Synapses and Neurotransmitters
On this page
Direct answer
Chemical synapses, 20-30 nanometres wide, convert presynaptic calcium entry into quantal transmitter release with a 0.5 millisecond synaptic delay, while electrical synapses — gap junctions only 2-3 nanometres across — transmit instantly and bidirectionally. Acetylcholine synthesis joins choline and acetyl-CoA through choline acetyltransferase, with high-affinity choline uptake the rate-limiting step (hemicholinium blocks it, vesamicol blocks vesicular storage); noradrenaline synthesis runs tyrosine to DOPA through tyrosine hydroxylase — the rate-limiting enzyme — to dopamine and noradrenaline, with phenylethanolamine-N-methyltransferase, induced by cortisol, adding the methyl group for adrenaline in the medulla. The transmitter roster is functional: glutamate is the chief excitatory transmitter of the central nervous system, GABA the chief inhibitory one (GABA-A ionotropic chloride, GABA-B metabotropic, baclofen), glycine the cord's inhibitor that strychnine antagonises, serotonin modulates mood, nitric oxide diffuses back as a retrograde messenger, and dopamine inhibits prolactin while vasodilating the kidney through D1 receptors. Degradation and reuptake, not synthesis, are where the pharmacology bites.
What you must remember
- Synapse mechanics: calcium entry through voltage-gated channels is the only release trigger; the SNARE complex (synaptobrevin, syntaxin, SNAP-25) fuses vesicles; 0.5 ms delay estimates chain neurons — 2 ms implies about four synapses.
- Cholinergic pharmacology points: organophosphates irreversibly phosphorylate acetylcholinesterase (treat with atropine plus pralidoxime before the enzyme ages); botulinum toxin cleaves SNAREs blocking release; hemicholinium stops choline uptake; vesamicol stops vesicular storage.
- Catecholamine cascade: tyrosine hydroxylase is rate-limiting (inhibited by alpha-methyltyrosine); dopamine beta-hydroxylase makes noradrenaline inside vesicles; PNMT needs cortisol's induction — hence the adrenal medulla's 80:20 adrenaline output; reserpine empties vesicles through VMAT blockade; cocaine and tricyclics block reuptake; metabolism through MAO and COMT yields VMA and metanephrines, the phaeochromocytoma analytes.
- Amino acid transmitters: glutamate chief excitatory — NMDA receptors need glutamate plus glycine plus depolarisation to dislodge magnesium, and their calcium influx underlies excitotoxicity in stroke; GABA chief inhibitory, synthesised by glutamic acid decarboxylase with pyridoxine (vitamin B6) as cofactor — the reason isoniazid-induced B6 depletion causes seizures.
- Modulators: serotonin (raphe nuclei, about 90 per cent of body serotonin in enterochromaffin cells) with seven receptor families — 5-HT3 ionotropic, the rest metabotropic; dopamine mesolimbic (reward), tuberoinfundibular (prolactin inhibition), and nigrostriatal (Parkinson's); nitric oxide synthesised by nitric oxide synthase from arginine, acting through cGMP — sildenafil's target downstream.
- Receptor families: ionotropic (nicotinic, GABA-A, glycine, 5-HT3, glutamate) are fast channels; metabotropic (muscarinic M1-M5, adrenergic, GABA-B, dopamine) are G-protein-coupled and slower.
- Co-transmission: small-molecule transmitters and neuropeptides share terminals, released at different firing frequencies — the autonomic co-release of ATP and neuropeptide Y with noradrenaline being the example.
One acetylcholine vesicle, traced
Follow a quantum of acetylcholine at the neuromuscular junction. Choline is pumped into the terminal (the step hemicholinium kills), choline acetyltransferase acetylates it, and the vesicular transporter packs it — vesamicol's target. An arriving action potential opens calcium channels, calcium binds synaptotagmin, SNARE complexes fuse the vesicle, and roughly 5,000-10,000 molecules spray across the 20-30 nanometre cleft in under a millisecond. Two acetylcholine molecules open each nicotinic receptor; the end-plate potential fires. Acetylcholinesterase in the cleft hydrolyses the transmitter within a millisecond, and choline is recycled. Now break the loop pharmacologically: organophosphates leave transmitter undegraded — muscarinic crisis (constricted pupils, secretions, bradycardia) plus nicotinic weakness, treated with atropine plus pralidoxime before the enzyme ages; botulinum stops fusion (flaccid paralysis); myasthenia gravis attacks the receptors (fatigable weakness improving with edrophonium); and neostigmine inhibits the esterase, amplifying each quantum — its myasthenia rationale.
The pharmacology bridge examiners love
The bridge from physiology to pharmacology is where FMGE marks concentrate. Isoniazid depletes pyridoxine, glutamic acid decarboxylase fails, GABA synthesis falls, and seizures follow — prevented by routine B6 supplementation in the Indian tuberculosis programme. L-Dopa crosses the blood-brain barrier (dopamine cannot), given with carbidopa to block peripheral decarboxylation. Baclofen, a GABA-B agonist, is the antispastic; benzodiazepines and barbiturates act at different GABA-A sites to prolong chloride opening. Fluoxetine blocks serotonin reuptake, and the triptans are 5-HT1B/1D agonists. Nitric oxide explains nitroglycerine's vasodilatation through cGMP, and sildenafil's potentiation of the same messenger — hence the contraindicated nitrate combination. Every one of these drug facts is a physiology fact wearing a prescription.
Frequently asked questions
What is the rate-limiting step in catecholamine synthesis?
Tyrosine hydroxylase converting tyrosine to DOPA; choline uptake plays the equivalent rate-limiting role for acetylcholine, which hemicholinium blocks.
Why must pyridoxine be given with isoniazid?
Isoniazid induces pyridoxine depletion, and pyridoxine is the cofactor for glutamic acid decarboxylase in GABA synthesis — deficiency causes seizures and peripheral neuropathy.
How do GABA-A and GABA-B receptors differ?
GABA-A is an ionotropic chloride channel (benzodiazepine and barbiturate sites) mediating fast inhibition; GABA-B is a G-protein-coupled potassium channel opener, agonised by baclofen.
What is the mechanism of organophosphate poisoning and its treatment?
Irreversible acetylcholinesterase inhibition causes cholinergic excess; atropine blocks muscarinic effects and pralidoxime reactivates the enzyme if given before it ages.
Why is nitric oxide called a retrograde messenger?
Synthesised postsynaptically, it diffuses back to the presynaptic terminal and raises cGMP, enhancing transmitter release — the unusual direction that underlies synaptic plasticity.