Divyan Bavan
Introduction
Hormones are chemical messengers within the body. They can take many forms: peptides, proteins, amine-derivatives, steroids, and more. As expected, this diversity in composition leads to different mechanisms of hormone action—the processes initiated after a hormone binds to its receptor. This leads to different responses, with speed and duration being the primary variables. However, other factors such as half-life, transport, and feedback also play crucial roles in determining the overall effects of a hormone. Therefore, the extent to which hormone action influences the speed and duration of effects is large, but not exclusive.
Hormone Receptors
There are three types of receptors which hormones can bind to: G protein-coupled receptors (GPCRs), enzyme-linked receptors, and nuclear receptors (McLaughlin et al., 2023). The mechanisms behind each of them are different. By comparing these mechanisms, it will become evident how receptor class shapes the overall response.
G Protein-Coupled Receptors
GPCRs are the largest class of hormone receptors. They are integrated into the cell membrane, making them useful for binding hydrophilic hormones: proteins, catecholamines, and others (Laycock and Meeran, 2012). These proteins have seven transmembrane helices, flanked by intracellular and extracellular domains of variable length. Hormones can bind to various places on the receptor. For example, noradrenaline’s binding site within the adrenergic receptors is found in the cleft between the helices of the transmembrane domain (Ritter et al., 2023). Another feature of these proteins is their associated G protein. These heterotrimeric complexes are made up of an α, β, and γ subunit. The α subunit has GTPase activity and is bound to GDP at rest. Once a hormone binds to this site, it leads to a conformational change in the intracellular domain. This leads to guanine exchange factor (GEF) activity, causing the α subunit to exchange GDP for GTP. Once this occurs, the α and βγ subunits dissociate and can activate their respective downstream targets. This process is fast, taking approximately 50ms. Therefore, hormones that bind to GPCRs often have fast effects (Ritter et al., 2023).
Enzyme-linked Receptors
Hydrophilic hormones can also bind to enzyme-linked receptors. These receptors, like GPCRs, are integrated into the cell membrane and have extracellular binding domains for hormones. A common ligand for these receptors is growth factors. One example is epidermal growth factor (EGF) and its receptor EGFR. When EGF binds, it causes dimerization of two EGFR monomers. This leads to autophosphorylation; the tyrosine residues in the intracellular domain of each monomer phosphorylate each other. Once both residues are phosphorylated, an adaptor protein such as Grb2 binds to the intracellular domain, recruiting downstream signalling proteins. This eventually leads to a kinase cascade. The end targets are often transcription factors, which are also activated by phosphorylation; thus, changes in gene expression are the final product. Since this process requires continual chemical reactions, it takes longer than a GPCR-mediated hormone response. Therefore, hormones which bind to enzyme-linked receptors act on longer time scales (Ritter et al., 2023).
Nuclear Receptors
Steroid hormones are hydrophobic. Thus, they can penetrate the cell membrane and bind to intracellular receptors. These proteins form the class of nuclear receptors—intracellular transcription factors which bind to hormones. Steroids such as progesterone can bind to type I nuclear receptors: homodimers which are found in the cytosol. Ligand binding leads to the translocation of these receptors to the nucleus (Miller et al., 2024; Ritter et al., 2023). This leads to a change in gene expression, a lengthy process which makes steroid hormones among the slowest acting in the body. However, the speed of a hormone often has an inverse relationship with its duration of effect.
Downstream Targets of Hormone Receptors
While the speed of hormonal effects is important for certain functions, duration is important for others. Hormone action plays a large role in determining this quality. For example, adrenaline can bind to the β1 adrenergic receptor expressed in cardiac tissue. This receptor is a stimulatory GPCR (Gs). After adrenaline binds and the α subunit of the G protein dissociates, it activates adenylyl cyclase. This enzyme catalyzes the conversion of AMP to cAMP, a secondary messenger within cells. It can have many effects, most notably the activation of protein kinase A. In cardiac tissue, this kinase phosphorylates calcium channels. This enables a higher influx of calcium, and thus, an increase in heart rate. While this effect has a rapid onset, it also has a quick offset (Alhayek et al., 2023). After a few seconds, the α subunit hydrolyzes its GTP into GDP. This causes the heterotrimer to re-form. Second messengers such as cAMP are also degraded quickly, ending the hormone’s effects in the cell (Ritter et al., 2023).
This differs from enzyme-linked receptors like RTKs, which have longer-lasting effects. This is because RTKs, unlike Gα subunits, rely primarily on external enzymes for terminating their signal. This is mediated by phosphatases—enzymes that remove phosphate groups from proteins (Ritter et al., 2023). Thus, the effects of hormones that bind to enzyme-linked receptors often take longer to reset than those that bind to GPCRs.
This effect is even more extended for nuclear receptors. As mentioned previously, steroid hormones such as progesterone lead to these receptors’ translocation to the nucleus. The active receptors then bind to hormone response elements (HREs) in the DNA. This leads to changes in gene expression (Ritter et al., 2023). However, unlike transcription factors activated by RTKs, nuclear receptors are activated directly by ligand binding. Therefore, nuclear receptor deactivation is mediated primarily by receptor turnover, ligand dissociation, and other factors. This takes a long time for hormones such as progesterone, as it has a high affinity for the progesterone receptor (Ritter et al., 2023). Since RTK-controlled transcription factors just need to be dephosphorylated, they often have more transient effects. For this reason, steroid hormones act on the longest time frames.
Other Mechanisms for Regulating Hormone Effects
While action is a major determinant of hormonal effects, it is not the only cause. To bind to its receptor, a hormone must first reach the target cell. In most cases, this is done through the bloodstream. However, the composition of blood—primarily water—makes it essential for hydrophobic hormones to be transported through proteins. This has major consequences on hormone half-life: a measure of how stable a hormone is within circulation. For example, adrenaline has a short half-life (about 1 minute) due to its accessibility within the bloodstream; enzymes can access and metabolize it. By contrast, steroid hormones such as cortisol (half-life of 60 to 90 minutes) are not as accessible and are less easily broken down (Betts et al., 2013). This is another reason why steroid hormones act for longer durations than hydrophilic hormones. However, once again, duration is inversely related to speed. Due to its high solubility in water, adrenaline can spread throughout the body rapidly. This increases the speed of action.
Another factor which affects the speed and duration of hormonal effects is feedback regulation. This process is defined by a hormone controlling its own production through its physiological effect. Most cases of this mechanism are negative feedback. For example, the hormone insulin leads to the uptake and storage of glucose after a meal. The effect of this is lowered blood sugar. Since β cells of the pancreas produce insulin in response to high blood glucose concentration, insulin production is reduced (Laycock and Meeran, 2012). This mechanism controls the speed and duration of hormone response tightly. On the other hand, there are hormones like oxytocin. This hormone is released in response to uterine contractions during childbirth, which in turn causes more contraction (Cleveland Clinic, 2022). Thus, the effects of this hormone are rapid and escalate quickly.
Conclusion
It is evident that the impact of a hormone’s action on its effects cannot be understated. Through the specific pathways involved with its respective receptor, a hormone can have varying levels of speed. As seen through examples, however, speed is often a trade-off for duration. Hormones which act more slowly often cause long-lasting changes in gene expression within the target cell. By understanding these mechanisms, it is possible to design better drugs for various endocrine diseases. The hormone’s mechanism of action should not be the only factor, however. Subtleties like feedback control and half-life are also very important for the effects of a hormone; designing good drugs involves understanding these factors as well. Therefore, a hormone’s profile is not a reflection of a single mechanism, but rather the interplay of many processes.
Works Cited
Alhayek, Soubhi, and Charles V Preuss. “Beta 1 Receptors.” National Library of Medicine, StatPearls Publishing, 2023, www.ncbi.nlm.nih.gov/books/NBK532904/.
Cleveland Clinic. “Oxytocin: What It Is, Function & Effects.” Cleveland Clinic, 27 Mar. 2022, my.clevelandclinic.org/health/articles/22618-oxytocin.
Dalal, Rajeev , and Dejan Grujic. “Epinephrine.” National Library of Medicine, StatPearls Publishing, 2024, www.ncbi.nlm.nih.gov/books/NBK482160/.
J Gordon Betts, et al. Anatomy & Physiology. Houston, Texas, Openstax College, Rice University, 25 Apr. 2013, openstax.org/details/books/anatomy-and-physiology.
Laycock, John, and Karim Meeran. Integrated Endocrinology. John Wiley & Sons, 1 Oct. 2012.
Miller, Eric J., and Sarah L. Lappin. “Physiology, Cellular Receptor.” PubMed, StatPearls Publishing, 14 Sept. 2022, www.ncbi.nlm.nih.gov/books/nbk554403/.
Ritter, James M, et al. Rang & Dale’s Pharmacology. 10th ed., Elsevier, 14 Apr. 2023.