Brain mineralocorticoid and glucocorticoid receptor balance in neuroendocrine regulation and stress-related psychiatric etiopathologies

Kloet, E. R. de

doi:10.1016/j.coemr.2022.100352

Cited by 5 publications

(6 citation statements)

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“…As a first step, to determine if there are differences in transcriptional activation of these MRs by corticosteroids, we are cloning these human and chimpanzee MR genes and are screening them for transcriptional activation by aldosterone, cortisol, and other corticosteroids. We also will screen dimers of these MRs with the GR for activation by aldosterone and other corticosteroids [28,42–45,49], which is an important mechanism for regulating corticosteroid activity in the brain [15,17,44,50,51].…”

Section: Resultsmentioning

confidence: 99%

“…These three human cortisol, and other corticosteroids. We also will screen MR-GR dimers for activation by aldosterone and other corticosteroids [28,[42][43][44][45]49], which is an important mechanism for regulating corticosteroid activity in the brain [15,17,44,50,51].…”

Section: Novel Mineralocorticoid Receptors In Humansmentioning

confidence: 99%

“…All four chimpanzee MRs contain (Ile-180, Val-241) in their NTD, which is similar to the NTD in one human MR (Figure 2 cortisol, and other corticosteroids. We also will screen dimers of these MRs with the GR for activation by aldosterone and other corticosteroids [28,[42][43][44][45]49], which is an important mechanism for regulating corticosteroid activity in the brain [15,17,44,50,51].…”

Section: Chimpanzees Have Four Full-length Mineralocorticoid Receptorsmentioning

confidence: 99%

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Novel Evolution of the Mineralocorticoid Receptor in Humans compared to Chimpanzees, Gorillas and Orangutans

Katsu,

Zhang,

Baker

2023

Preprint

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Five distinct full-length mineralocorticoid receptor (MR) genes have been identified in humans. These human MRs can be distinguished by the presence or absence of an in-frame insertion of 12 base pairs coding for Lys, Cys, Ser, Trp (KCSW) in their DNA-binding domain (DBD) and the presence of two amino acid mutations in their amino terminal domain (NTD). Two human MRs with the KCSW insertion (MR-KCSW) and three human MRs without KCSW in the DBD have been identified. The three human MRs without KCSW contain either (Ile-180, Ala-241) or (Val-180, Val-241) or (Ile-180, Val-241) in their NTD. The two human MRs with KCSW contain either (Val-180, Val-241) or (Ile-180, Val-241) in their NTD. Human MR-KCSW with (Ile-180, Ala-241) has not been cloned. In contrast, chimpanzees contain two MRs with KCSW and two MRs without KCSW in their DBD and both contain only Ile180, Val-241 in their NTDs. Each pair of chimpanzee MRs differ at another amino acid in the NTD. A chimpanzee MR with either Val-180, Val-241 or Ile-180, Ala-241 in the NTD has not been cloned. Gorillas and orangutans each contain one MR with KCSW in the DBD and one MR without KCSW. Both gorilla and orangutan MRs contain I-180, Val-241 in their NTD. Neither Val-180, Val-241 nor Ile-180,Ala-241 are found in the NTD in either a gorilla MR or an orangutan MR. These data suggest that human MRs with Val-180, Val-241 or Ile-180, Ala-241 in the NTD evolved after humans and chimpanzees diverged from their common ancestor. These unique human MRs may have had a role in the divergent evolution of humans from chimpanzees. Studies are underway to characterize transcriptional activation of the five human MRs by aldosterone, cortisol, and other corticosteroids for comparison with each other to elucidate the roles of these MRs in human physiology.

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Section: Resultsmentioning

confidence: 99%

Section: Novel Mineralocorticoid Receptors In Humansmentioning

confidence: 99%

Section: Chimpanzees Have Four Full-length Mineralocorticoid Receptorsmentioning

confidence: 99%

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Novel Evolution of the Mineralocorticoid Receptor in Humans compared to Chimpanzees, Gorillas and Orangutans

Katsu,

Zhang,

Baker

2023

Preprint

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“…Second, we analyse variation in one type of glucocorticoid receptor only (i.e. GR) because we focused on short time periods and acute responses, but there is evidence suggesting an effect of MR levels, or MR/GR ratio, on GC functional outcomes [ 21 , 79 , 80 ]. Third, we focused on a relatively simple relationship to simulate GC-mediated physiological responses.…”

Section: Discussionmentioning

confidence: 99%

Modelling the role of glucocorticoid receptor as mediator of endocrine responses to environmental challenge

Jimeno,

Rubalcaba

2024

Phil. Trans. R. Soc. B

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Glucocorticoid hormones (GCs) modulate acute ‘stress’ responses in vertebrates, exerting their actions across many physiological systems to help the organism face and overcome challenges. These actions take place via binding to the glucocorticoid receptor (GR), which determines not only the magnitude of the GC-mediated physiological response but also the negative feedback that downregulates GCs to restore homeostasis. Although GR function is assumed to determine GC regulation capacity, the associations between GR abundance and individuals' coping abilities remain cryptic. We developed a dynamic model fitted to empirical data to predict the effects of GR abundance on both plasma GC response patterns and the magnitude of GC-mediated physiological response. Individuals with higher GRs showed lower GC exposure, stronger physiological responses and greater capacity to adjust this response according to stressor intensity, which may be translated into more resilient and flexible GC phenotypes. Our results also show that among-individual variability in GR abundance challenges the detectability of the association between plasma GC measurements and physiological responses. Our approach provides mechanistic insights into the role of GRs in plasma GC measurements and function, which point at GR abundance fundamentally driving complex features of the GC regulation system in the face of environmental change. This article is part of the theme issue ‘Endocrine responses to environmental variation: conceptual approaches and recent developments’.

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“…We propose that MRs with (Ile-180, Ala-241) or (Val-180, Val-241) in their NTD evolved in humans after their divergence from chimpanzees. In the light of the diverse physiological functions of the MR in humans in regulating transcription in kidney, brain, heart, skin, lungs and other tissues[11,[13][14][15][16][17][18][19][20][21][22]48], the evolution of human MRs with (Ile-180, Ala-241) or (Val-180, Val-241) in their NTD may have been important in the evolution of humans from chimpanzees[41].The interaction of the MR with the GR to form heterodimers is important[49][50][51][52][53][54][55]. The response to aldosterone and other corticosteroids to heterodimers of human MRs containing KCSW in the DBD, as well as either (Ile-180, Ala-241), (Ile-180, Val-241) or (Val-180, Val-241) in the NTD with human GR needs to be explored.…”

mentioning

confidence: 99%

Lysine-Cysteine-Serine-Tryptophan Inserted into the DNA-Binding Domain of Human Mineralocorticoid Receptor Increases Transcriptional Activation by Aldosterone

Katsu,

Zhang,

Baker

2024

Preprint

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Due to alternative splicing in the DNA-binding domain (DBD) of the mineralocorticoid receptor (MR), humans contain two almost identical MR transcripts with either 984 amino acids (MR-984) or 988 amino acids (MR-988), in which their DBDs differ by only four amino acids, Lys,Cys,Ser,Trp (KCSW). Human MRs also contain mutations at two sites, codons 180 and 241, in the amino terminal domain (NTD). Together, there are five human MR genes in GenBank. Human MR-984, which was cloned in 1987, has been extensively studied. Human MR-988, cloned in 1995, contains KCSW in its DBD. Neither this human MR-988 nor the other human MR-988 genes have been studied for their response to aldosterone and other corticosteroids. Here, we report that transcriptional activation of human MR-988 by aldosterone is increased by about 50% compared to activation of human MR-984 in HEK293 cells transfected with the TAT3 promoter, while the half-maximal response (EC50) is similar for aldosterone activation of MR-984 and MR-988. The physiological responses in humans with MR genes containing KCSW and with differences in the NTD warrant investigation.

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Brain mineralocorticoid and glucocorticoid receptor balance in neuroendocrine regulation and stress-related psychiatric etiopathologies

Cited by 5 publications

References 100 publications

Novel Evolution of the Mineralocorticoid Receptor in Humans compared to Chimpanzees, Gorillas and Orangutans

Novel Evolution of the Mineralocorticoid Receptor in Humans compared to Chimpanzees, Gorillas and Orangutans

Modelling the role of glucocorticoid receptor as mediator of endocrine responses to environmental challenge

Lysine-Cysteine-Serine-Tryptophan Inserted into the DNA-Binding Domain of Human Mineralocorticoid Receptor Increases Transcriptional Activation by Aldosterone

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