had display similar binding properties for aldosterone, to be of crucial importance for the action of adrenal the certified mineralocorticoid Krozowski( & Funder hormones on the processing of salient information 1983). Finally, the hippocampal cells expressing irGR (McEwen et al. 2015). (Fuxe et al. 1985) did not match the autoradiograms Tracer amounts of corticosterone are retained of the naturally occurring corticosterone (Gerlach & and accumulated by mineralocorticoid receptors in McEwen 1972). Notably, the hippocampal CA3 virtually extrahypothalamic limbic brain regions. lacked GR, whereas the very same area was known to http://joe.endocrinology-journals.org © 2017 Society for Endocrinology Published by Bioscientifica Ltd. DOI: 10.1530/JOE-16-0660 Printed in Great Britain Downloaded from Bioscientifica.com at 09/30/2021 06:49:57PM via free access Thematic Review M JOËLS and E R DE KLOET Brain MR 234:1 T51 highly retain tracer amounts of 3H-corticosterone in contrast, the 11HSD-1 reductase regenerates bioactive adrenalectomised rats. glucocorticoids and is widely expressed in neurons and That was the moment the idea sparked that we glial cells of the brain (Chapman et al. 2013). probably missed the GR in the autoradiograms because In most brain cells, therefore, MR retains corticoste- its affinity was too low to produce a signal after the tracer rone with very high affinity. Consequently, this receptor doses of 3H-corticosterone. Thus, we administered in is expected to be substantially occupied by corticosterone. vivo graded doses of corticosterone to adrenalectomised
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