Opening the book…
Neurotransmitters are chemical messengers orchestrating the transmission of signals from a neuron to a designated target cell across synaptic junctures. The transformative impact of these agents upon the postsynaptic entity rests entirely upon the unique receptor configuration therein. Without a receptor in the postsynaptic cell, the neurotransmitter remains without any consequential effect. The specific depolarizing or hyperpolarizing influence hinges upon the receptor type. For example, acetylcholine binding to the nicotinic receptor culminates in postsynaptic depolarization. It is due to the nature of a receptor as a cation channel, permitting an influx of positively charged sodium ions into the cell. However, acetylcholine binding to the muscarinic receptor may evoke either depolarization or hyperpolarization within the target cell.
Efficient clearance of neurotransmitters from the synaptic cleft is a dynamic facet. Various mechanisms facilitate this clearance. Neurotransmitters might diffuse away from the synaptic cleft, undergo inactivation via specialized enzymes within the presynaptic membrane, or be internalized into the axon terminal for subsequent storage and release upon the arrival of an action potential.
It is crucial to recognize that neurotransmitters engage with receptors from two primary classes on the cell surface: ionotropic and metabotropic (Figure 26). Ionotropic receptors constitute ligand-gated ion channels, such as the acetylcholine-sensitive nicotinic or glycine receptors. In contrast, metabotropic receptors entail intricate protein complexes culminating in metabolic modifications within the target cell.33
Metabotropic receptors involve a receptor complex that includes the transmembrane receptor protein, a G protein. G Protein-coupled receptors (GPCRs) have seven membrane-spanning domains. They are coupled to a guanosine triphosphate (GTP)-binding protein complex. When a neurotransmitter (or another receptor-specific ligand) binds to a GPCR, it brings about a conformational change in the receptor, causing the activation of a G protein. In the inactive state, guanosine diphosphate (GDP) is bound to the G subunit (Figure 27). The activated G subunit exchanges GTP in place of GDP, which triggers the dissociation of the G subunit from the G dimer and the receptor. Both G-GTP and G subunit are then free to activate other membrane proteins.
Three classes of G subunits initiate most of the subsequent events within the cell. Gs stimulates adenylyl cyclase, Gi inhibits it, and Gq stimulates phospholipase (PLC). The Gq-mediated signal transduction is shown in Figure 27.35
Neurotransmitters often need help from second messengers to send signals from receptors to different parts of the cell. These messengers come in various types, such as cyclic adenosine monophosphate (cAMP). An enzyme called adenylate cyclase changes ATP to cAMP when activated by the G protein-mediated mechanism. Second messengers lead to changes inside the cell, usually by activating other enzymes. In neurons, they often tweak ion channels, causing them to open or close. These enzymes can also trigger changes like activating genes in the nucleus, which leads to more protein production. Such changes often form the basis for stronger connections between cells at synapses, which can be linked to learning and memory.
Types of Neurotransmitters
Acetylcholine
Acetylcholine is the oldest known neurotransmitter in the body. It is associated with many physiological roles including memory, learning, and movement. Acetylcholine is found in both CNS and PNS. It is the most abundant neurotransmitter in the PNS. Acetylcholine is synthesized in the cytoplasm of the axon terminal from two substrates, acetyl CoA and choline, in a reaction that is catalyzed by choline acetyltransferase. Once synthesized, it is stored in synaptic vesicles until an action potential causes its release by exocytosis. Soon after its release, acetylcholine is degraded by acetylcholinesterase (AChE), an enzyme in pre- and postsynaptic membranes. The degradation products are acetate, which enters the blood, and choline, which is taken up by the presynaptic neuron and recycled.
Acetylcholine binds to receptors called cholinergic receptors. There are two types of cholinergic receptors: the nicotinic and muscarinic receptors. Nicotine binds to the nicotinic receptor and activates it, similar to acetylcholine. Muscarine, a product of a specific type of mushroom, binds to the muscarinic receptor. There are two subtypes of nicotinic receptors: NM (N1) and NN (N2). NM is present in the neuromuscular junction, whereas NN is found in the autonomic ganglia. Muscarinic receptors are also subdivided into five types, M1-M5. M1, M4, and M5 are expressed in the CNS, M2 in the heart, and M3 in the smooth muscle and glands. Nicotinic receptors are ionotropic, whereas muscarinic receptors are metabotropic.37
Biogenic Amines
Another group of neurotransmitters falls into the category of biogenic amines. These neurotransmitters are produced through the modification of certain amino acids. Although they contain amino groups, they no longer have carboxyl groups, so they are no longer classified as amino acids. Some biogenic amines are derived from the amino acid tyrosine, including dopamine, norepinephrine, and epinephrine.
Dopamine has its own system called the dopaminergic system, with specific receptors D1 to D5. Soon after its release, dopamine is taken back into the cell by transporting proteins in its membrane to limit its action. Cocaine interferes with the reuptake process, causing dopamine to remain in the synapse longer.
Norepinephrine and epinephrine are part of the adrenergic neurotransmitter system. Both these neurotransmitters attach to the same alpha- and beta-adrenergic receptors. These receptors have different subtypes and work through metabotropic mechanisms. Norepinephrine and epinephrine are also taken back into the cell after use. The name epinephrine (also known as adrenaline) comes from "epi-" meaning "on" and "nephrine," referring to "kidney," while norepinephrine is sometimes called noradrenaline. These two chemicals are produced by the adrenal gland (situated above each kidney) and released into the bloodstream as hormones.
Tyrosine is made within the body using yet another amino acid, phenylalanine. It goes through various steps to become dopamine, norepinephrine, and epinephrine. For instance, tyrosine is turned into dihydroxyphenylalanine (DOPA), an intermediate metabolite, and then into dopamine. Dopamine is converted into norepinephrine, which is subsequently changed into epinephrine (Figure 39).
Serotonin, also called 5-hydroxytryptamine, is derived from the amino acid tryptophan. It is a crucial part of the serotonergic system, which operates through specific receptors named 5-HT1 to 5-HT7. When serotonin is no longer required, it is taken back into the cell for later use. Monoamine oxidase (MAO) and catechol-O-methyltransferase are vital enzymes that help break down dopamine, norepinephrine, epinephrine, and serotonin when their actions ought to be seized.39 Low levels of serotonin production or a lack of receptors in the brain can lead to conditions such as depression. Drugs known as Selective Serotonin Reuptake Inhibitors (SSRIs) help prevent serotonin reuptake and are often used to treat depression.40
Amino Acid Neurotransmitters
Another significant category of neurotransmitters is composed of amino acids. This group encompasses glutamate, gamma-aminobutyric acid (GABA), a derivative of glutamate, and glycine. These amino acid neurotransmitters display a chemical structure characterized by amino and carboxyl groups. Each amino acid neurotransmitter operates within its distinct system, the glutamatergic, GABAergic, and glycinergic systems. These neurotransmitters are effectively cleared from the synaptic cleft through the reuptake process. A specialized mechanism in the presynaptic cell membrane or occasionally in adjacent glial cells expedites the removal of these amino acids from the synaptic cleft. Such clearance allows for recycling, repackaging into vesicles, and eventually re-releasing.
Glutamate serves as an excitatory neurotransmitter. It undergoes conversion from glutamine within the presynaptic axon terminal. Its subsequent fate involves reuptake, repackaging within the presynaptic cell, and converting to glutamine, a process facilitated by astrocytes. Glutamate binds primarily to ionotropic receptors but also interacts with metabotropic receptors within the CNS. Among the ionotropic receptors are AMPA, NMDA, and kainate receptors. Stimulation of AMPA and kainate receptors triggers increased sodium influx and potassium efflux, resulting in EPSPs. NMDA receptor activation leads to substantial calcium and sodium influx. Activation of metabotropic glutamate receptors prompts the release of IP3 and DAG or increases cAMP levels via G-protein-mediated mechanisms. Notably, involvement of glutamate in NMDA receptor-mediated pain conduction has sparked interest in developing NMDA receptor antagonists for managing chronic pain, utilizing intraspinal or extradural administration.
GABA takes on a primary role as an inhibitory neurotransmitter. Its inhibitory effect is achieved by initiating the opening of either chloride or potassium ion channels, which results in cellular hyperpolarization. Among GABA receptors, GABAA and GABAC receptors belong to the category of ligand-gated ion channels and predominantly facilitate the opening of chloride channels. Conversely, the GABAB receptor functions as a metabotropic receptor employing G-protein mechanisms. Substances like benzodiazepines (with anti-anxiety, muscle relaxants, anticonvulsants, and sedative properties) and barbiturates (acting as anticonvulsants) exert their influence via GABAA receptors.
Glycine yields both excitatory and inhibitory effects within the CNS. Its binding to NMDA receptors enhances sensitivity to glutamate, thereby facilitating pain transmission. Furthermore, glycine binding can lead to the opening of chloride channels. Interestingly, the same neuron may secrete both glycine and GABA, which are stored within the same vesicles.41
Neuropeptide Neurotransmitters
A neuropeptide constitutes a neurotransmitter molecule formed by sequences of amino acids interconnected through peptide bonds. Neuropeptides are frequently discharged at synapses in conjunction with other neurotransmitters, often serving as hormones in diverse bodily systems, such as vasoactive intestinal peptide (VIP) or substance P.
Among the prominent neuropeptides are endogenous opioid peptides, pivotal in regulating pain sensitivity. This classification encompasses enkephalins, endorphins, and dynorphins. Neurons containing these endogenous opioid peptides are distributed across various bodily tissues, particularly in regions implicated in the nociceptive response, including the thalamus, periaqueductal gray, limbic system, cerebral cortex, and spinal cord.
Three categories of opioid receptors, namely mu, kappa, and delta, come with multiple subtypes. These receptors operate through G-protein-mediated metabotropic mechanisms, employing strategies such as adenylyl cyclase inhibition, heightened potassium ion conductivity, and calcium ion channel closure. Endogenous opioid peptides do not exclusively bind to one distinct receptor type but exhibit a degree of affinity for other opioid receptors. Generally, enkephalins exhibit pronounced binding to delta receptors, dynorphins favor kappa receptors, and beta-endorphins display affinity for both mu and delta receptors.42
Gaseous Neurotransmitters
Nitric oxide is a gas that can travel freely and move in any direction from where it is produced. Thus, nitric oxide exhibits retrograde signaling, where a postsynaptic neuron produces this neurotransmitter and communicates with a presynaptic neuron. Nitric oxide operates as a short-acting inhibitory neurotransmitter, finding its place in the gastrointestinal tract, blood vessels, and the CNS. It is the smallest of all the neurotransmitters. Nitric oxide, unlike other neurotransmitters, is not stored in vesicles. It does not directly engage with cell membrane receptors either. Instead, it connects with a heme moiety of a guanylyl cyclase molecule, which acts as its unique receptor.
Carbon monoxide is another gaseous neurotransmitter sharing similar traits as nitric oxide. Interestingly, some enteric neurons combine nitric oxide and carbon monoxide as co-neurotransmitters. These gases might work together to send important messages to enteric neurons.43
| Neurotransmitters | Acetylcholine | Glutamate, Glycine, GABA | Serotonin, Dopamine, Norepinephrine, Epinephrine | Opioid Peptides, VIP, Substance P, Nitric Oxide |
|---|---|---|---|---|
| Receptors | Nicotinic and muscarinic receptors | Glu receptors, gly receptors, GABA receptors | 5-HT receptors, D1 and D2 receptors, \(\alpha\) adrenergic, and \(\beta\) adrenergic receptors | Receptors are too many to list |
| Termination of Action | Degradation by acetylcholines terase | Reuptake by neurons or glia | Reuptake by neurons | Degradation by peptidases |
Effects of Anesthetics on Neurotransmitters in the Induction of Sedation
Anesthesia employs various mechanisms to alter neuronal activity and neurotransmission, resulting in sedation, loss of consciousness, and reduced responsiveness to sensory stimuli. These include anesthetic agents increasing the permeability of cell membranes to potassium ions, leading to hyperpolarization. This hyperpolarization minimizes the excitability of neurons, contributing to the sedative and anesthetic effects. Some anesthetics can block the action of acetylcholine, thus disrupting neurotransmission processes and bringing about a loss of consciousness. Some other anesthetic agents also decrease the uptake of GABA, a neurotransmitter that promotes inhibitory signals in the brain. By slowing GABA uptake, anesthetics prolong the inhibitory effect of GABA on neurons, leading to sedation and reduced neuronal activity. Anesthetics could act as agonists on GABAA receptors, enhancing the inhibitory effects of GABA neurotransmission, which further contributes to sedation and reduced neuronal activity. Anesthetics can also decrease the activity of NMDA and AMPA receptors, which transmit excitatory signals. This reduction in excitatory signaling contributes to the overall sedative and anesthetic effects.44
This page titled 2.3.10: Neurotransmitters was last modified on Tue, 01 Sep 2026 04:02:32 GMT and is shared under a CC BY-NC-SA 4.0 license and was authored, remixed, and/or curated by Chaya Gopalan (Consortium of Academic and Research Libraries in Illinois (CARLI)) .
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