describe the structure of a cholinergic synapse and explain how it functions, including the role of calcium ions

Control and Coordination in Mammals – Cholinergic Synapse (Neuromuscular Junction)

1. Big‑picture overview

The neuromuscular junction (NMJ) is a specialised chemical synapse that links a somatic motor neurone (part of the peripheral nervous system) to a skeletal‑muscle fibre. It forms the final link in the reflex arc and in voluntary movement, converting an electrical impulse in the neurone into a mechanical contraction of the muscle.

2. Types of synapse required by the Cambridge syllabus

3. Action‑potential generation & propagation (prerequisite for release)

• Resting membrane potential ≈ –70 mV (high K⁺ permeability, Na⁺/K⁺‑ATPase).
• Depolarisation opens voltage‑gated Na⁺ channels → rapid Na⁺ influx → upstroke of the AP.
• Na⁺‑channel inactivation + opening of voltage‑gated K⁺ channels → repolarisation.
• Absolute and relative refractory periods limit firing frequency.
• The AP travels down the motor‑neuron axon to the presynaptic terminal, where it triggers Ca²⁺ entry.

4. Structure of a cholinergic synapse (NMJ)

• Presynaptic terminal

  • Synaptic vesicles densely packed with acetylcholine.
  • Voltage‑gated Ca²⁺ channels (P/Q‑type, N‑type).
  • Mitochondria – supply ATP for vesicle cycling and ACh synthesis.
  • Choline transporter (CHT) in the plasma membrane.

• Synaptic cleft

  • ≈ 20 nm wide extracellular space.
  • Basal lamina containing collagen‑like proteins and the enzyme acetylcholinesterase (AChE).

• Postsynaptic membrane (motor end‑plate)

  • Deep folds increase surface area for receptors.
  • High density of nicotinic ACh receptors (nAChR) – ligand‑gated Na⁺/K⁺ channels.
  • Voltage‑gated Na⁺ channels just beneath the folds to generate the muscle action potential.

5. Synthesis, storage, release and inactivation of ACh

• Synthesis – In the presynaptic cytoplasm, choline (taken up from the cleft) combines with acetyl‑CoA in a reaction catalysed by choline acetyl‑transferase (ChAT). The reaction requires ATP for the formation of acetyl‑CoA.
• Storage – ACh is packaged into synaptic vesicles by the vesicular ACh transporter (VAChT), using a proton gradient generated by a V‑type ATPase.
• Release – Triggered by the Ca²⁺ surge described below (exocytosis).
• Inactivation – AChE in the cleft hydrolyses ACh to choline + acetate within < 1 ms, terminating the signal.
• Re‑uptake – Choline is recaptured by the high‑affinity choline transporter (CHT) and recycled into new ACh.

6. Functional sequence of a cholinergic synapse

1. Action potential reaches the presynaptic terminal and depolarises the membrane.
2. Voltage‑gated Ca²⁺ channels open → Ca²⁺ influx (extracellular ≈ 1–2 mM, intracellular ≈ 0.1 µM).
3. Local [Ca²⁺] rises to >10 µM; Ca²⁺ binds to synaptotagmin.
4. Synaptotagmin‑Ca²⁺ complex interacts with the SNARE proteins (syntaxin, SNAP‑25, synaptobrevin) pulling the vesicle membrane into close apposition with the plasma membrane → exocytosis of ACh.
5. ACh diffuses across the ~20 nm cleft and binds to nAChRs on the motor end‑plate.
6. nAChR channels open, allowing Na⁺ influx (and a small K⁺ efflux) → end‑plate potential (EPP).
7. If the EPP reaches threshold (≈ –55 mV), voltage‑gated Na⁺ channels open, producing a muscle action potential that propagates along the sarcolemma and triggers contraction.
8. AChE hydrolyses remaining ACh, terminating the signal.
9. Choline is taken up by CHT, re‑esterified with acetyl‑CoA by ChAT, and vesicles are refilled.

7. Role of calcium ions (Ca²⁺) – the molecular switch

• Entry point – Voltage‑gated Ca²⁺ channels open only when the presynaptic membrane is depolarised.
• Driving force – Extracellular [Ca²⁺] ≈ 1–2 mM, intracellular ≈ 0.1 µM; the steep gradient produces a massive inward flux.
• Sensor mechanism – Ca²⁺ binds to synaptotagmin; the Ca²⁺‑synaptotagmin complex activates the SNARE complex, pulling vesicle and plasma membranes together.
• Temporal precision – Ca²⁺ concentration rises in ≈ 0.5 ms and decays in < 2 ms, ensuring that each presynaptic AP releases a discrete packet of ACh.
• Regulation – Intracellular Ca²⁺ buffers (e.g., calbindin) and Ca²⁺‑ATPases (PMCA, SERCA) restore basal levels, preventing uncontrolled release.

8. Key molecules and their functions

9. Nernst equation for Ca²⁺ (useful for understanding driving force)

\(E{Ca}= \dfrac{RT}{zF}\ln\!\left(\dfrac{[Ca^{2+}]{\text{outside}}}{[Ca^{2+}]_{\text{inside}}}\right)\)

• R = 8.314 J mol⁻¹ K⁻¹ (gas constant)
• T ≈ 310 K (37 °C)
• z = +2 (charge of Ca²⁺)
• F = 96 485 C mol⁻¹ (Faraday’s constant)
• With typical concentrations the equilibrium potential is ≈ +120 mV, giving a strong inward driving force when Ca²⁺ channels open.

10. Suggested diagram

11. Summary

The cholinergic synapse at the NMJ exemplifies how structure underpins function in the nervous system. An arriving action potential opens voltage‑gated Ca²⁺ channels; the resulting Ca²⁺ surge triggers the SNARE‑mediated exocytosis of ACh. ACh binds to nicotinic receptors, producing a rapid Na⁺ influx that generates an end‑plate potential. When this depolarisation reaches threshold, voltage‑gated Na⁺ channels fire a muscle action potential, leading to contraction. Calcium ions act as the indispensable “molecular switch” that couples electrical activity to chemical transmission, allowing the high‑speed, high‑fidelity signalling required for precise motor control.