In the first part of this series, I introduced a bit about the endocrine system, some common characteristics of hormones, and detailed how they’re classified. Here, I’ll expand further and discuss how they’re made, transported, and briefly discuss what they do when they reach their target.
Synthesizing Protein and Peptide Hormones
Protein hormones are made just like any other protein – they’re transcribed from genes (you have a gene for each hormone) and translated on ribosomes. Most protein and peptide hormones are translated in the form of a prohormone. A prohormone is a larger protein complex that’s eventually cleaved down to generate the active hormone. This cleavage takes place in the ER, along with some other processing like glycosylation. Here’s an example of just that:
Here, we can see that the proglucagon prohormone houses several different hormones, each with their own effects. In fact, some of these hormones have opposite or site-specific effects: glucagon releases glucose into the bloodstream, while GLP-1 has blood glucose-lowering effects.
If you recall from my introductory post, protein hormones don’t cross the lipid bilayer. So, they’re packaged and stored inside secretory vesicles until a stimulus initiates the signal for the cell to secrete them. This is your body’s mechanism for transporting protein and peptide hormones across the lipid bilayer and into cells.
Synthesizing Steroid Hormones
Steroid hormones are all created off the backbone of cholesterol. There are six major types that all start from cholesterol. These are the progestins, mineralocorticoids, glucocorticoids, androgens, estrogens, and vitamin D. A series of enzymes acts on cholesterol, the rate limiting one being P450SCC (side chain cleavage). This enzyme is the first step in all steroid hormones. This enzyme converts cholesterol to pregnenolone and the pathway branches off from there.
You can see the similarities between the structures of these hormones. As such, there’s some cross-reactivity at the receptor level when steroid hormone levels are high. Aldosterone, a mineralocorticoid, can interact with the receptor for glucocorticoids for example. This can happen a bit with androgens and estrogens as well – an often occurrence for those abusing anabolic steroids.
Because these hormones stem from the same parent molecule, if there’s a problem, mutation, or defect in any of the converting enzymes, the final product can be changed. Let’s say there’s a defect in the production pathway of cortisol, preventing cortisol from being produced. This is a stress hormone, and without it, you wouldn’t be able to respond to stress. Other levels of steroid hormones would change as a result (particularly the androgens). This happens because the shared precursors aren’t effectively being converted to the next product – picture an assembly line being backed up.
Secretion and Transport
Catecholamines (like dopamine, norepinephrine, and epinephrine), protein, and peptide hormones a secreted via exocytosis as I previously mentioned. Steroid and thyroid hormones (even though made off a tyrosine backbone, are lipophilic) can readily diffuse out of the cell. Protein and peptide hormones are hydrophilic, hence why they can’t cross the plasma membrane. Because of this, they’re typically found free in the plasma. They don’t need to be bound to another protein, and they can circulate freely. But as always, there are a few exceptions. Growth hormone and IGF, for example, require binding proteins for transport. These binding proteins aren’t really here to keep them soluble, but rather to extend their half-life. Steroid and thyroid hormones are the opposite. These need to be bound to proteins to stay soluble in the blood. Typically 99% are bound by protein, around 1% circulates freely. These free amounts are biologically active and it’s this that is regulated by our negative feedback mechanisms to maintain homeostasis.
Some of this free hormone gets metabolized. Steroid hormones have a half-life from minutes to hours, sometimes a few days. Being bound to a binding protein increases the half-life of the steroid hormone. These binding proteins are somewhat like a reservoir, so you always have some hormone available – it’s much quicker than having to synthesize new hormones. The little bit that’s coming off the binding protein (and that isn’t metabolized) can enter the cells and cause some response.
Specific binding proteins for their respective steroid hormones are made in liver – cortisol-binding globulin, thyroid-binding globulin, sex hormone-binding globulin (SHBG). Albumin is another protein that’s made in the liver. It also can bind steroids too, albeit at a lower affinity than that of the specific binding protein. Testosterone, for example, is mostly bound to albumin and SHBG, with only 1-2% actually free and biologically active (which is why it’s important to have this checked when going in for blood work, not just the total level).
The binding affinity to the binding proteins is still less than that of the steroid hormone’s receptors, so when in proximity, they’ll want to bind to their receptors.
What Happens When A Hormone Reaches Its Target?
Protein & Peptide Hormones
All the actions of a hormone are mediated by a receptor, and there are specific receptors for every hormone. The high binding affinity for these receptors is what confers specificity. Hormones are circulating throughout the blood, so every cell comes in contact with them. But every cell doesn’t respond to every hormone – only the cells that have the specific receptors. The cell that responds to the hormone we’re looking at is the target cell.
Because protein and peptide hormones cannot cross the plasma membrane, they all interact with cell surface receptors. When a hormone binds, the signal is transmitted intracellularly through some signaling pathway(s) – we call this cascade of events an intracellular second messenger pathway. A typical 2nd messenger pathway starts with a stimulus, activation of an enzyme, which in turn activates another. This pattern repeats until a cellular response is reached, whatever that may be. There are several types (and sub-types) of receptors and 2nd messenger systems, allowing for a diversity of cellular responses. The vast majority of protein hormone receptors activate enzymes (or are enzymes themselves) or are G-protein coupled receptors (GPCRs). I’ll save the details of the enzyme-receptors in a future post, and briefly cover GPCRs here.
GPCRs Amplify A Signal
GPCRs go by a number of names – heptahelical receptors, metabotropic receptors, 7-transmembrane receptors, and serpentine receptors. This class of receptors is so big, and so diverse that there really isn’t any sequence conservation – there isn’t a characteristic sequence feature that defines the family of GPCRs. Instead, we recognize them by their architecture. They have a seven transmembrane domain structure, with its amino terminus outside the cell and its carboxy terminus inside. Nearly all of these activate heterotrimeric G proteins that define the family. These are proteins that send different downstream signals within the cell. This setup allows GPCRs to rapidly amplify a signal. Although not a hormone, let’s look at a photon of light as an example:
A photon of light strikes the GPCR rhodopsin – these are rod photoreceptors in your eye. Rhodopsin, in its activated state, will act on around 500 molecules of G alpha T (a G protein, also called transducin). 500 molecules of transducin molecules will act on around 500 molecules of phosphodiesterase – an enzyme that cleaves cyclic GMP (a second messenger molecule). The activation of this phosphodiesterase will cause the cleavage of 100,000 molecules of cyclic GMP. So, we’ve gone from amplification of a single photon to 100,000 molecules of cyclic GMP – five orders of magnitude increase.
Steroid hormone receptors are entirely different. Remember, steroids are lipophilic and able to cross the plasma membrane. As such, their receptors reside within the cell. Usually steroid receptors are in the cytoplasm, but some are in the nucleus.
These receptors are transcription factors. Once bound, they enter the nucleus where the bind to very specific sequences of DNA called hormone response elements (these are about 12 nt sequences) in the promoters of target genes. They mediate and (typically) activate gene transcription. Whatever the gene is, RNA is made, it gets processed, and ultimately a new protein is produced.
Because of all these steps, it takes longer for steroid hormones to act. Protein hormones bind to cell-surface receptors and rapidly activate a signal transduction pathway within or less than seconds. Steroid hormones have to bind, enter the nucleus, initiate gene transcription, produce RNA, have it translated, synthesize and modify a new protein. This usually takes minutes, if not hours after exposure to see change.
In a newer area of research, we’re seeing that there are some cell types with membrane steroid receptors. Estrogen receptors, for example, are present within the membrane. Membrane bound steroid receptors elicit rapid responses. We call these nongenomic responses and they’ll mediate 2nd messenger signaling, much like protein and peptide hormones.
You can see how hormones could have many points of regulation. And, you can imagine how your body takes advantage of these. Your hormones are under tight regulation through several mechanisms that’ll be the topic of the next article in this series.