Daily Newsletter

September 19, 2012 Ligand & Receptor

Ligands are chemical signals, and receptors are proteins. The receptor is folded so that it forms a binding space (active or binding site*) where the ligand can dock and bind. A common thought is that every receptor has a specific ligand, and that nothing else binds to the receptor. A lovely fiction.
To the right is an image of the μ-Opioid receptor (μ is the Greek Letter Mu).

This receptor is found in human neural tissue, and provides analgesic effects and feelings of euphoria. It can also cause respiratory depression and reduced GI motility. The main ligands for this receptor are enkephalins and β-endorphin. Yes, this receptor set has two potential ligands. It also has a list of agonistic and antagonistic compounds that can bind to the receptor.
When we speak of receptors and ligands, we talk about the affinity of the receptor for a particular ligand. Remember, we have folded the protein to create a 3-D shape. In the case of the μ-Opioid receptor, the folded protein has a notch where the ligand can slip in. This notch will have chemical properties complementary to the ligand. A high affinity would imply that the physical shape and chemical properties of the notch are a good match to a given ligand. In this case, beta-endorphin is a strong chemical and physical match to the binding site (notch) of the μ-Opioid receptor. Dynorphins, which are another type of neurotransmitter (ligand) in the brain, have a low affinity for the μ-Opioid receptor's binding site, meaning the shape and chemical properties are not a good match.
This sets up another aspect of receptors: agonists and antagonists. These terms represent chemical mimics of the natural ligand(s) of a given receptor. Agonists are chemical mimics that bind to a receptor and trigger a cellular response; in other words they work like the ligand. Antagonists on the other hand are chemical mimics that bind to a receptor and block a cellular response.

In fact, antagonists can stay bound and prevent activation of the receptor. A well known agonist for μ-Opioid receptor is morphine. Morphine can bind to the μ-Opioid receptor and active the cellular response that leads to analgesic effects, feelings of euphoria and respiratory depression. To the left is an image depicting agonistic and antagonistic bindings possible with the μ-Opioid receptor. NOTE: The agonist relationship implies an activation of the cellular response, while the antagonistic relationship implies an inactivation of the cellular response.
Morphine is a powerful analgesic with many well known side effects. One of the most dangerous of these side effects is physical addiction and an increased tolerance for the drug (you need more and more to get the same effect over time). This provides a good example of another principle of receptors: Regulation.
Down Regulation: When a cell receives too much signal, it will begin to down regulate the receptors. This means that the cell stops producing the quantity of the specific receptor it usually makes. For membrane bound receptors, over time, as the membrane is repaired and refurbished (a constant dynamic process), the number of expressed receptors drops. The result is that the cell is less sensitive to the signal. Why does a cell do this? Think of it as a person being exposed to loud noises. If it happens once, for a short period of time, the body can compensate. What if the person is continuously exposed to the loud noise? Eventually they become less sensitive to sound, i.e., they become functionally deaf. The same thing is happening to a cell that is overexposed to a ligand. To protect themselves, they produce less and less of the given receptor. In some cases this becomes an irreversible loss of the receptor from the cell. In the case of the μ-Opioid receptor, your body produces only small temporary doses of β-endorphin. With morphine, you have a large dose, and it is usually for a long duration. The longer the duration (over a week), the more likely you will have desensitization (down regulation) of the receptors.
Up Regulation: The reverse of down regulation is up regulation. If a cell is not getting enough signal, it will start building more receptors. In this case, there is a deficency in the amount of the ligand preset. The cell is compensating by building more receptors.
Both Down Regulation and Up Regulation are examples of Negative Feedback.
*NOTE: Receptors and Enzymes are both proteins. They both have a site where a ligand (receptor) or substrate (enzyme) can bind. As with receptors, we will see that enzymes have an affinity for their substrate, and like receptors, other chemicals can bind into the enzyme. In addition, like ligand-receptor, when a substrate binds into an enzyme, the enzyme will change shape.

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Daily Challenge

Modern drugs tend to act as either agonists or antagonists to specific receptors in the body. This includes both medicinal and illegal drugs. Pick one of the following drugs and discuss the effect it has on its target receptor. Include the effect on the human body. (NOTE: You're not expected to write a massive paper on this; just show an understanding of the concepts presented here and an understanding of the drug you chose to write about).