BIPN 100 - Midterm Practice Prelecture 11

Synaptic Transmission

Types of Synapses

• Chemical: Involves neurotransmitters and receptors.
• Electrical: Faster than chemical synapses; used for different purposes.

Ligand-Gated Ion Channels

• Vast diversity; includes the nicotinic acetylcholine receptor at the neuromuscular junction.
• Ligand binding follows the law of mass action.
  • More neurotransmitter leads to more ligand-receptor binding due to entropy and chemical gradients.
  • $L + R \rightleftharpoons LR$ (Ligand + Receptor forming Ligand-Receptor complex)

Toxins and Synaptic Interference

• Toxins can interfere at various points:
  • Blocking $Ca^{2+}$ channels prevents calcium influx (PQ calcium channels).
  • Cleaving SNARE proteins inhibits vesicle exocytosis (botulinum toxin, tetanus toxin).

Botulinum Toxin (Botox)

• Cleaves SNARE proteins, preventing vesicular release.
• Used in Botox at low doses to relax facial muscles, reducing wrinkles.
• Also used for migraine treatment by preventing neuron overactivation.

Neurotransmitter Dynamics

• Critical processes in the synaptic cleft:
  • Neurotransmitter binding to receptors.
  • Termination of neurotransmitter activity.
    • Diffusion away from the synapse.
    • Reuptake into the presynaptic neuron.
    • Enzymatic degradation.

Acetylcholinesterase and its Inhibition

• Acetylcholinesterase degrades acetylcholine into acetate and choline.
• Inhibiting acetylcholinesterase increases acetylcholine levels in the cleft.
  • Leads to more binding to receptors, larger EPPs (Excitatory Postsynaptic Potentials), and increased muscle action potentials.

Reuptake Inhibition

• SSRIs (Selective Serotonin Reuptake Inhibitors) block serotonin reuptake.
  • Results in more serotonin in the cleft, increasing receptor binding and downstream signaling.
• Following the chemical equation:
  • Receptors and ligands bind, shifting the equilibrium towards the bound state.
  • $R + L \rightleftharpoons RL$
• Equilibrium is influenced by ligand concentration; excess ligand shifts the reaction towards receptor-ligand complex formation.
• Termination occurs via:
  • Ligand unbinding.
  • Enzymatic degradation.
  • Diffusion.
  • Reuptake.

Receptor Affinity

• Equilibrium state reflects ligand-receptor binding preferences.
• High-affinity receptors favor the bound state.
• $K_{eq}$ (Equilibrium Constant) indicates binding strength.
  • Higher $K_{eq}$ means higher binding affinity.
• High-affinity receptors signal more easily, leading to EPSPs.

Neurotransmitter Removal Mechanisms

• Termination occurs via enzymes, diffusion, or reuptake.
• Drugs can block enzymes or reuptake, increasing neurotransmitter levels.
• Example:
  • Treating Botox intoxication by blocking acetylcholinesterase to increase acetylcholine levels.

Excitatory and Inhibitory Postsynaptic Potentials (EPSPs and IPSPs)

• Neuromuscular Junction:
  • Specialized synapse; uses "excitatory end plate potential" (EPP) instead of EPSP.
  • EPP must exceed threshold voltage ($V_{threshold}$) to trigger a muscle action potential.
  • EPPs are typically larger than $V_{threshold}$.
  • Motor neuron releases acetylcholine, which binds to nicotinic acetylcholine ionotropic channels.

Nicotinic Acetylcholine Receptors

• Ionotropic channels permeable to both sodium ($Na^+$) and potassium ($K^+$).
  • Driving force favors sodium influx.
  • Triggers an EPP exceeding $V_{threshold}$, causing a muscle action potential.
• Motor end plate has sodium and potassium channels.
  • Reaching threshold triggers a muscle action potential.

Neuromuscular Junction Dynamics

• $Ca^{2+}$ influx through PQ-type channels in the alpha motor neuron triggers acetylcholine release.
• Blocking nicotinic acetylcholine receptors prevents EPPs and muscle action potentials.
  • Voltage-gated sodium channels will not open without sufficient depolarization.
• Blocking voltage-gated sodium channels (e.g., with TTX, a cone snail toxin) prevents action potentials.
• Blocking voltage-gated potassium channels can cause cell death or seizures.
  • Impairs repolarization and hyperpolarization phases.
  • Potassium leak channels provide some repolarization.

Acetylcholine Removal and Recycling

• Acetylcholine is primarily broken down by acetylcholinesterase into choline and acetate.
• Blocking acetylcholinesterase increases acetylcholine levels.
  • Drives the equilibrium towards acetylcholine binding to nicotinic acetylcholine receptors.
• Choline is recycled via a sodium-choline transporter.
  • Blocking this transporter reduces acetylcholine synthesis due to lack of precursors.

Strategies to Reduce Acetylcholine Release

• Blocking the sodium-choline transporter or choline acetyltransferase (ChAT) reduces acetylcholine production.
• Blocking the acetylcholine vesicle transporter prevents acetylcholine storage in vesicles.
  • Results in less acetylcholine release and diminished EPPs.

Quantal Release of Acetylcholine

• Acetylcholine is released in discrete packets (vesicles).
• EPP amplitude is a multiple of the mini EPP (quantal release).
• Each vesicle contains approximately 10,000 acetylcholine molecules.
• An EPP resulting from 300 vesicles involves $300 \times 10,000 = 3,000,000$ acetylcholine molecules.

Timing Considerations

• Slowest steps:
  • Calcium influx through PQ channels.
  • Vesicle docking and SNARE protein activation.
• Activation of nicotinic acetylcholine receptors and EPP initiation also take time.
• Diffusion across the cleft is relatively fast.
• Chemical synapses are the slowest step in electrochemical signaling.