How Does Nicotine Act?

Those substances which we call "drugs" cause their effects either by mimicking some substance that naturally occurs in the body (whenever I say "body," I mean most multicellular organisms) or by interfering with some process which naturally goes on. For instance, the anti-viral drug AZT works by inhibiting the replication of DNA (the genetic code of the cells). Nicotine acts in the former manner, e.g., by mimicking a naturally occurring substance in the body. That substance is the chemical neurotransmitter acetylcholine or ACh (you can learn more about ACh in the section on nicotine). So, first we will discuss what acetylcholine does and then how nicotine mimicks it.

For anything to act within the body, it needs a mechanism through which to "talk" to the inside of the cells (the units of the body). (If someone doesn't knock on your door, you don't know they are out there.) Often, that mechanism involves a specialized kind of protein, called a receptor (like the receiver on your telephone). In fact, these receptors usually recognize only one of the millions of chemicals naturally floating in your body (to push the telephone analogy, a person often has only one phone number at which they can be reached). We biologists being literalists refer to the receptors which recognize ACh as acetylcholine receptors or AChRs.

There are two major types (or classes) of acetylcholine receptors in the body, and they are commonly named by the other drugs which bind to them: nicotine and muscarine. Muscarinic acetylcholine receptors (mAChRs) can bind muscarine as well as ACh, and they function to change the metabolism (just think of the overall metabolism of your body) of the cells, enough said. For this page, since we are discussing nicotine's action, we will focus on the other class, the nicotinic acetylcholine receptors (nAChRs).

Acetylcholine acts on nicotine acetylcholine receptors to open a channel (pore or hole) in the cell's membrane. Opening such a hole allows certain types of ions (charged atoms) to flow into or out of the cell. Now if you are thinking about your house's wiring, when ions flow, there is an electrical current, and the same is true in the nervous system. The flowing of ions, or the passing of current, can cause other things to happen, usually those "things" involve the opening of other types of channels and the passing of information from one neuron to another.

Nicotinic AChRs are found throughout the body, but they are most concentrated in the nervous system (the brain, the spinal cord, and the rest of the nerve cells in the body) and on the muscles of the body (in vertebrates). The most studied nAChRs are in fact those on the muscles, because those receptors are what cause the muscle to get excited and contract. (The whole process is very detailed and pretty well understood, but it is far too complicated to get into right here.) If you dissect out a muscle, and you apply nicotine to it, the muscle will still contract. We say that nicotine acts like ACh at the receptors to activate them, and both substances are called agonists. The opposite type of drug, something that binds to the receptors and does not allow them to be activated is called an antagonist.

When a substance comes into the body that can interfere with ACh binding to muscle nAChRs, that chemical can cause death in a relatively short time (because you use muscles to do things like breathe). A class of chemicals in snake and other poisonous venoms, neurotoxins, do exactly that. If you are bitten by a krait or a cobra, for example, and enough venom gets into the blood, there will be enough of their neurotoxin in your body to shut down the diaphragm muscle expands your lungs. Without that muscle functioning, the person ceases to breathe and dies of asphyxiation.

One of the reasons we know so much about these receptors is precisely that--plants and people have used substances which cause paralysis and asphyxiation for a long time. Plants use them to prevent being eaten by herbivores. Animals use similar substances to paralyze their prey. At least one human neuromuscular disease is related to nAChRs, and that is myastenia gravis (as time progresses, I will be adding a page on nAChRs and disease). So, as you can see, nAChRs are important to life.

In the nervous system, the actions of nAChRs are not nearly as well characterized. We know that someone nicotine administration (through smoking and such) is capable of causing addiction. We also know that nicotine's effects are diverse and at least somewhat dependent on its actions within the nervous system. One complication is that several types of nicotinic receptors are expressed in the nervous system.

Some "subtypes" of nAChRs are expressed in different regions of the brain and peripheral nervous system, but some types of cells express many classes of the receptors. What we do know is that each of these classes is just a little different. Some are more sensitive to nicotine than others. Some activate quickly and then turn off (desensitize) while others stay active as long as the agonist (ACh, nicotine, etc.) is present. These differences are the potential basis for therapies, because hope that there is at least one drug out there or to be designed which can selectively interact with each of these different subtypes.

All known nicotinic receptors do share some common features. They are composed of 5 protein subunits which assemble like barrel staves around a central pore. Currently, we believe that each of these subunits crosses the cell membrane 4 times. Each receptor consists of at least two ligand-binding subunits (called "alpha") and additional "structural" subunits. When the ligand (ACh or nicotine) binds to the receptor, it causes the receptor complex to twist and open the pore in the center.

Many groups have worked to model this receptor and its action, and you can find some of their models on the web:

The electrostatic isopotential surface--a surface representing constant electric potential--for a model of the nicotinic acetylcholine receptor. An Image of the Week from the San Diego Supercomputer Center.
A set of ion channel movies in both MPEG and QuickTime formats from the University of Texas. The ones most relevant to this topic are the Pentameric and the Ligand-gated ion channel models. Be warned, while these are really nice, they are also very large files.

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