Neurotransmitters

Neurotransmitters Classes

Neurotransmitters are organic molecules that allow neurons to communicate with each other and with target cells. Neurotransmitters fall into four classes based on their chemical makeup.

Small molecule neurotransmitter:

Acetylcholine (ACh) is a small molecule formed from acetate and choline. It is in a class by itself. Acetylcholine is the sole neurotransmitter used at the neuromuscular junction and is also the neurotransmitters used by the parasympathetic nervous system.

The molecular structure of acetylcholine, pointing out the choline and acetyl groups of the molecule.

The structure of acetylcholine.
 
 
Amino acids:
The molecular structures of various amino acid and biogenic amine neurotransmitters - Epinephrine, Norepinephrine, Dopamine, Serotonin, Histamine.

Figure 1. The structures of select amino acid and biogenic amine neurotransmitters.

Some amino acids act as neurotransmitters. Glycine and γ-aminobutyric acid (GABA) are the most common inhibitory neurotransmitters in the spinal cord and brain, respectively. Glutamate (glutamic acid) and aspartate are excitatory neurotransmitters found in the brain and spinal cord, respectively (Figure 1). 
 
The amino acid neurotransmitters, glutamate, glycine, and GABA, are almost exclusively associated with just one effect. Glutamate is considered an excitatory amino acid, but only because Glu receptors in the adult cause depolarization of the postsynaptic cell. Glycine and GABA are considered inhibitory amino acids, again because their receptors cause hyperpolarization. 
 
Each amino acid neurotransmitter would be part of its own system, namely the glutamatergic, GABAergic, and glycinergic systems. They each have their own receptors and do not interact with each other. Amino acid neurotransmitters are eliminated from the synapse by reuptake. A pump in the cell membrane of the presynaptic element, or sometimes a neighboring glial cell, will clear the amino acid from the synaptic cleft so that it can be recycled, repackaged in vesicles, and released again.
 
Biogenic Amines:
 
Biogenic amines (monoamines) are formed from amino acids from which the carboxyl terminus is removed (Figure 1). Three of the biogenic amines, called the catecholamines, are grouped together as they are all derived from the same amino acid, L-tyrosine. The catecholamines include: norepinephrine (noradrenalin), epinephrine (adrenalin) and dopamine (dopamine can also be made from phenylalanine). Norepinephrine (NE) is the neurotransmitter of the sympathetic nervous system (your fight or flight response). Epinephrine (E) has similar effects to NE, but is less abundant. Dopamine is best known for its role in motor inhibition. Loss of dopamine producing neurons in Parkinson disease leads to dyskinesias (movement disorders). Catecholamines bind to adrenergic receptors. Other biogenic amines include serotonin and histamine. 
 
Serotonin is made from tryptophan. It is the basis of the serotonergic system, which has its own specific receptors. Serotonin is transported back into the presynaptic cell for repackaging.  Other biogenic amines are made from tyrosine, and include dopamine, norepinephrine, and epinephrine. Dopamine is part of its own system, the dopaminergic system, which has dopamine receptors. Dopamine is removed from the synapse by transport proteins in the presynaptic cell membrane. Norepinephrine and epinephrine belong to the adrenergic neurotransmitter system. The two molecules are very similar and bind to the same receptors, which are referred to as alpha and beta receptors. Norepinephrine and epinephrine are also transported back into the presynaptic cell. The chemical epinephrine (epi– = “on”; “-nephrine” = kidney) is also known as adrenaline (renal = “kidney”), and norepinephrine is sometimes referred to as noradrenaline. The adrenal gland produces epinephrine and norepinephrine to be released into the blood stream as hormones. 
 
The biogenic amines have mixed effects on target cells. For example, the dopamine receptors that are classified as D1 receptors are excitatory whereas D2-type receptors are inhibitory. Biogenic amine receptors and neuropeptide receptors can have even more complex effects because some may not directly affect the membrane potential, but rather have an effect on gene transcription or other metabolic processes in the neuron.
 
Neuropeptides:
 
 A neuropeptide is a neurotransmitter molecule made up of chains of amino acids connected by peptide bonds (Figure 2). This is what a protein is, but the term protein implies a certain length to the molecule. Some neuropeptides are quite short, such as met-enkephalin, which is five amino acids long. Others are long, such as beta-endorphin, which is 31 amino acids long. Neuropeptides are often released at synapses in combination with another neurotransmitter, and they often act as hormones in other systems of the body, such as vasoactive intestinal peptide (VIP) or substance P.  Another example of a neuropeptide neurotransmitters is β-endorphin, the chemical associated with the elevated mood experienced with exercise. 
Molecular examples of neuropeptide neurotransmitters - Enkephalin, Substance P, Cholecystokinin, B-endorphin.

Figure 2. Examples of neuropeptide neurotransmitters.

 

Neurotransmitter Systems

There are several systems of neurotransmitters that are found at various synapses in the nervous system. These groups refer to the chemicals that are the neurotransmitters, and within the groups are specific systems.

The first group, which is a neurotransmitter system of its own, is the cholinergic system. It is the system based on acetylcholine. This includes the NMJ as an example of a cholinergic synapse, but cholinergic synapses are found in other parts of the nervous system. They are in the autonomic nervous system, as well as distributed throughout the brain.

The cholinergic system has two types of receptors, the nicotinic receptor is found in the NMJ as well as other synapses. There is also an acetylcholine receptor known as the muscarinic receptor. Both of these receptors are named for drugs that interact with the receptor in addition to acetylcholine. Nicotine will bind to the nicotinic receptor and activate it similar to acetylcholine. Muscarine, a product of certain mushrooms, will bind to the muscarinic receptor. However, nicotine will not bind to the muscarinic receptor and muscarine will not bind to the nicotinic receptor.

The effect of a neurotransmitter on the postsynaptic element is entirely dependent on the receptor protein. First, if there is no receptor protein in the membrane of the postsynaptic element, then the neurotransmitter has no effect. The depolarizing or hyperpolarizing effect is also dependent on the receptor. When acetylcholine binds to the nicotinic receptor, the postsynaptic cell is depolarized. This is because the receptor is a cation channel and positively charged Na+ will rush into the cell. However, when acetylcholine binds to the muscarinic receptor, of which there are several variants, it might cause depolarization or hyperpolarization of the target cell.

The characteristics of the various neurotransmitter systems presented in this section are organized in Table 1.

Table 1. Characteristics of Neurotransmitter Systems
System Chlolinergic Amino acids Biogenic amines Neuropeptides
Neurotransmitters Acetylchlonie Glutamate, glycine, GABA Serotonin (5-HT)  met-enkaphalin, beta-endorphin, VIP, Substance P, etc.
Receptors Nicotonic and muscarinic receptors Glu receptors, gly receptors, GABA receptors 5-HT receptors, D1 and D2 receptors, a-adrenergic and B-adrenergetic receptors Receptors are too numerous to list, but are specific to the peptides
Elimination Degredation by acetylcholinesterase Reuptake by neurons of glia Reuptake by neurons Degredation by enzymes called peptidases
Postsynaptic effect Nicotonic receptor causes depolarization. Muscarinic receptors can cause both depolarization of hyperpolarization depending on the subtype Glu receptors cause depolarization. Gly and GABA receptors cause hyperpolarization Depolarization or hyperpolarization depends on the specific receptor. For example, D1 receptors cause depolarization and D2 receptors cause hyperpolarization Depolarization or hyperpolarization depends on the specific receptor

The important thing to remember about neurotransmitters, and signaling chemicals in general, is that the effect is entirely dependent on the receptor. Neurotransmitters bind to one of two classes of receptors at the cell surface, ionotropic or metabotropic (Figure 4). Ionotropic receptors are ligand-gated ion channels, such as the nicotinic receptor for acetylcholine or the glycine receptor. A metabotropic receptor involves a complex of proteins that result in metabolic changes within the cell. The receptor complex includes the transmembrane receptor protein, a G protein, and an effector protein. The neurotransmitter, referred to as the first messenger, binds to the receptor protein on the extracellular surface of the cell, and the intracellular side of the protein initiates activity of the G protein. The G protein is a guanosine triphosphate (GTP) hydrolase that physically moves from the receptor protein to the effector protein to activate the latter. An effector protein is an enzyme that catalyzes the generation of a new molecule, which acts as the intracellular mediator of the signal that binds to the receptor. This intracellular mediator is called the second messenger.

This diagram contains two images, labeled A and B. Both images show a cross section of a postsynaptic membrane. There are two proteins embedded in each of the two membrane cross sections. In diagram A, direct activation brings about an immediate response. Here, both of the membrane proteins are ion channels. Several hexagonal neurotransmitters bind to ionotropic receptors on the extracellular fluid side of the channels. The binding of neurotransmitters causes the channels to open, allowing ions to flow from the extracellular fluid into the cytosol. Image B shows indirect activation, which involves a prolonged response, amplified over time. Here, one of the cell membrane proteins is solid while the other is a channel. Neurotransmitters bind to metabotropic receptors on the extracellular side of the solid protein. This triggers the solid protein to activate a G protein in the cytoplasm. The G protein binds to an effector protein in the cytoplasm, which results in the production of several second messenger particles. The second messenger activates enzymes that open the channel protein, allowing ions to enter the cytoplasm.

Figure 4. Receptor Types. (a) An ionotropic receptor is a channel that opens when the neurotransmitter binds to it. (b) A metabotropic receptor is a complex that causes metabolic changes in the cell when the neurotransmitter binds to it (1). After binding, the G protein hydrolyzes GTP and moves to the effector protein (2). When the G protein contacts the effector protein, a second messenger is generated, such as cAMP (3). The second messenger can then go on to cause changes in the neuron, such as opening or closing ion channels, metabolic changes, and changes in gene transcription.

Different receptors use different second messengers. Two common examples of second messengers are cyclic adenosine monophosphate (cAMP) and inositol triphosphate (IP3). The enzyme adenylate cyclase (an example of an effector protein) makes cAMP, and phospholipase C is the enzyme that makes IP3. Second messengers, after they are produced by the effector protein, cause metabolic changes within the cell. These changes are most likely the activation of other enzymes in the cell. In neurons, they often modify ion channels, either opening or closing them. These enzymes can also cause changes in the cell, such as the activation of genes in the nucleus, and therefore the increased synthesis of proteins. In neurons, these kinds of changes are often the basis of stronger connections between cells at the synapse and may be the basis of learning and memory.

Neurotransmitter Effects

The response of the postsynaptic cell to a neurotransmitter depends on the specific receptors that are present on its cell membrane. Most neurotransmitters can bind to more than one receptor found in the body and the cell’s response is dependent on which receptor is bound. Different receptors produce different cellular responses because they activate processes in the cell.

Cholinergic Receptors

Let’s look at an example. Receptors that can bind the neurotransmitter acetylcholine (ACh) are termed cholinergic receptors – this is the type of receptor. There is more than one cholinergic receptor – the different cholinergic receptors are termed subtypes. One subtype, the nicotinic cholinergic receptor, opens a sodium channel when it binds ACh. Stimulation of a nicotinic cholinergic receptor leads to depolarization of the cell. Another subtype, the muscarinic cholinergic receptor, opens a potassium channel when it binds ACh. Stimulation of a muscarinic cholinergic receptor leads to cell hyperpolarization. Acetylcholine can either excite or inhibit the postsynaptic cell depending on whether that cell has the nicotinic or muscarinic receptor subtype.

A receptor that produces a second messenger in the postsynaptic cell. Second messengers can lead to a wide range of effects in the postsynaptic cell.

Figure 5. A receptor that produces a second messenger in the postsynaptic cell. Second messengers can lead to a wide range of effects in the postsynaptic cell.

Cholinergic receptors that open ion channels cause changes in membrane potential. 

In the example we just considered, both receptor subtypes were linked to distinct ion channels. It is also possible for one receptor subtype to be linked to an ion channel while another subtype leads to the production of a second messenger. In this case, the timing of the postsynaptic cell’s response is different. Opening an ion channel takes very little time compared to the complex signaling that occurs with a second messenger. The response is fast with a receptor linked to an ion channel and is slow with a receptor that leads to a second messenger cascade. Although slower, second messenger cascades can produce more diverse cellular effects and have the advantage of amplification. Binding of a single molecule of neurotransmitter can produce many molecules of the second messenger (Figure 5). In contrast, if the receptor opens an ion channel, a single molecule of neurotransmitter (or sometimes two molecules) is needed to open a single ion channel in the postsynaptic cell.