Gehînke Ku
4.1 Criteria and receptor classes #
4.1.1 What counts, and the two speeds of receptor #
A molecule is a transmitter at a given synapse only if the whole sequence is shown. The neuron synthesises it, or accumulates it specifically. It is stored in vesicles and released when the terminal is depolarised, in a calcium-dependent way. The next cell has receptors, and applying the molecule mimics stimulation. The transmitter is removed, and the same antagonists block both the applied molecule and the synaptic response. Glutamate in a tissue is not proof, because it is also a metabolite.
Dale’s principle is often quoted too broadly. The narrow claim is that a neuron releases the same set of transmitters from all of its terminals, not that it has only one. Co-release is normal. Clear vesicles hold a small-molecule transmitter for the fast, local signal. Dense-core vesicles hold peptides, released when firing is intense enough to raise calcium away from the active zone.
Ionotropic receptors are ligand-gated channels and act within a millisecond. Nicotinic acetylcholine receptors, GABAA and glycine receptors, and the 5-HT3 receptor are pentamers of the cys-loop family. AMPA, NMDA, and kainate receptors are tetramers of a different build. Metabotropic receptors are seven-helix G-protein-coupled receptors. The Gs, Gi, and Gq cycles, and the making of cAMP, IP3, and diacylglycerol, are Biochemistry, summarised in the Cell Biology signalling notes. These notes name a messenger only where it changes the synapse. Metabotropic actions start in tens of milliseconds and can last seconds. They alter channels, release probability, or transcription, so one transmitter can excite one cell and inhibit another.
| Transmitter | Main receptors | Usual effect | How the action ends |
|---|---|---|---|
| Glutamate | AMPA, NMDA, kainate; mGluRs | Cation EPSP; NMDA also admits Ca2+ | Excitatory amino-acid transporters, mostly glial |
| GABA | GABAA; GABAB | Cl− conductance, or slower G-protein effects | GABA transporters |
| Glycine | Ionotropic glycine receptor | Cl− conductance in cord and brainstem | Glycine transporters |
| Acetylcholine | Nicotinic; muscarinic | Cation entry at end-plate and ganglia; slower muscarinic effects | Acetylcholinesterase, then choline uptake |
| Catecholamines | G-protein-coupled families | cAMP and related modulation | Reuptake, then MAO and COMT |
| Serotonin | Mostly metabotropic; 5-HT3 ionotropic | Modulation; 5-HT3 is a cation channel | Serotonin transporter, then MAO |
| Neuropeptides | G-protein-coupled receptors | Slow modulation | Peptidases and diffusion |
“Excitatory transmitter” is shorthand for the usual fast action. Move the chloride gradient, or change the G protein, and the shorthand fails.
4.2 Glutamate, GABA, and glycine #
4.2.1 Glutamate and the NMDA receptor #
Glutamate is the principal fast excitatory transmitter of the vertebrate central nervous system. AMPA receptors carry the fast EPSP. They pass sodium and potassium and usually exclude calcium if GluA2 is present and RNA-edited at the pore. They close when glutamate leaves. NMDA receptors are slower, pass calcium as well, and at negative voltages are blocked by magnesium in the pore. Depolarisation expels the magnesium. Current therefore requires glutamate and depolarisation together, plus a co-agonist, glycine or D-serine. Those joint requirements make the NMDA receptor a coincidence detector, and the calcium it admits is a trigger for long-term potentiation (Chapter 9). Kainate receptors are a third ionotropic class, real at some synapses and easy to overlook beside AMPA and NMDA.
Group I metabotropic receptors (mGluR1 and mGluR5) couple through Gq to phospholipase C. Groups II and III couple through Gi/o and often reduce release. The enzymology is generic. Clearance is by excitatory amino-acid transporters on astrocytes, then glutamine synthetase and return of glutamine to the neuron. If uptake fails, as in ischaemia when ion gradients collapse, glutamate keeps channels open, calcium overloads the cell, and neurons die.
4.2.2 GABA and glycine #
GABA is made from glutamate by glutamic acid decarboxylase. The inhibitory transmitter is the excitatory one after one decarboxylation, segregated by which cells express the enzyme. GABAA receptors are pentameric chloride channels, often two α, two β, and one γ. In adult neurons the usual result is inhibition, including shunt.
GABAB receptors are metabotropic and Gi/o-coupled. Postsynaptically they open potassium channels. Presynaptically they close calcium channels and reduce release. The messengers are the ordinary Gi effects: less cAMP, and βγ subunits on channels. Glycine is the other fast inhibitory transmitter of spinal cord and brainstem. Its chloride receptor is blocked by strychnine, so strychnine poisoning is disinhibition and spasm. Glycine is also the NMDA co-agonist. The same molecule inhibits at one receptor and permits excitation at another. Both amino acids are cleared by transporters, not by a cleft enzyme of the acetylcholinesterase type.
4.3 Acetylcholine and the monoamines #
4.3.1 Nicotinic and muscarinic acetylcholine #
Acetylcholine is the transmitter of skeletal motor neurons, of all autonomic preganglionic neurons, of parasympathetic postganglionic neurons, and of the sympathetic supply to sweat glands. In the brain, basal-forebrain cells project widely to cortex and hippocampus, and pedunculopontine cells lie in the brainstem. Central acetylcholine modulates state. Glutamate is the fast excitatory transmitter.
Neuronal nicotinic receptors differ in subunits from the muscle receptor and can pass more calcium. Ganglionic transmission is nicotinic. Muscarinic receptors are metabotropic: M1, M3, and M5 through Gq; M2 and M4 through Gi/o. Cardiac M2 slows the pacemaker by opening potassium channels. The cardiac cycle itself is Animal and Human Physiology. There is no acetylcholine reuptake of the monoamine type. Acetylcholinesterase ends the signal, and the terminal recovers choline.
4.3.2 Catecholamines and serotonin #
Dopamine, noradrenaline, and adrenaline are made from tyrosine. This outline is biosynthesis, not a laboratory recipe. Tyrosine hydroxylase, the rate-limiting step, makes L-DOPA and needs tetrahydrobiopterin. Aromatic L-amino-acid decarboxylase makes dopamine. Dopamine β-hydroxylase, inside the vesicle, makes noradrenaline. In chromaffin cells and a few brainstem neurons, phenylethanolamine N-methyltransferase then methylates noradrenaline to adrenaline. Which amines a cell releases is which of these enzymes it keeps.
Vesicular monoamine transporters load the amines in exchange for protons. Plasma-membrane transporters take them back up. Cocaine blocks those transporters and prolongs the extracellular amines. Amphetamines disturb vesicular stores and can reverse the transporters, so transmitter leaves without exocytosis. Monoamine oxidase and catechol-O-methyltransferase degrade what is not repackaged.
D1-like dopamine receptors (D1, D5) raise cAMP through Gs. D2-like receptors (D2, D3, D4) lower it through Gi/o and often act as autoreceptors. α1-adrenergic receptors use Gq, α2 use Gi, and β receptors use Gs. The messenger does not fix the sign: β1 excites heart muscle, while β2 can relax smooth muscle. Substantia nigra pars compacta supplies dorsal striatum, the path lost in Parkinson disease. The ventral tegmental area supplies nucleus accumbens and frontal cortex. The locus coeruleus supplies noradrenaline widely.
Serotonin is made from tryptophan by tryptophan hydroxylase and the same decarboxylase. Cell bodies in the raphe nuclei project widely, including to the dorsal horn. Most receptors are metabotropic. 5-HT3 is the exception, a cys-loop cation channel. Clearance is the serotonin transporter, then monoamine oxidase.
4.4 Peptides and nitric oxide #
4.4.1 A slow class, and an unconventional gas #
Neuropeptides — substance P, enkephalins, endorphins, neuropeptide Y, orexin, oxytocin, vasopressin — are defined by how they are made. Each is synthesised on rough endoplasmic reticulum as a prepropeptide, processed in the secretory pathway, and stored in dense-core vesicles that must be shipped from the soma. A terminal cannot make more peptide on the spot. Release generally needs intense firing, and there is no high-affinity reuptake. Extracellular peptidases end the signal. Receptors are metabotropic.
Nitric oxide is not stored in vesicles. Calcium–calmodulin activates neuronal nitric oxide synthase, which makes the gas from arginine. It diffuses, decays within seconds, and commonly activates soluble guanylyl cyclase to raise cGMP. At some synapses it is a candidate retrograde signal. It is not the universal retrograde messenger of long-term potentiation.
4.5 Key terms, summary, and self-check #
Key terms. Ionotropic; metabotropic; AMPA; NMDA; coincidence detector; GABAA; GABAB; nicotinic; muscarinic; tyrosine hydroxylase; reuptake; neuropeptide; nitric oxide.
Summary. A transmitter is defined by synthesis, calcium-dependent release, receptors, mimicry, and termination. Ionotropic receptors are fast pores; metabotropic receptors use G proteins. AMPA receptors carry the glutamate EPSP, and NMDA receptors admit calcium only when binding and depolarisation coincide. GABA and glycine open chloride channels. Acetylcholine is cleared by an enzyme; the catecholamines and serotonin are cleared by transporters and made from amino acids in short pathways. Peptides are made in the soma and act slowly. Nitric oxide is made on demand and diffuses.
Self-check.
1. Why does finding glutamate in a region not prove it is the local transmitter?
2. Why does the magnesium block make the NMDA receptor a coincidence detector?
3. A drug blocks acetylcholinesterase but not choline uptake. What happens in the cleft, and what can the terminal still recover?
4. Why does a noradrenergic neuron keep dopamine β-hydroxylase inside its vesicles?
5. Why can a terminal follow a long train with glutamate more easily than with a co-stored peptide?
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