In one breath
A neurotransmitter is a chemical a neuron makes, stores in its endings, releases at the synapse onto specific postsynaptic receptors, and then clears away. Grouped by chemistry they are acetylcholine, the amines (noradrenaline, adrenaline, dopamine, serotonin, histamine), the amino acids (glutamate and aspartate excitatory; GABA and glycine inhibitory), the polypeptides, the purines and the gases. Glutamate carries about 75% of excitatory transmission in the brain; GABA is the chief inhibitory transmitter of brain and retina, and glycine the chief one of brainstem and spinal cord. Which receptor a transmitter meets decides everything: GABA on GABA-A opens a Cl⁻ channel, GABA on GABA-B works through a G protein.
Builds on: Synapses and synaptic transmission · Properties of synapses · Leads to: Endogenous pain control and gate control theory · Parkinson’s and Huntington’s disease
What counts as a neurotransmitter
A transmitter is released at a nerve ending and carries the message from the presynaptic to the postsynaptic neuron. The same chemicals are also released onto muscle and gland cells.
Five criteria a chemical must meet:
- the neuron itself makes it;
- it is stored in the presynaptic ending;
- it is released at the synapse;
- the postsynaptic membrane carries specific receptors for it;
- once its job is done, it is disposed of by a suitable mechanism.
Four neighbouring terms are easy to mix up:
| Term | What it means |
|---|---|
| Neurotransmitter | acts across a synapse (or at a neuromuscular junction) |
| Neurohormone | enters the blood and travels as a hormone: noradrenaline, ADH, GnRH |
| Neurosecretion | poured straight onto a target organ or into the ECF |
| Neuromodulator | alters how the postsynaptic neuron behaves rather than carrying the message itself |
Classification
Classified by chemical structure, in six groups:
| Group | Members |
|---|---|
| Acetylcholine | in a class of its own |
| Amines | noradrenaline, adrenaline, dopamine; serotonin, histamine |
| Amino acids | excitatory: glutamate, aspartate; inhibitory: glycine, GABA |
| Polypeptides | ADH and oxytocin; somatostatin; the tachykinins, substance P among them; the endorphins and enkephalins; GnRH, TRH, CRH; angiotensins; activins and inhibins; CGRP and neuropeptide Y |
| Purines | adenosine, ATP |
| Gases | nitric oxide, carbon monoxide |
- Worth knowing, though not in your pages: transmitters are also sorted by size (small-molecule transmitters against the neuropeptides) and by effect (excitatory against inhibitory). If the question says “classify”, the chemical grouping above is the one to write.
Acetylcholine
Distribution
ACh is the transmitter at:
- all autonomic preganglionic neurons;
- postganglionic parasympathetic neurons;
- the few postganglionic sympathetic fibres that supply sweat glands and the blood vessels of skeletal muscle;
- the axons of spinal motor neurons, at the neuromuscular junction;
- many parts of the brain, including the Betz cells of the motor cortex and the basal ganglia;
- amacrine cells of the retina.
Synthesis and breakdown
- Choline is acetylated in the presynaptic ending: choline + acetyl-CoA → acetylcholine + CoA, by choline acetyltransferase.
- ACh is stored in the small clear vesicles and released by exocytosis, triggered by the Ca²⁺ that enters when the action potential reaches the terminal.
- In the cleft, cholinesterase splits ACh rapidly into choline and acetate.
- The choline is taken back into the terminal and used again to build fresh ACh.
Draw it: the cholinergic synapse
Draw a synaptic knob with small clear vesicles and label the reaction inside it: choline + acetyl-CoA → ACh, with choline acetyltransferase written beside the arrow. Show one vesicle emptying into the cleft, with a Ca²⁺ arrow entering the knob. In the cleft, put cholinesterase splitting ACh into choline + acetate, and draw a return arrow carrying choline back into the knob (reuptake). On the postsynaptic membrane, draw two receptors and label them nicotinic (ion channel) and muscarinic (G protein).
Nicotinic receptors
These behave as ligand-gated ion channels, and they belong to the same superfamily as the GABA-A, glycine and a few glutamate receptors.
| Feature | Detail |
|---|---|
| Structure | five subunits around a central channel |
| Channel passes | Na⁺ and other ions |
| Subunits known | 16 in all: α1–α9, β2–β5, γ, δ, ε |
| Fetal type | two α1, one β2, one γ, one δ |
| Adult type | γ replaced, per your book by δ |
| Autonomic ganglia | usually include an α3 subunit |
- Swapping the γ subunit shortens the time the channel stays open but raises the rate at which ions flow through it.
- Blockers differ by site: α-bungarotoxin blocks the receptor at the motor end plate but not at the ganglia; mecamylamine blocks the ganglionic receptor but not the one at the neuromuscular junction.
- In the brain, nicotinic receptors sit on the postsynaptic membrane, especially at glutamatergic axon terminals.
- Neuronal nicotinic receptors are unusual in being highly permeable to Ca²⁺.
Muscarinic receptors
- Found in brain, smooth muscle and glands.
- Five subtypes: M1, M2, M3, M4, M5.
- Each subtype has its own selective blocker, but atropine blocks them all.
- They are serpentine membrane proteins coupled to G proteins and, through them, to K⁺ channels and other intracellular machinery.
Nicotinic or muscarinic: the two habits
A nicotinic receptor is the channel: the transmitter binds and ions move at once. A muscarinic receptor is not a channel: it works through a G protein, so its effect is slower and longer. Both are cholinergic, so “ACh is excitatory” is wrong as a blanket statement; ACh on the M2 receptors of the heart slows it.
Catecholamines
The three catecholamines are adrenaline, noradrenaline and dopamine. All are built on a catechol nucleus (1,2-dihydroxybenzene) and all are found at synapses in brain, spinal cord and peripheral nerves.
- Noradrenaline comes mainly from postganglionic sympathetic endings; adrenaline mainly from the adrenal medulla.
- They are stored in the dense-core granules of the terminal and released by exocytosis.
| Receptor family | Subtypes |
|---|---|
| α adrenergic | α1, α2 |
| β adrenergic | β1, β2, β3 |
- All adrenergic receptors are serpentine proteins. They sit on the postsynaptic membrane and also on the presynaptic membrane, where α2 is the important one (see the autoreceptors on Synapses and synaptic transmission).
- Catecholamine receptors are present in nearly every tissue, and they respond both to circulating transmitter and to transmitter released from nearby endings.
- Disposal: MAO (monoamine oxidase) and COMT (catechol-O-methyl transferase) break the catecholamines down, and noradrenaline is also taken back into the presynaptic ending.
Dopamine
- Released by dopaminergic neurons onto dopamine receptors, mostly at synapses in the brain.
- The nigrostriatal dopaminergic neurons of the basal ganglia are needed for normal motor function (Parkinson’s and Huntington’s disease).
- Five receptors: D1 to D5. All are membrane proteins and many have subtypes.
Applied: dopamine receptors in schizophrenia
D2 and D4 receptors are increased in number in schizophrenia. D2 blockers help the illness a great deal, and they bind D4 receptors as well, which is the evidence your book gives for the receptor count being raised.
GABA
Gamma aminobutyric acid is the major inhibitory transmitter of the brain and the retina.
Synthesis and metabolism
- Made from glutamate by decarboxylation, using glutamate decarboxylase.
- Broken down by transamination, using GABA transaminase, to succinate, which enters the Krebs cycle.
- Your book notes that in body fluids it is present as β-aminobutyrate.
Receptors
Three receptors: GABA-A and GABA-B in the brain, GABA-C in the retina.
| Receptor | Type | On activation |
|---|---|---|
| GABA-A | ion channel, five subunits | ↑ Cl⁻ conductance |
| GABA-C | ion channel, five subunits | ↑ Cl⁻ conductance |
| GABA-B | metabotropic, G protein | ↑ K⁺ conductance, ↓ Ca²⁺ influx, ↓ adenylyl cyclase |
- GABA-A and GABA-C are built like the nicotinic receptor: five subunits ringing a pore.
- Benzodiazepines and other tranquillizers act on the GABA-A receptor.
Functions
- Every one of GABA’s actions — more Cl⁻ in, more K⁺ out, less Ca²⁺ in — drives the neuron toward hyperpolarization, which is an IPSP.
- Benzodiazepines (sedatives, muscle relaxants, anticonvulsants, anti-anxiety drugs) work by raising Cl⁻ conductance through GABA-A, binding its α subunit.
- A second family of benzodiazepine receptors, the peripheral benzodiazepine receptors (PBR), is found in peripheral tissues and in steroid-secreting endocrine cells, and may have a part in steroid synthesis.
- Alcohol and barbiturates also act partly by opening Cl⁻ channels.
- Progesterone and deoxycorticosterone in large doses bring on sleep and act as anaesthetics, working through GABA-A.
- Low-grade, continuous stimulation of brain GABA receptors is helped along by GABA in intestinal fluid; your book credits this with lowering the signal-to-noise ratio of neuronal discharge across billions of neurons. GABA activity falls with age, and retinal neurons lose some of their specificity as it does.
Applied: anaesthetics work at the inhibitory receptors
Alcohol, barbiturates and many volatile inhaled anaesthetics raise Cl⁻ conductance at GABA-A and glycine receptors. Some anaesthetics instead block NMDA and AMPA receptors. Local anaesthetics do something different again: they block Na⁺ channels in peripheral nerves, so no impulse is generated in the first place.
GABA-A against GABA-B: the commonest MCQ
GABA-A (and GABA-C) is the channel: it lets Cl⁻ in, and it is the target of benzodiazepines, barbiturates and alcohol. GABA-B is metabotropic: through a G protein it raises K⁺ conductance, cuts Ca²⁺ entry and lowers adenylyl cyclase, and its agonist is baclofen (Properties of synapses). Both end in inhibition, by different routes. GABA-C is the retinal one.
Glycine
Glycine is both inhibitory and excitatory, depending on which receptor it reaches.
- Its own receptor is a pentamer of two kinds of subunit: the α subunit binds the ligand, and there is a β subunit.
- That receptor is a Cl⁻ channel. Opening it raises Cl⁻ conductance and makes an IPSP, so glycine is mainly inhibitory: it is the transmitter of direct postsynaptic inhibition in the brainstem and spinal cord.
- In some parts of the brain it turns excitatory instead, by influencing NMDA receptors, which glutamate is bound to.
- In the dorsal horn of the spinal cord, glycine binds the NMDA receptor and helps pain get through (Pain pathways and perception).
Neurons that cause direct inhibition fall into three groups:
| Group | Marker your book names |
|---|---|
| Secrete glycine | GLYT2, the glycine transporter |
| Secrete GABA | GAD |
| Secrete both | — |
Glycine cuts both ways
Asked whether glycine is excitatory or inhibitory, the full answer is both: inhibitory at its own Cl⁻-channel receptor in brainstem and cord, excitatory where it works through the NMDA receptor. It is the one inhibitory amino acid that also facilitates pain transmission.
Glutamate
- The usual excitatory transmitter of the CNS, responsible for about 75% of excitatory transmission in the brain.
- Made from α-ketoglutarate of the Krebs cycle, and loaded into synaptic vesicles by the transporter BNP1.
- Clearance and recycling: astrocytes take the released glutamate up and turn it into glutamine; the glutamine goes to the nerve ending, where it is turned back into glutamate.
- It opens NMDA channels, and the Ca²⁺ that enters through them is what produces long-term potentiation (Properties of synapses).
Applied: glutamate as an excitotoxin
If astrocytes cannot keep up and glutamate piles up, it acts on the neuronal cell bodies and drives so much Ca²⁺ into them that the cells die. Glutamate in high concentration is therefore an excitotoxin, and is used deliberately to make excitotoxic lesions in experimental animals. The same thing happens in ischemia, hypoxia, hypoglycemia and trauma, and it is one of the ways brain tissue is destroyed in stroke.
Serotonin
Serotonin (5-hydroxytryptamine, 5-HT) is a transmitter in the CNS, the enteric nervous system and the retina.
- An amine, made from the amino acid tryptophan by hydroxylation and decarboxylation.
- Seven receptors, 5-HT1 to 5-HT7, and several have subtypes: six under 5-HT1 (A to F), three under 5-HT2 (A, B, C) and two under 5-HT5 (A, B).
- Most of them act by switching on adenylyl cyclase and phospholipase C.
- Analgesia: the raphespinal pathway runs from the nucleus raphe magnus down onto neurons of the cord, and its serotonergic transmission is a key part of the body’s own pain-control system (Endogenous pain control and gate control theory).
- Mood: serotonin is a mood elevator. LSD, the hallucinogen, is a serotonin agonist acting at 5-HT2 receptors.
- Serotonin also circulates in the blood, secreted by enterochromaffin cells, platelets and basophils, and helps with smooth muscle contraction and the platelet plug.
Histamine
- Works both as a transmitter and as a circulating hormone.
- Histaminergic neurons are found mainly in the hypothalamus and the limbic system.
- Three receptors: H1, H2, H3.
- In the CNS it governs behavioural functions. Its peripheral actions are the familiar ones: smooth muscle contraction (hence bronchospasm), HCl secretion in the stomach, more capillary permeability, and arteriolar dilatation.
Peptide transmitters
Substance P and tachykinins
- Substance P is the major tachykinin: a polypeptide of 11 amino acids, found in many parts of the CNS, in the intestine and in peripheral nerves.
- Other tachykinins are neurokinin A, neurokinin A (3–10), neurokinin B, neuropeptide K and neuropeptide α.
- NK-1, NK-2 and NK-3 are the neurokinin receptors, three in all, and your book calls the first two G-protein coupled.
| Receptor | Its ligand |
|---|---|
| NK-1 | substance P |
| NK-2 | neurokinin K, as printed |
| NK-3 | neurokinin B |
- Substance P turns on phospholipase C, so IP3 and DAG rise inside the cell.
What substance P does:
- carries pain through the dorsal horn of the spinal cord;
- acts as a co-transmitter with dopamine in the nigrostriatal pathway, its concentration tracking dopamine’s;
- in the hypothalamus, modulates neuroendocrine output;
- mediates the axon reflex in skin;
- mediates peristalsis in the intestine;
- lowers mood — which is why an NK-1 antagonist has been tried as an antidepressant.
CGRP
Calcitonin-gene related peptide comes in two forms, CGRP α and CGRP β.
- CGRP β is mainly in the GI tract.
- CGRP α sits alongside substance P in the primary sensory afferent neurons of the spinal cord and in the neurons of blood vessels; it is also in the thalamus and the median forebrain bundle.
- In the cord it modulates pain transmission; in the vessels it is a potent vasodilator.
- One gene makes both CGRP and calcitonin, yet each keeps to its own job: CGRP barely lowers calcium, and calcitonin barely dilates vessels.
Neuropeptide Y
- A polypeptide of 36 amino acids, spread widely through brain and autonomic nervous system.
- Its cell bodies are packed into the arcuate nucleus of the hypothalamus and project to the paraventricular nuclei.
- It is a powerful orexigenic transmitter: it raises food intake sharply, and NPY antagonists are used to cut food intake.
- Acts through G-protein coupled Y receptors; four are known: Y1, Y2, Y4, Y5.
Purines
The transmitters in this group are adenosine, ATP, uridine and adenosine’s metabolites.
Adenosine
- A general depressant in the CNS, and a potent vasodilator in many regional circulations.
- Four receptors: A1, A2A, A2B, A3, all G-protein coupled, and they pull in opposite directions:
| Receptors | Effect on cAMP |
|---|---|
| A2A, A2B | ↑ cAMP |
| A1, A3 | ↓ cAMP |
- Theophylline and the caffeine in tea and coffee stimulate by blocking adenosine receptors, which lifts adenosine’s braking effect.
- A1 antagonists are used in stroke: they cut glutamate release and so hold off the excitotoxic damage above.
ATP
- A recent addition to the list of CNS transmitters. In the ANS it produces rapid synaptic responses, and in the habenula fast responses too.
- Acts through P2X and P2Y receptors, found widely in the body.
- P2X are ligand-gated ion channels, with seven subtypes, P2X1 to P2X7.
- P2Y has eight subtypes: P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, P2Y14.
- P2X receptors in the dorsal horn point to a part for ATP in carrying sensory information through the spinal cord.
Nitric oxide
- NO, the same molecule as endothelium-derived relaxing factor (EDRF), is released by the endothelial cells of blood vessels and is also a transmitter in the brain.
- Made from arginine by NO synthase, which needs NADPH.
- In the brain it is the signal that lets the postsynaptic neuron talk back to the presynaptic one, during long-term potentiation and long-term depression.
Nitric oxide runs backwards
Every other transmitter here goes presynaptic → postsynaptic. NO goes the other way: it is made in the postsynaptic cell and diffuses back into the terminal, which is why it is called a retrograde messenger. It is also not stored in vesicles at all — it is made on demand and diffuses straight through the membrane.
Co-transmitters
- A co-transmitter is a chemical released along with the transmitter proper.
- The standard pairs: VIP with ACh, and neuropeptide Y with noradrenaline.
- Sometimes the co-transmitter helps the main transmitter’s action at the synapse.
- Aspartate, the enkephalins and the prostaglandins are also counted as CNS transmitters.
A few slips in your book
- Adult nicotinic receptor: your book says γ is replaced by δ, which would leave two δ subunits. The standard account replaces γ with ε — and ε appears in your book’s own list of 16 subunits. If the option is offered, choose ε.
- MAO and COMT are said to act on adrenaline and noradrenaline “respectively”. Both enzymes act on both catecholamines.
- GAD is glutamate decarboxylase, the enzyme that makes GABA, not a transporter. The vesicular GABA transporter is VGAT.
- NK-2 is the receptor for neurokinin A; “neurokinin K” looks like neuropeptide K and neurokinin A run together. All three NK receptors are G-protein coupled, not only NK-1 and NK-2.
- β-aminobutyrate: the transmitter is the γ isomer, as its own name says.
- NADPH diaphorase is another name for NO synthase itself, not for NADPH.
Exam-answer skeleton: "Classify neurotransmitters, and describe acetylcholine as a transmitter" (long essay)
- Define a neurotransmitter and give the five criteria; separate it from neurohormone, neurosecretion and neuromodulator.
- Classify by chemical structure, in the six groups, with examples in each.
- Name the chief excitatory (glutamate, 75% of brain excitation) and inhibitory (GABA in brain, glycine in cord) transmitters in a line each.
- Acetylcholine — distribution: the six sites, preganglionic through to retinal amacrine cells.
- Synthesis by choline acetyltransferase, storage in clear vesicles, Ca²⁺-triggered release; breakdown by cholinesterase and reuptake of choline. Draw the cycle.
- Nicotinic receptor: ligand-gated channel, five subunits, fetal against adult form, α-bungarotoxin and mecamylamine.
- Muscarinic receptor: M1 to M5, serpentine and G-protein coupled, atropine blocks all.
- Close with a table of the other transmitters, their main receptors and one function each.
Asked in exams
- GABA and its receptors: Jan/Feb 2022, MCQ · Mar 2024, MCQ · Oct 2024, MCQ