Why Caffeine Is My Best Friend
It is not hard to imagine that being a graduate student, doing research and trying to somewhat maintain a social life would need for me to find ways to stay alert during the day and night. Getting a good night’s sleep to accomplish this is completely out the window at this point, to read more about how sleep has taken a passenger seat in my day to day as of late, check out “A Letter to Sleep.” Like most college age adults coffee has become a staple in my diet, Starbucks, Dunkin Donuts, Local Coffee shops, I’m on a first name basis with every employee in any of these establishments within a 6 block radius of the university. 5 to 6 hours of sleep per day will do that to you, but its not just coffee, I consume energy drinks as well. Monster and Redbull are my preferred lightly carbonated caffeine sources, it also depends on my mood at the moment.
Its important to note that caffeine and I have been in this relationship for awhile, whether or not my caffeine consumption is exactly “healthy” is currently up for debate between me and my physician. There are definitely some pros and cons to consuming large quantities of caffeine depending on how your body reacts (sensitivity) to caffeine to begin with. I typically never get jitters, restlessness or tachycardia, likely because I’m on the brink of sleep deprivation to begin with, and have been for several months. So begs the question, how does caffeine continue to keep me awake, or any of us for that matter? I’m going to explain below, so everyone put on their science hats so we can see why coffee and energy drinks are so effective.
When it comes to staying awake there are a few ways to go about achieving this, but lets focus on the suspect in question, Caffeine. At the root of all physiological effects and biological interactions is chemistry, and its the chemistry of Caffeine that helps produce its anti-slumber activity. Caffeine is very similar to another molecule called Adenosine, the two structures are pictured to the left. Adenosine is a nucleoside that has multiple purposes inside the cell and binds to multiple receptors, but for the sake of our conversation I will focus on its ability to bind to a specific adenosine receptor, A1.
A1 receptors are highly expressed in the brain, and are a major player in the mechanism of which Caffeine exhibits its activity. Normally, the activation of A1 recpetors by adenosine down regulates adenylyl cyclase and increases (↑) phospholipase C activity. Adenylyl cyclase (AC) is responsible for making a second messenger named Cyclic AMP that signals for multiple processes inside of the cell, so a decrease (↓) in AC leads to a decrease in Cyclic AMP. Phospholipase C is responsible for creating IP3 and DAG, also second messengers, that form from the lipid bound IP2 molecule. Both of these second messengers lead to the regulation of that neuron’s activity.
Adenosine + A1 receptor = ↓Adenylyl cyclase (AC) + ↑Phospholipase C
As mentioned above, the A1 receptor is abundant in the brain but more importantly, it is abundant on certain types of neurons that have specified functions, such as the inhibition or activation of other neurons. Let me explain what all this receptor binding means to your brain. During prolonged wakefulness Adenosine accumulates in the brain and starts to create a concentration dependent action that makes you want to sleep via binding to the A1 receptor, got it?? Cool. A slightly more detailed explanation is that Adenosine starts to inhibit gabaergic neurons that are responsible for inhibiting the neurons that make you sleepy.
Meaning, Adenosine + A1 receptor = ↓ activity of Neurons responsible for wakefulness
Now that we understand one of the mechanisms that adenosine works in the brain, we can talk about how caffeine affects this process. In biology its easy to think of some interactions in a lock and key fashion. For definition purposes lets call Adenosine the “key” to the A1 receptor the “lock”. When you place Adenosine with its A1 receptor the key is turned, the internals of the lock change shape induced by the key and the door opens. In this case a biological signaling event takes place, the one highlighted above. When this process occurs in this way, Adenosine acts as an agonist. Caffeine, although a unique molecule of its own, is similar enough to Adenosine’s shape that it to can fit into the A1 receptor “lock”. When Caffeine binds to the A1 receptor nothing happens, the key is in the lock but no shape change takes place that allows for the door to open, or in this case, the biological cascade to take place. When a process occurs in this way, Caffeine is acting as an antagonist of the A1 receptor. This means that caffeine blocks the effect of Adenosine because no two keys can occupy any one lock at any one time, this occurs in a competitive action as both compete for the A1 receptor “lock”. The “lock” is the Adenosine receptor binding pocket, or also called the Ligand binding site.
Consistent use of Caffeine creates a feedback that results in the increase of A1 receptors due to them being blocked frequently, so neurons will simply put more receptors for Adenosine to bind to alleviate the affect of Caffeine. Also, the reasons why we experience a “crash” after consuming Caffeine is due to the accumulation of Adenosine taking place while we are awake, as it normally does. When Caffeine is principally excreted away by the kidneys, a bunch of accumulated of Adenosine binds to the A1 receptors, decreasing the feeling of wakefulness in a dramatic fashion.
There are caveats to this process such as binding affinity, receptor desensitization, concentration dependence of the receptor and of the agonist or antagonist, but lets spare that for now until I can cover Biomolecular Thermodynamics and Enzyme Kinetics in the educations section of Bio Is Life Media the Concept Corner. So lets recap what I’ve covered thus far.
Caffeine blocks.. [Adenosine + A1, receptor binding = ↓ activity of Neurons responsible for wakefulness]..Thus you feel an ↑ in wakefulness
caffeine + A1 receptor = maintenance of Adenylyl cyclase activity (AC) + ↓Phospholipase C = Increased alertness and wakefulness
Caffeine works by blocking receptors in the brain on neurons that normally would propagate a sleepy feeling.
Wait! There is more, Caffeine is also metabolized by your liver into a bunch of other compounds, but 3 compounds, Paraxanthine, Theobromine, and Theophylline are the ones most abundant after metabolism that deliver a biologically relevant effect. These compounds are called metabolites because they are products of metabolism, and metabolism is the process of chemical changes to a compound via enzymatic pathways in the body. Previously I was discussing how caffeine specifically produces the feeling of wakefulness, which puts Caffeine’s mechanism of action in the context of the brain.
Not aforementioned, Adenosine receptors are all over the body in different places and exhibit different biological effects depending on the cell they reside on. Remember earlier when I mentioned Cyclic AMP as a product of Adenylyl cyclase, well Cyclic AMP is broken down by a group of enzymes that caffeine and its metabolites also block proteins called PDEs. This effect of blocking Cyclic AMP degradation is principally in muscle and fat cells, it leads to fat breakdown known as lipolysis, which feeds into energy metabolism.
Caffeine and its metabolites also illicit effects in smooth muscle, skeletal muscle, adipocytes (fat cells), the kidneys, and cardiac cells. Caffeine has many pleiotropic effects from increased urination, wanting to poop, to the vasoconstriction of cerebral blood vessels that some migraine medications are built around. Either way, caffeine does a great job of keeping us alert and awake at a time of need, and that’s what best friends are for, to help you when you need a hand, or in this case an espresso.