The Language of Cells with the advent of the modern tools of biochemistry and molecular biology, it is almost impossible to read a scientific paper nowadays without hearing about cellular signaling. When researchers try to distill a physiological reaction down to an effector (a hormone, exercise, heat, cold, etc), they without fail turn to signaling pathways to explain their findings. Pharmaceutical companies center their drug development research on specific “targets,” which inevitably are either signaling molecules, or are enzymes that became noticed because of work that furthered understanding of a particular signal transduction cascade. To state that cell signaling is a cornerstone of modern biomedical research is no exaggeration; thus, given the immense importance of this topic, the current and ensuing articles will attempt to enhance the reader’s understanding of this exciting, but often confusing subject.
To all readers with no formal scientific training, fear not. While perusing a paper replete with signaling terminology may initially appear as daunting as deciphering hieroglyphs, minus the pretty pictures, understanding the process of cellular signal transduction is no harder than learning a new language. As such, a great deal of effort is required on the reader’s part; however, the rewards go a long way, for understanding signal transduction not only gives one the knowledge to comprehend, but also the tools and power to manipulate physiological responses to almost any component of nutrition, training, or supplementation. Like any language, signaling has its own special vocabulary, which requires little more than rote memory. More important are the basic structural rules- the grammar, so to speak- of signal transduction.
The ultimate goal of this series of articles is not to overwhelm or to impress the audience with technical knowledge, but rather lay a foundation for understanding cellular signal transduction. Obviously, a subject matter as expansive as signaling cannot be reviewed in a few short articles- there are entire texts dedicated to the subject, and the field is constantly evolving. However, by initially focusing on understanding concepts rather than details, the conscientious reader will be well-equipped to brave PubMed and educate him or herself. For those with a more advanced understanding of cellular communication, this first article may come across as more or less of a review- with subsequent essays going into greater detail by analyzing current literature as it relates to the metabolic syndrome, obesity, and type II diabetes, using insulin signaling as a paradigm. Therefore, the purpose of this article is to explain a few key concepts of cell signaling.
What is Cell Signaling?
Cellular signaling is, at the most basic level, the method by which cells communicate with each other, and process various environmental cues to mount an appropriate response. Of course, the survival of the organism is of utmost importance, so all signaling events strive towards the good of the creature. This means making compensatory physiological changes to bring the being back to baseline (maintenance of homeostasis), or altering physiology to enable the being to better cope with the newly introduced stressor (adaptation). Keep these two concepts in mind, and always refer back to them when reading any kind of biological research- one should always ask “Why would the cell do this? What are the benefits?”
What are the Signals?
The signals a cell must respond to come in many forms, including hormones (steroids, catecholamines, small peptides), nutrients (glucose, amino acids, fatty acids), and mechanical stress (stretching, contraction, heat, cold, atmospheric pressure and gas content). Cells are equipped with tools for detecting these cues. Most often, there are receptors on the surface of the cell (the cell membrane, AKA plasma membrane) that bind to a particular signal (i.e. a hormone in the blood), much like two pieces of a jigsaw puzzle coming together. Other times, actual physical stress can be sensed by a cell’s internal architecture, the cytoskeleton. Perturbation of the cytoskeleton initiates a chain of events that leads to a response, termed “mechanotransduction.”
How do Cells Communicate with One Another?
Once a cell has detected a signal, it must decide what the appropriate action is. Thus, in a series of ordered cascades, the initial signal sets off events in the cell, much like a domino effect. One thing leads to another, and eventually the message reaches its appropriate location in the cell and accomplishes its goal. Note that the actual initiating signal may have no direct role in causing the end result, as the latter is governed by downstream molecules in the chain of events.
Visually, one of two situations is possible with hormone x:
(1) x à binds to receptor à causes an effect; this will be referred to later as “direct” signaling.
(2) x à binds to receptor à initiates molecule (a) à initiates molecule (b) à initiates molecule (c) à causes an effect; this will be referred to as “web” signaling.
Note that in the first example (diagram A), the original signal, hormone x, binds to its receptor, and personally triggers an effect- a direct and straightforward pathway. For example, this is the case with steroid hormones. However, in the second situation (see diagram B on the right), hormone x binds to a receptor, which sets off a cascade of events, bringing intermediary signaling molecules (a), (b), and (c) into the picture. Eventually, molecule (c) mediates the end effect- this is the case with most amino acid-based hormones (i.e. insulin, norepinephrine). This is an important concept to understand, because it explains to a large degree why different classes of hormones have short, versus long-term effects (more on this later). It also begs the question of why a cell would even go through the trouble to use complicated cascades (as in example 2 above) as opposed to a more direct mechanism (example 1).
How do Cells Confer Specificity and Conduct Cross-Talk?
As stated in the previous paragraph, the message has to reach an appropriate location within the cell to have the desired effect. Understand that the “message” is nothing more than another signaling molecule in the cascade of events thus far. It just so happens that this particular signaling molecule is the last one in the chain of a particular signaling pathway. Read that sentence again. Now, look at the figure below: the rectangular box represents the cell, and the six parallel lines signify six signaling pathways. At the end of each line is the end-signaling molecule. What you should now see is that six different initiators can lead to six different end-events.
Now, imagine that at any point on each line, you can make a branch to any point on any of the other 5 lines. If you really get creative, your original cell with six nice, neat, parallel lines becomes a massive web of criss-crossed lines. This is signaling. Simplified.
Before you decide that this is all too confusing, remember that the goal here is not to decipher what pathway interacts with what other pathway- these details are still unclear in many cases, and we are here to learn concepts and not memorize details. So, what concepts can we take away from the previous example?
First, notice that you can make several pathways converge onto one particular pathway, much like merging a five-lane highway into one or two lanes. Or, you can make one pathway affect five others- akin to splitting one lane into five. This is one mechanism of signal amplification- many different initiators converge at one common point, or one signal activates several pathways, the net result being amplification, either of a particular end result (physiological response), or turning a single signal into a multi-effect response.
Second, you also have the freedom to connect pathways at any point between the beginning and the end. Thus, you can regulate the later events of one pathway by the early events of a separate pathway (see leftmost pathway- the one that begins with “1”). This gives the cell the capacity for rapid regulation, so that when a growth-promoting hormone is dominant, growth occurs, but when a growth-inhibiting molecule binds, said molecule can quickly inhibit the growth-stimulating pathway. As well, the early portion of one pathway (see rightmost pathway, the one that starts with “AA”) can inhibit the early effects of another pathway (see middle pathway, the one that starts with “A”). You should now see that a specific reaction can be prevented by blocking the chain of events at any point. Stopping the cascade at the first, the fifth, or the second-to-last link, will result in inhibition of the same end result (growth, in the figure below). Keep in mind that this does NOT mean that the NET effect of the different pathways is the same; the total effect on the cell inhibition of the middle pathway by the left, versus the right cascades, might be very distinct. Go back to the previous figure and look at the potential cross-talk between pathways, and you will easily see why this is so.
Third, you can make one pathway inhibit its neighbor on the left but stimulate the pathway to the right. This is a way to specifically augment one effect, while inhibiting another- cooperativity, if you will. In the example below, the leftmost pathway normally inhibits the growth (the middle pathway). However, the rightmost pathway, when bound by its hormone/signal, inhibits the inhibitory pathway, resulting in growth; additionally, the rightmost pathway may also promote growth, separate of its relief of the inhibition. This means there are two primary mechanisms for regulation: (1) Inhibit the inhibitor (double negative = positive), and (2) Directly affect the target pathway.
Finally, there are many ways to get to the same point, creating safety nets and backup systems, so that loss of one component of one cascade, or even of a receptor, does not necessarily mean complete loss of the original effect (See figure C). Note, however, that loss of points of divergence/convergence, or a receptor, will be more noticeable than loss of a non-critical intermediate molecule (figure D). If a receptor is lost, the entire downstream cascade is lost, and consequences can be dire, especially if redundant pathways cannot compensate- and often, they cannot, because one hormone has many effects on different tissues, meaning that a few effects may be preserved by alternate cascades, but full compensation is not possible. In the second figure (figure D), loss of point “B” would be much more noticeable than loss of point X3; this is both because point B can substitute (at least somewhat) for the other several other pathways, and also because points upstream of B can be activated by other pathways.
Loss of the convergence/divergence point, “X,” would be devastating to the cell. It also means that X is a promising target for intervention, although one must tread carefully when manipulating central regulators. Fortunately, physiology does have a rhyme and a reason to it, and you will find that factors that govern multiple effects are consistent in their function. In other words, if point X’s end results are increased fat oxidation, increased glucose uptake, increased glycogen storage, and decreased fat synthesis, you can safely assume that the cell is responding to a situation where it senses a need to stock up on labile fuel stores –glycogen,- at the expense of less readily accessible fuel stores (fat).
Cells have a variety of sensors that are able to detect environmental cues and respond appropriately, as well as communicate the perturbance to other cells. These environmental cues come in the form of chemicals in the blood (hormones, prostaglandins, nutrients, antigens) as well as physical stresses (heat, cold, radiation, stretch, contraction). No matter the form of the initial stressor, though, the information must be integrated by the cell via biological means, through the use of some kind of sensing mechanism- often a receptor. However, given the diversity of signals a cell is exposed to, and the many specialized cell types in the body, it is necessary to distinguish multiple effects of a hormone; on the other hand, the cell strives to maintain homeostasis with its environment, so no one signal must be allowed to dictate the cell’s response beyond what is needed. This problem is solved by the fact that signaling cascades all display cross-talk (to some degree) and are subject to regulation both at the level of competing initiating signals and product inhibition.
This concludes the first section of this series. The next issue will cover short versus long-term regulation and elaborate on mechanisms of specificity and control by introducing some details of insulin signaling to show how this one pathway is so very similar to that of countless other growth factors, yet manages to maintain its uniqueness with respect to nutrient uptake. The final articles will focus on how abonormalities in the common signaling intermediaries used by insulin and other hormones cause multiple metabolic pathologies, and explain at the molecular level why it is so difficult to separate the inducers from the responses.