Page 3 of 9

PY3.1-12 | Nerve and Muscle Physiology — Part 2

Synaptic Transmission — How Neurons Talk to Each Other (PY3.5)

Neurons communicate at specialised junctions called synapses. There are two types:

1. Electrical synapses (gap junctions):
• Direct cytoplasmic connection via connexin proteins forming connexons (gap junction channels)
• Current flows directly from one cell to the next — very fast transmission (~0.1 ms delay)
• Bidirectional — current can flow either way
• Found in: cardiac muscle (intercalated discs), smooth muscle (visceral), some CNS interneurons
• Function: synchronise activity in cell groups (e.g., cardiac myocytes beating in unison)

2. Chemical synapses (the majority):
Signal is converted from electrical → chemical → electrical:

Step-by-step mechanism:
1. AP arrives at the presynaptic terminal (axon terminal)
2. Voltage-gated Ca²+ channels open — Ca²+ flows into the terminal
3. Ca²+ triggers vesicle fusion — synaptic vesicles containing neurotransmitter fuse with the presynaptic membrane via SNARE proteins (synaptobrevin, syntaxin, SNAP-25). This is exocytosis.
4. Neurotransmitter is released into the synaptic cleft (~20 nm wide)
5. Neurotransmitter binds receptors on the postsynaptic membrane
6. Postsynaptic response — ion channels open, producing either:
- EPSP (Excitatory Postsynaptic Potential) — depolarisation (e.g., Na+ channels open) — mediated by glutamate, acetylcholine (nicotinic)
- IPSP (Inhibitory Postsynaptic Potential) — hyperpolarisation (e.g., Cl- channels open, K+ channels open) — mediated by GABA, glycine
7. Neurotransmitter is removed — by reuptake (e.g., serotonin, noradrenaline), enzymatic degradation (e.g., acetylcholine by acetylcholinesterase), or diffusion

Synaptic integration:
• Spatial summation — EPSPs from multiple synapses arriving simultaneously add together
• Temporal summation — rapid, repeated EPSPs from the same synapse add together
• If the sum of EPSPs minus IPSPs reaches threshold at the axon hillock → AP fires

Clinical pearl: Botulinum toxin (Botox) cleaves SNARE proteins, preventing vesicle fusion and neurotransmitter release. Tetanus toxin blocks the release of inhibitory neurotransmitters (GABA, glycine), causing uncontrolled excitation and muscle spasms.

The Neuromuscular Junction — Where Nerve Meets Muscle (PY3.6)

The neuromuscular junction (NMJ) is the specialised chemical synapse between a motor neuron and a skeletal muscle fibre. It's the critical link that converts the nerve's electrical signal into muscle contraction.

Figure: The Neuromuscular Junction — Where Nerve Meets Muscle (PY3.6)

Structure of the NMJ:
• Presynaptic terminal (axon terminal) — contains ~300,000 synaptic vesicles, each filled with ~10,000 molecules of acetylcholine (ACh). One vesicle = one quantum of ACh.
• Synaptic cleft (~50 nm) — wider than a CNS synapse. Contains acetylcholinesterase (AChE) anchored to the basal lamina.
• Motor end plate — the specialised postsynaptic region of the muscle fibre membrane (sarcolemma). It has deep junctional folds that increase surface area and concentrate nicotinic ACh receptors (nAChRs) at the crests of the folds. Voltage-gated Na+ channels are concentrated in the depths of the folds.

Sequence of events at the NMJ:
1. AP arrives at the axon terminal
2. Voltage-gated Ca²+ channels open → Ca²+ influx
3. Ca²+ triggers fusion of ~100-200 vesicles with the presynaptic membrane (each AP releases ~60 quanta)
4. ACh is released into the synaptic cleft
5. ACh binds to nicotinic receptors on the motor end plate — these are ligand-gated Na+/K+ channels (Na+ influx >> K+ efflux)
6. The resulting depolarisation is the end-plate potential (EPP) — typically ~70 mV, well above threshold
7. EPP triggers an AP in the muscle fibre, which propagates along the sarcolemma and into the T-tubules
8. AChE rapidly hydrolyses ACh → choline + acetate. Choline is taken back up into the presynaptic terminal for recycling.

Safety factor: The NMJ has a large safety factor — the EPP (~70 mV) is much larger than needed to reach threshold (~-55 mV). This ensures reliable 1:1 transmission (every nerve AP produces a muscle AP).

Miniature end-plate potentials (MEPPs): Even at rest, single vesicles spontaneously fuse, releasing one quantum of ACh. Each MEPP is ~0.4 mV — too small to reach threshold. These were the key evidence for the quantal hypothesis of neurotransmitter release.

Clinical correlations:
• Myasthenia gravis — autoantibodies against nAChRs reduce the number of functional receptors. The EPP shrinks below the safety factor → fatiguable weakness (worse with activity, better with rest). Treated with AChE inhibitors (neostigmine, pyridostigmine) that prolong ACh action.
• Curare (tubocurarine) — competitive antagonist at nAChRs → muscle paralysis. Used historically by Indigenous peoples on arrow tips.
• Succinylcholine — depolarising neuromuscular blocker. Mimics ACh, causing initial depolarisation (fasciculations) then persistent depolarisation block.
• Organophosphates — irreversibly inhibit AChE → ACh accumulates → continuous stimulation → paralysis. Nerve agents (sarin) and some pesticides work this way.

Skeletal Muscle Contraction — The Sliding Filament Theory (PY3.7)

Now that the AP has reached the muscle fibre, how does it make the muscle shorten? The answer is excitation-contraction coupling and the sliding filament mechanism.

Structure reminder — the sarcomere:
The sarcomere (Z-line to Z-line) is the functional unit of contraction. It contains:
• Thick filaments — made of myosin (each myosin molecule has a globular head with ATPase activity and an actin-binding site)
• Thin filaments — made of actin (with tropomyosin and troponin complex). Tropomyosin covers the myosin-binding sites on actin at rest. Troponin has three subunits: TnT (binds tropomyosin), TnC (binds Ca²+), TnI (inhibits actin-myosin interaction)

Excitation-Contraction (E-C) Coupling:
1. The AP propagates along the sarcolemma and into the T-tubules (transverse tubules — deep invaginations of the sarcolemma)
2. The depolarisation activates L-type Ca²+ channels (dihydropyridine receptors, DHPRs) in the T-tubule membrane
3. DHPRs are mechanically linked to ryanodine receptors (RyR1) on the sarcoplasmic reticulum (SR) — the intracellular Ca²+ store
4. RyR1 opens → Ca²+ floods out of the SR into the cytoplasm (Ca²+ rises from ~0.1 μM to ~10 μM — a 100-fold increase)

The Cross-Bridge Cycle (sliding filament mechanism):
1. Ca²+ binds to troponin C → conformational change → tropomyosin shifts → exposes myosin-binding sites on actin
2. Cross-bridge formation — myosin head (already 'cocked' and loaded with ADP + Pi) binds to actin
3. Power stroke — Pi is released → myosin head pivots, pulling the thin filament toward the centre of the sarcomere. ADP is released. The sarcomere shortens.
4. ATP binds to the myosin head → myosin detaches from actin
5. ATP is hydrolysed (ATPase activity) → myosin head is 're-cocked' to the high-energy position. Cycle repeats.

Relaxation: The SR Ca²+-ATPase (SERCA) pump actively pumps Ca²+ back into the SR. As cytoplasmic Ca²+ falls, Ca²+ dissociates from troponin C → tropomyosin slides back to cover the binding sites → cross-bridges cannot form → muscle relaxes.

Rigor mortis: After death, ATP is depleted. Without ATP, myosin heads cannot detach from actin → permanent cross-bridges → muscle stiffness. Resolves after ~48 hours when muscle proteins degrade.

Anatomy link: In your dissection of the upper limb, the muscles you're studying — biceps, triceps, forearm flexors — all contract by this exact mechanism. The tendons you see are the connective tissue that transmits the force of millions of sarcomeres shortening in parallel.

Types of Skeletal Muscle Fibres (PY3.8)

Not all skeletal muscle fibres are the same. They differ in their speed of contraction, resistance to fatigue, and metabolic profile. There are three main types:

Type I — Slow oxidative (SO) fibres ('red' fibres):
• Slow myosin ATPase → slow contraction speed
• Highly resistant to fatigue — can sustain activity for hours
• Rich in myoglobin (oxygen-binding protein — gives the red colour), mitochondria, and capillaries
• Primary metabolism: aerobic oxidative phosphorylation (fatty acids, glucose)
• Function: postural muscles, endurance activities (marathon running)
• Example: soleus muscle (stands you up all day without fatigue)

Type IIa — Fast oxidative-glycolytic (FOG) fibres:
• Fast myosin ATPase → fast contraction speed
• Moderately resistant to fatigue
• Good mitochondrial content and capillary supply, PLUS significant glycolytic capacity
• Metabolism: both aerobic and anaerobic (versatile)
• Function: sustained power activities (swimming, cycling)

Type IIb (IIx) — Fast glycolytic (FG) fibres ('white' fibres):
• Fastest myosin ATPase → fastest contraction speed
• Fatigues rapidly — can sustain activity for only seconds to minutes
• Few mitochondria, low myoglobin (pale colour), large glycogen stores
• Primary metabolism: anaerobic glycolysis (produces lactate)
• Function: powerful, brief bursts (sprinting, jumping, lifting)
• Example: extraocular muscles (rapid eye movements)

Clinical relevance:
• Training shifts fibre type: endurance training converts Type IIb → IIa (more oxidative). Sprint training increases IIb fibre size.
• Muscle wasting in disuse or denervation preferentially affects Type II (fast) fibres.
• Duchenne muscular dystrophy — absence of dystrophin affects all fibre types but fast fibres deteriorate first.
• Most human muscles contain a mix of all three types — the proportion determines the muscle's functional characteristics.