ReviewRole of corticosteroid binding globulin in the fast actions of glucocorticoids on the brain
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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2019, Pharmacological ReportsCitation Excerpt :CBG and albumin act as delivery molecules and as reservoirs and buffers for GCs [6]. They also regulate the metabolic clearance of GCs [6]. Reduction in the serum levels of GC carrier proteins may lead to increases in the concentration of unbound corticosterone that can be easily subjected to degradation in the liver.