Synaptic Transmission and Excitation-Contraction Coupling

Lecture 2 covers chemical synaptic transmission, integration of synaptic signals, and the sequence of events from motor nerve action potential to skeletal muscle contraction.

SYNAPTIC TRANSMISSION

Chemical synapses transmit signals between neurons (or between neurons and effector cells) via release of neurotransmitters into the synaptic cleft. The synapse consists of: presynaptic terminal (bouton) containing synaptic vesicles filled with neurotransmitter; synaptic cleft (~20 nm); postsynaptic membrane with transmitter-gated (ionotropic) or G protein-coupled (metabotropic) receptors.

Sequence of events at the neuromuscular junction (NMJ) and chemical synapses:

1. An AP arrives at the presynaptic terminal, depolarising it.
2. Voltage-gated Ca2+ channels (P/Q type at NMJ; N-type at some synapses) open. Ca2+ enters the terminal down a steep gradient ([Ca2+]o ~1.2 mM, [Ca2+]i ~0.0001 mM resting).
3. Elevated intracellular Ca2+ triggers vesicle fusion with the presynaptic membrane via SNARE protein complex (synaptobrevin on the vesicle, syntaxin and SNAP-25 on the membrane). This is the molecular mechanism of exocytosis; botulinum toxin cleaves SNARE proteins, blocking neurotransmitter release.
4. Neurotransmitter (e.g., acetylcholine at the NMJ) diffuses across the cleft and binds postsynaptic receptors.
5. At the NMJ: nicotinic ACh receptors (ligand-gated ion channels — fast ionotropic) open, allowing Na+ and K+ flux (Na+ influx dominates, causing depolarisation of the end-plate — the end-plate potential, EPP).
6. If the EPP is large enough to depolarise the surrounding muscle membrane to threshold, a muscle AP is generated.
7. Termination: ACh is hydrolysed by acetylcholinesterase (AChE) in the synaptic cleft into choline + acetate; choline is taken back up by the presynaptic terminal (choline transporter) and re-acetylated. Myasthenia gravis: autoantibodies against nicotinic ACh receptors (or MuSK) reduce the number of functional receptors — fatigable weakness. Treatment: anticholinesterases (neostigmine, pyridostigmine) and immunosuppression.

EPSPs AND IPSPs

Postsynaptic potentials are classified as: EPSP (excitatory postsynaptic potential): depolarising — brings the membrane closer to threshold; typically caused by Na+ (or Na+/K+) influx (e.g., AMPA receptor activation by glutamate). IPSP (inhibitory postsynaptic potential): hyperpolarising (or stabilising) — moves the membrane away from threshold; typically caused by Cl- influx through GABA-A receptors (reversal potential for Cl- ~ -65 mV, which is close to but slightly more negative than the resting potential) or K+ efflux through GIRK channels (GABA-B or opioid receptor activation).

Temporal summation: successive EPSPs arrive at the same synapse before the previous potential has decayed — they summate. Spatial summation: EPSPs from different synapses on the same neuron are simultaneously integrated. The axon hillock integrates all inputs; if the net depolarisation reaches threshold, an AP fires.

EXCITATION-CONTRACTION COUPLING

The process linking an AP in the motor neurone to contraction of the muscle fibre:

1. Motor AP → NMJ → end-plate potential → muscle fibre AP propagates along the sarcolemma.
2. T-tubules carry the AP deep into the fibre to the triad junction.
3. The dihydropyridine receptor (DHPR, voltage-sensitive L-type Ca2+ channel in T-tubule membrane) changes conformation — in skeletal muscle, it directly (mechanically) activates the ryanodine receptor (RyR1) in the SR membrane via a physical link (unlike cardiac muscle, where Ca2+-induced Ca2+ release via RyR2 predominates).
4. RyR1 opens: Ca2+ floods out of the SR into the cytoplasm (sarcoplasmic [Ca2+] rises from ~0.1 microM at rest to ~10 microM during activation).
5. Ca2+ binds troponin C (subunit of the troponin complex on thin filaments), causing a conformational change: troponin I detaches from actin, tropomyosin shifts to expose myosin-binding sites on actin.
6. Myosin heads (activated by ATP hydrolysis — forming myosin-ADP-Pi) bind actin, then undergo the power stroke (Pi released → conformational change pulling actin toward the M line), shortening the sarcomere. ADP is released; ATP binds → detachment of myosin from actin → cocking of the myosin head (ATP hydrolysis).
7. Relaxation: Ca2+ is actively pumped back into the SR by SERCA (sarco/endoplasmic reticulum Ca2+ ATPase); Ca2+ falls; troponin C releases Ca2+; tropomyosin shifts back; myosin-binding sites are blocked; cross-bridge cycling stops.

RIGOR MORTIS: after death, ATP synthesis ceases; SERCA can no longer pump Ca2+ into SR; myosin cannot detach from actin (requires ATP for dissociation); permanent cross-bridge formation → rigidity. Resolves as muscle proteins are proteolysed.