Elsevier

Steroids

Volume 81, March 2014, Pages 109-115
Steroids

Review
Role of corticosteroid binding globulin in the fast actions of glucocorticoids on the brain

https://doi.org/10.1016/j.steroids.2013.10.013Get rights and content

Highlights

  • Corticosteroid Binding Globulin (CBG) influences glucocorticoids bioavailability.

  • CBG deficiency alters behaviors involving fast actions of glucocorticoids on brain.

  • CBG’s impact on glucocorticoid clearance is crucial in these processes.

Abstract

Corticosteroid binding globulin (CBG) is a glycoprotein synthesized in liver and secreted in the blood where it binds with a high affinity but low capacity glucocorticoid hormones, cortisol in humans and corticosterone in laboratory rodents. In mammals, 95% of circulating glucocorticoids are bound to either CBG (80%) or albumin (15%) and only the 5% free fraction is able to enter the brain. During stress, the concentration of glucocorticoids rises significantly and the free fraction increases even more because CBG becomes saturated. However, glucocorticoids unbound to CBG are cleared from the blood more quickly. Our studies on mice totally devoid of CBG (Cbg k.o.) showed that during stress these mutant mice display a lower rise of glucocorticoids than the wild-type controls associated with altered emotional reactivity. These data suggested that CBG played a role in the fast actions of glucocorticoids on behavior. Further analyses demonstrated that stress-induced memory retrieval impairment, an example of the fast action of glucocorticoids on the brain is abolished in the Cbg k.o. mice. This effect of stress on memory retrieval could be restored in the Cbg k.o. mice by infusing corticosterone directly in the hippocampus. The mechanisms explaining these effects involved an increased clearance but no difference in corticosterone production. Thus, CBG seems to have an important role in maintaining in blood a glucocorticoid pool that will be able to access the brain for the fast effects of glucocorticoids.

Introduction

CBG also called transcortin is known since 1956 and was purified from human and rat plasma in the 1960s [1], [2]. More recently, the gene encoding transcortin, called SerpinA6 due to its sequence similarity with other SERPINS (Serine Protease Inhibitors and Substrates), has been cloned and characterized in more than 25 species [3], [4], (www.ensembl.org). This gene lies in a cluster of eleven SERPINS probably derived from a common ancestor and partially regulated by a common locus control region that recruits liver-specific transcription factors [5]. Its existence in a wide variety of species together with a highly conserved structure supports the idea that CBG plays a crucial role in corticosteroid physiology.

CBG is a glycoprotein synthesized mainly from hepatocytes and then secreted in the blood where it binds glucocorticoids (GCs) with a high affinity (Ka = 76 × 106 M−1 in humans) but with a low capacity in contrast to albumin that display a low affinity, high capacity binding for GCs. CBG has low affinity for aldosterone (Ka = 1.9 × 106 M−1 in humans) and for the synthetic GC dexamethasone (Ka < 0.1 × 106 M−1 in humans) but binds progesterone with high affinity (Ka = 24 × 106M−1 in humans) albeit lower than for GCs [6]. CBG is always reported as the most important transporter for glucocorticoids. However, this role is now discussed because cortisol or corticosterone do circulate normally in CBG-deficient individuals (human CBG-deficient patients or CBG k.o. mice), as well as in many species devoid of CBG such as teleost fish. Furthermore, circulating aldosterone is as hydrophobic as GCs and does not have a specific binding protein. Therefore, it seems more likely that the transport of glucocorticoids is ensured by albumin, a protein present in every vertebrate species [7], [8].

According to the free hormone hypothesis, only the free fraction of GCs can reach target tissues [9]. Because CBG forms an inactive complex with GCs in the plasma, CBG has an important role in GCs bioavailability and access to their receptors. A dual role of CBG acting as a buffer and as a reservoir/delivery molecule of GCs in blood has been reported in the literature [10], [11].

Section snippets

CBG as a GC delivery molecule

CBG is often described as a protein that buffers the rise of GCs in response to stress by sequestering GCs in an inactive complex. In conditions where CBG levels decrease, active free GC would then reach high levels [12], [13]. However, in contrast to this view, recent data points towards a major role of CBG in maintaining a circulating GC pool and in delivering GCs to target tissues.

In mice the maximum physiological values of GCs range around 150–200 nM at the peak of secretion and CBG, which

Fast action of GC: stress-induced alteration of memory retrieval

In addition to the emotional component, stress and GC also affect learning and memory phases, namely encoding, consolidation and retrieval [23], [24], [25], [26], [27]. For example, rodents exposed to foot-shock stress before memory testing in the Morris water maze (a test for hippocampus-dependent spatial memory) exhibited spatial memory retrieval impairments. Systemic injections of GCs produced the same long-term spatial memory impairments [28]. Similarly, in healthy humans, per os

Role of CBG in the fast actions of GCs on memory retrieval

The behavioral paradigms and tools developed by Beracochéa’s group were very well suited to test the hypothesis that CBG had a role in the rapid actions of GCs on behavior. Thus, both Moisan and Beracohéa groups set up a collaboration in which they first studied the performance of Cbg k.o. mice and controls in the delayed alternation task as described above [38], known to be affected by GC levels on hippocampal MR membrane receptors [37]. As expected when the wild-type mice were subjected to

Conclusion

These studies have demonstrated that CBG, a GC binding protein produced and secreted by liver cells, is crucial in promoting GC access to target tissue such as brain under stress conditions. Thus, CBG impacts indirectly on the rapid effects of GC on memory retrieval. Inasmuch as under stress conditions, the free GC levels are suboptimal in Cbg k.o. mice, the membrane MR is thus not or not enough activated in Cbg k.o. mice hippocampus to respond the way it does in wild-type animals.

CBG

Acknowledgements

This work was funded by INRA, Department of Animal Genetics, and CNRS and Conseil Regional d’Aquitaine.

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