In the vast and intricate world of biology, hormones play a pivotal role in regulating various bodily functions, including our emotions. One such group of hormones is the glucocorticoids, which are often spotlighted for their involvement in the stress response.
Glucocorticoids and Emotions
Glucocorticoids are a type of steroid hormone produced in the adrenal cortex of the kidneys. The most well-known glucocorticoid is cortisol, often dubbed the "stress hormone" (Figure 1). These hormones are essential for various bodily functions, including metabolism regulation, immune response modulation, and assisting the body in dealing with stress. However, their influence extends to the realm of emotions as well.
When we encounter a stressful situation, our bodies release cortisol, preparing us to either fight the challenge or flee from it—a response known as the "fight or flight" mechanism. While this is beneficial in the short term, chronic exposure to high levels of cortisol can lead to emotional disturbances such as anxiety and depression. This is because prolonged stress can alter brain function, particularly in areas involved in mood regulation, such as the hippocampus and prefrontal cortex.
Figure 1. Molecular structure of cortisol.
The Receptors That Bind to Glucocorticoids: aGPCR
To exert their effects, glucocorticoids must first bind to specific receptors in the body. This is where adhesion G protein-coupled receptors (aGPCRs) come into play. aGPCRs are a large family of receptors that play crucial roles in various biological processes, including cell adhesion, which is the process by which cells stick to each other or to their surrounding framework. Although aGPCRs are not the primary receptors for glucocorticoids—the glucocorticoid receptors (GRs) are—they do play a significant role in mediating some of the effects glucocorticoids have on immune responses and potentially on emotions through complex signalling pathways.
Structure of aGPCRs
These receptors are embedded in the cell membrane and have a unique architecture that distinguishes them from other receptor families. aGPCRs are characterised by a long extracellular region that is involved in cell adhesion. This region contains various domains that enable the receptor to interact with other molecules and cells in the body. The transmembrane domain, which spans the cell membrane, is connected to the intracellular domain that transmits signals inside the cell upon activation. Structures of several aGPCRs family members, such as ADGRD1 (PDBe-KB Q6QNK2) and ADGRG3 (PDBe-KB Q86Y34) (Figure 2), have been experimentally determined, to name a few. Understanding the 3D structure of aGPCRs is crucial for unravelling how these receptors function and for designing drugs that can target them effectively.
Figure 2. Cryo-EM structure of cortisol-bound adhesion receptor ADGRG3-Go complex (PDBe 7D77). The receptor is shown in cartoon representation while the bound cortisol is shown in ball and stick representation. The G-protein is hidden for clarity. The image was prepared using Mol*
aGPCRs as potential drug targets
Given their pivotal role in numerous physiological processes and diseases, aGPCRs present attractive targets for therapeutic intervention. Their involvement in pathologies such as cancer, fibrosis, and inflammatory diseases makes them particularly appealing for drug development. The ability of aGPCRs to mediate cell adhesion and migration, processes that are often dysregulated in cancer metastasis, positions these receptors as potential targets for anticancer therapies. Moreover, the modulation of aGPCR activity could provide therapeutic benefits in conditions characterised by excessive fibrosis or inflammation, such as pulmonary fibrosis and rheumatoid arthritis. The development of small molecules, antibodies, or peptide-based drugs that can specifically target adhesion-GPCRs offers a promising approach to modulate their activity for therapeutic purposes. However, challenges remain in drug development, including the need for a deeper understanding of the complex signalling mechanisms of adhesion-GPCRs and the identification of specific ligands and signalling pathways that can be targeted selectively.
Sri Appasamy
About the artwork
Ellie Statham, a Year 10 student from Leventhorpe in Cambridge, created an artwork featuring butterfly wings that represents the feeling of deception associated with telling lies. This analogy draws on how a butterfly's wings can deceive predators and camouflage them from danger. This deception can be accompanied by an increased amount of stress, which is linked to the hormone cortisol.
View the artwork in the
Structures mentioned in this article
Structure of the adhesion receptor ADGRD1 bound to G protein (PDBe 7WU2) (PDBe-KB Q6QNK2)
Structure of cortisol-bound adhesion receptor ADGRG3-Go complex (PDBe 7D77) (PDBe-KB Q86Y34)
Relevant references
1. Rosa, M., Noel, T., Harris, M. & Ladds, G. Emerging roles of adhesion G protein-coupled receptors. Biochem. Soc. Trans. 49, 1695�1709 (2021).
2. Hamann, J. et al. International Union of Basic and Clinical Pharmacology. XCIV. Adhesion G Protein–Coupled Receptors. Pharmacol. Rev. 67, 338�367 (2015).
3. Qu, X. et al. Structural basis of tethered agonism of the adhesion GPCRs ADGRD1 and ADGRF1. Nature 604, 779�785 (2022).
4. Ping, Y.-Q. et al. Structures of the glucocorticoid-bound adhesion receptor GPR97–Go complex. Nature 589, 620�626 (2021).
