Posts Tagged ‘ receptor

Receptors and Agonism

We know that receptors in a synapse bind to neurotransmitters, and this binding can change the likelyhood of a nerve cell to fire. But do these receptors only bind to one specific neurotransmitter, or is there more to it? We can think of a receptor as a lock that only a specific key can open, a particular geometric and chemical structure that only certain molecules can interact with.

Agonists, Partial Agonists, and Antagonists

This is the nicotinic acetylcholine receptor, one of two acetylcholine receptors. It is a complex tangle of amino acids, where only molecules of a specific geometry can fit inside.

Obviously acetylcholine fits, as this is an acetylcholine receptor. This means acetylcholine is called a agonist at this receptor. Nicotine is also a agonist at the nicotinic acetylcholine receptor.

Since the structure of the receptor is so complex, other molecules can “kind of” fit, but activate the receptor only partially. Varenicline is one of these compounds, and is called a partial agonist. It simulates the pleasurable effects of nicotine, although not nearly as well, and prevents nicotine from binding to the receptors it is already attached to - which is why it is sold as an aid to quit smoking.

Other compounds can fit in the receptor, but do not activate it at all. Bupropion is one of these, and is called an antagonist. It is sold as an antidepressant and smoking cessation aid, as it binds to nicotinic acetylcholine receptors but does not activate them.

Selective Agonists

But there are two acetylcholine receptors, nicotinic and muscarinic. Acetylcholine is an agonist at both, while each compound is selective for its particular receptor.

Compound Nicotinic Acetylcholine Agonist? Muscarinic Acetylcholine Agonist?

We then call nicotine and muscarine selective agonists at the acetylcholine receptor. This concept is important in modern medicine, as a certain drug may want to target only a specific subreceptor to create a certain effect, as a full agonist may activate far too many other receptors and overwhelm the intent of the drug.

The people trying to make drugs that mimic the cancer inhibiting effects of cannabis without the pleasurable high? Yep, they’re searching for selective cannabinoid agonists, although they may be missing the point.

Neurons and Neurotransmitters

Fundamentally, the nervous system is simple. It receives sensory input, then translates this into an appropriate response. Things get a bit more complicated when we try to find out just what happens in between those two events. Sensory impulses travel through neurons, brain cells that can be thought of as switches, turning on or off depending on their input. It is important to realize that no overall response is determined solely by one structure of the brain or even one system, and it is not a simple yes-no decision but the interaction of many yes-no decisions. Like the collapse of a building or the stampede of a crowd, it is the influence of many small factors or decisions that cause a critical yet vague threshold to be reached.

The brain can be thought of somewhat as a tangled web of neurons, with dendrites connecting to axons. At the receiving end, a single neuron thrusts out many dendrites, which bring signals toward the nerve cell. They reach out for stimuli, like branches of a tree toward the sun. Their twigs swarm with tiny receptors. Receptors are small structures designed to recognize and lock on to certain chemical compounds released by other nerve cells. The junction between these dendrites and other axons is called a synapse, and this is where the chemical release and recognition occur.

If a receptor is activated by one of these chemical signals, it adjusts the flow of ions through the membrane of the underlying nerve cell. If many receptors are activated and the flow of ions changes significantly, the nerve cell may lose its polar, charged electrical properties. Instantly the whole depolarized cell fires, sending a signal down the axon causing the release of specific chemical signals. These molecules pour out of tiny round storage packets called vesicles, and deliver this chemical message at the synapse to another dendrite. This process continually echos throughout our brain.

In general, when the first primary chemical messengers reach their receptors, they change the way the next cell acts in one of three ways.

Chemical messengers can act as transmitters. In this case the chemical messenger acts directly and is the prime mover. It quickly transfers the signal from the near side of the synapse (presynaptic side) to the far side of the synapse (postsynaptic side). To transmit its fast excitatory messages, the brain usually uses molecules of acetylcholine or glutamate. They increase the excitability of the next cell (and hence the likelyhood to fire) by depolarizing it. Other primary neurotransmitters decrease the next cells excitability. GABA, for instance, excels in this role and hyperpolarizes the next cell.

The nerve cell which released its transmitter into the synapse quickly prepares to fire again. It recaptures most of its transmitter molecules, recycles them back up into storage vesicles, and releases them again. Many nerve cells fire as fast as the wingbeat of a hummingbird, firing several hundred times a second.

We can refer to this as neurotransmission, and think of it like a private telephone line. Two people are conducting a brisk and efficient conversation, on a hardwired private link which corresponds to the synapse.

Chemical messengers can act as modulators. Instead of being the prime movers, these messengers merely modify the way other primary neurotransmitters are acting. They nudge whatever excitation or inhibition is underway in one direction or the other, but with less influence than the primary neurotransmitter. For instance, norepinephrine (NE) can act as a modulator. Some NE receptors cover the terminal endings of acetylcholine nerve cells, and can stop them from releasing their acetylcholine.

In a broad generalization, norepinephrine enhances sensate responses (including those from noxious stimuli), dopamine energizes, and serotonin enters into mood-related behaviours. Neuromodulators can be thought of as a volume knob - given an ongoing conversation, they can either amplify it or mute it.

Chemical messengers can act as neurohormones. A nerve cell may release a hormone into tissue fluids, and it may diffuse a long distance before it can find the specific receptor it binds to, and it needs no synapse to act. We can think of neurohormonal communication like a radio station broadcasting across the country. The messages travel widely, but only specific radio sets tuned into a certain station will receive any information.

The brain has trillions of these receptors, attached to dendrites, cell bodies, and axon terminals. They are precisely shaped structures that will attach to a single neurotransmitter. Each receptor can be thought of as “voting” for excitation or inhibition of the nerve cell. The result determines whether the cell fires, how frequently the cell fires, and for how long the burst of firing will last.

Each chemical messenger is used in many different circuits throughout the brain. No one modulator, no one transmitter, no one receptor can be said to be the sole cause of any behavior. A given chemical messenger does two major things:

  1. It subtly influences many behaviors by acting at many levels simultaneously in the brain.
  2. It increases or decreases the contributions made by other chemical messengers and their receptor systems.

As a result of this feedback on multiple levels, the brain is gifted with a huge array of functions and experiences, each subject to wide variation and gradation.