Neurotransmitters and receptors

Did you know there are billions of neurons—and trillions of synapses—in your amazing brain?$^1$start superscript, 1, end superscript (No wonder you can learn anything, including neurobiology!) Most of your synapses are chemical synapses, meaning that information is carried by chemical messengers from one neuron to the next.

In the article on synapses, we discussed how synaptic transmission works. Here, we’ll focus on neurotransmitters, the chemical messengers released from neurons at synapses so that they can “talk” to neighboring cells. We’ll also look at the receptor proteins that let the target cell “hear” the message.

Neurotransmitters: Conventional and unconventional

There are many different kinds of neurotransmitters, and new ones are still being discovered! Over the years, the very idea of what makes something a neurotransmitter has changed and broadened. Because the definition has expanded, some recently discovered neurotransmitters may be viewed as "nontraditional” or “unconventional” (relative to older definitions).

We’ll discuss these unconventional neurotransmitters at the end of article. For now, let's start out by discussing the conventional ones.

Conventional neurotransmitters

The chemical messengers that act as conventional neurotransmitters share certain basic features. They are stored in synaptic vesicles, get released when $\text{Ca}^{2+}$start text, C, a, end text, start superscript, 2, plus, end superscript enters the axon terminal in response to an action potential, and act by binding to receptors on the membrane of the postsynaptic cell.

Diagram of a synapse, showing neurotransmitters stored in synaptic vesicles inside the axon terminal. In response to an action potential, the vesicles fuse with the presynaptic membrane and release neurotransmitter into the synaptic cleft.

Image modified from "The synapse," by OpenStax College, Anatomy & Physiology (CC BY 3.0).

The conventional neurotransmitters can be divided into two main groups: small molecule neurotransmitters and neuropeptides.

Small molecule neurotransmitters

The small molecule neurotransmitters are (not too surprisingly!) various types of small organic molecules. They include:

• The amino acid neurotransmitters glutamate, GABA (γ-aminobutyric acid), and glycine. All of these are amino acids, though GABA is not an amino acid that's found in proteins.
  

  

  
  

  Glycine, glutamic acid, and GABA structures. All are amino acids.
• The biogenic amines dopamine, norepinephrine, epinephrine, serotonin, and histamine, which are made from amino acid precursors.
  

  [More about the biogenic amines

Dopamine structure

• The purinergic neurotransmitters ATP and adenosine, which are nucleotides and nucleosides. 
  

  
  

  Adenosine structure.
• Acetylcholine, which does not fit into any of the other structural categories, but is a key neurotransmitter at neuromuscular junctions (where nerves connect to muscles), as well as certain other synapses.
  

  
  

  Acetylcholine structures.

Neuropeptides

The neuropeptides are each made up of three or more amino acids and are larger than the small molecule transmitters. There are a great many different neuropeptides. Some of them include the endorphins and enkephalins, which inhibit pain; Substance P, which carries pain signals; and Neuropeptide Y, which stimulates eating and may act to prevent seizures.

Amino acid sequence of enkephalin: N-Tyr-Gly-Gly-Phe-Met-C.

A neurotransmitter’s effects depend on its receptor

Some neurotransmitters are generally viewed as “excitatory," making a target neuron more likely to fire an action potential. Others are generally seen as “inhibitory," making a target neuron less likely to fire an action potential. For instance:

• Glutamate is the main excitatory transmitter in the central nervous system.
• GABA is the main inhibitory neurotransmitter in the adult vertebrate brain.
• Glycine is the main inhibitory neurotransmitter in the spinal cord.

However, "excitatory" and "inhibitory" aren't really clear-cut bins into which we can sort neurotransmitters. Instead, a neurotransmitter can sometimes have either an excitatory or an inhibitory effect, depending on the context.

How can that be the case? As it turns out, there isn’t just one type of receptor for each neurotransmitter. Instead, a given neurotransmitter can usually bind to and activate multiple different receptor proteins. Whether the effect of a certain neurotransmitter is excitatory or inhibitory at a given synapse depends on which of its receptor(s) are present on the postsynaptic (target) cell.

Example: Acetylcholine

Let's make this more concrete by looking at an example. The neurotransmitter acetylcholine is excitatory at the neuromuscular junction in skeletal muscle, causing the muscle to contract. In contrast, it is inhibitory in the heart, where it slows heart rate. These opposite effects are possible because two different types of acetylcholine receptor proteins are found in the two locations.

Cell type specificity in response to acetylcholine.

Left panel: skeletal muscle cell. The acetylcholine molecule binds to a ligand-gated ion channel, causing it to open and allowing positively charged ions to enter the cell. This event promotes muscle contraction.

Right panel: cardiac muscle cell. The acetylcholine molecule binds to a G protein-coupled receptor, triggering a downstream response that leads to inhibition of muscle contraction.

• The acetylcholine receptors in skeletal muscle cells are called nicotinic acetylcholine receptors. They are ion channels that open in response to acetylcholine binding, causing depolarization of the target cell.
• The acetylcholine receptors in heart muscle cells are called muscarinic acetylcholine receptors. They are not ion channels, but trigger signaling pathways in the target

Types of neurotransmitter receptors

As the example above suggests, we can divide the receptor proteins that are activated by neurotransmitters into two broad classes:

• Ligand-activated ion channels: These receptors are membrane-spanning ion channel proteins that open directly in response to ligand binding.
• Metabotropic receptors: These receptors are not themselves ion channels. Neurotransmitter binding triggers a signaling pathway, which may indirectly open or close channels (or have some other effect entirely).

Ligand-activated ion channels

The first class of neurotransmitter receptors are ligand-activated ion channels, also known as ionotropic receptors. They undergo a change in shape when neurotransmitter binds, causing the channel to open. This may have either an excitatory or an inhibitory effect, depending on the ions that can pass through the channel and their concentrations inside and outside the cell.

Ligand-activated ion channels are large protein complexes. They have certain regions that are binding sites for the neurotransmitter, as well as membrane-spanning segments that make up the channel.

Diagram of ligand-activated channel. When neurotransmitter binds to the channel, it opens and cations flow down their concentration gradient and into the cell, causing a depolarization.

Ligand-activated ion channels typically produce very quick physiological responses. Current starts to flow (ions start to cross the membrane) within tens of microseconds of neurotransmitter binding, and the current stops as soon as the neurotransmitter is no longer bound to its receptors. In most cases, the neurotransmitter is removed from the synapse very rapidly, thanks to enzymes that break it down or neighboring cells that take it up.

Metabotropic receptors

Activation of the second class of neurotransmitter receptors only affects ion channel opening and closing indirectly. In this case, the protein to which the neurotransmitter binds—the neurotransmitter receptor—is not an ion channel. Signaling through these metabotropic receptors depends on the activation of several molecules inside the cell and often involves a second messenger pathway. Because it involves more steps, signaling through metabotropic receptors is much slower than signaling through ligand-activated ion channels.

Diagram of one way that a metabotropic receptor can act. The ligand binds to the receptor, which triggers a signaling cascade inside the cell. The signaling cascade causes the ion channel to open, allowing cations to flow down their concentration gradient and into the cell, resulting in a depolarization.

Some metabotropic receptors have excitatory effects when they're activated (make the cell more likely to fire an action potential), while others have inhibitory effects. Often, these effects occur because the metabotropic receptor triggers a signaling pathway that opens or closes an ion channel. Alternatively, a neurotransmitter that binds to a metabotropic receptor may change how the cell responds to a second neurotransmitter that acts through a ligand-activated channel. Signaling through metabotropic receptors can also have effects on the postsynaptic cell that don’t involve ion channels at all.

[Examples of metabotropic receptor

Conventional neurotransmitters and their receptor types

Neurotransmitter	Ligand-activated ion channel receptor(s)?	Metabotropic receptor(s)?
Amino acids
GABA	Yes (inhibitory)	Yes
Glutamate	Yes (excitatory)	Yes
Glycine	Yes (inhibitory)
Biogenic amines
Dopamine		Yes
Norepinephrine		Yes
Epinephrine		Yes
Serotonin	Yes (excitatory)	Yes
Histamine		Yes
Purinergic
Adenosine		Yes
ATP	Yes (excitatory)	Yes
Acetylcholine	Yes (excitatory )	Yes
Neuropeptides (many)		Yes

This table isn't a comprehensive listing, but it does cover some of the most well-known conventional neurotransmitters.

Unconventional neurotransmitters

All of the neurotransmitters we have discussed so far can be considered “conventional” neurotransmitters. More recently, several classes of neurotransmitters have been identified that don’t follow all of the usual rules. These are considered “unconventional” or “nontraditional” neurotransmitters.

Two classes of unconventional transmitters are the endocannabinoids and the gasotransmitters (soluble gases such as nitric oxide, $\text{NO}$start text, N, O, end text, and carbon monoxide, $\text {CO}$start text, C, O, end text). These molecules are unconventional in that they are not stored in synaptic vesicles and may carry messages from the postsynaptic neuron to the presynaptic neuron. Also, rather than interacting with receptors on the plasma membrane of their target cells, the gasotransmitters can cross the cell membrane and act directly on molecules inside the cell.