Cholinergic Neuron

  • Cholinergic neurons secrete acetylcholine and are found in both the central and peripheral nervous system. In our current discussion we focus on their role in the Autonomic Nervous System (ANS) where cholinergic neurons account for all preganglionic autonomic neurons and all parasympathetic postganglionic neurons. We then discuss the synthesis of acetylcholine in these neurotransmitters and highlight loci of this synthetic pathway which are modulated by drugs.
  • Autonomic Nervous System
    • All preganglionic neurons in both the sympathetic and parasympathetic arms of the ANS are cholinergic. In terms of postganglionic fibers: All parasympathetic postganglionic neurons are cholinergic; however, only a small minority of sympathetic postganglionic neurons are cholinergic (those innervating sweat glands) whereas the rest are adrenergic.
  • Somatic Nervous System
    • Motorneurons that innervate skeletal muscle are cholinergic
  • Central Nervous System
    • Cholinergic neurons are critical for cognition, especially memory. In fact, Alzheimer Disease is thought to occur in part due to degeneration of central cholinergic fibers.
Synthesis and Neurotransmission
  • Overview
    • Acetylcholine is originally synthesized from choline found in the extracellular fluid. Intracellularly transported choline is then modified to acetylcholine which is packaged into vesicles and released following stimulation of the nerve terminal. Once released, synaptic Ach is rapidly degraded and recycled to prevent overstimulation of the post-synaptic membrane.
  • Transport
    • Choline is transported into the cytosol from the extracellular fluid via a membrane transporter. This transport step is the rate limiting step of the entire acetylcholine synthetic pathway and can be inhibited by Hemicholinium.
  • Synthesis
    • The cytosolic enzyme "Choline Acetyltransferase" (ChAT) uses acetyl-CoA to add an acetyl group to choline, thus generating acetylcholine.
  • Storage
    • Cytosolic acetylcholine is transported via a membrane transporter into preformed vesicles where it is stored until its release into the synapse
  • Release
    • When an action potential reaches the synapse an influx of calcium ions occurs which triggers the acetylcholine-laden vesicles to fuse to the pre-synaptic membrane and release their contents into the synaptic cleft.
    • The exotoxin of Clostridium botulinum, also known as Botulinum Toxin or Botox, is a protease which degrades a variety of proteins critical for fusing of these vesicles with the presynaptic membrane
  • Degradation
    • Once released, acetylcholine within the synapse is rapidly degraded by the synaptic enzyme acetylcholinesterase. This guarantees that the length of action of the acetylcholine is short, preventing overstimulation of the post-synaptic cell.
    • Inhibition of acetylcholinesterase by anticholinesterases results in an extended half-life of acetylcholine within the synapse and thus hyperactivation of cholinergic pathways.
  • Recycling
    • Degradation by acetylcholinesterase regenerates choline which can be re-transported back into the cytosol as described above.