6/4/13

The Cholinergic Neuron

Neurotransmission at cholinergic neurons

Neurotransmission in cholinergic neurons involves sequential six steps. The first four—synthesis, storage, release, and binding of acetylcholine to a receptor—are followed by the fifth step, degradation of the neurotransmitter in the synaptic gap (that is, the space between the nerve endings and adjacent receptors located on nerves or effector organs), and the sixth step, the recycling of choline.




Figure : Synthesis and release of acetylcholine from the cholinergic neuron. AcCoA = acetyl coenzyme A.


1. Synthesis of acetylcholine: Choline is transported from the extra-cellular fluid into the cytoplasm of the cholinergic neuron by an energy-dependent carrier system that cotransports sodium and that can be inhibited by the drug hemicholinium.

[Note: Choline has a quaternary nitrogen and carries a permanent positive charge, and thus, cannot diffuse through the membrane.] The uptake of choline is the rate-limiting step in acetylcholine synthesis. Choline acetyltransferase catalyzes the reaction of choline with acetyl coenzyme A (CoA) to form acetylcholine—an ester—in the cytosol. Acetyl CoA is derived from the mitochondria and is produced by the Krebs cycle and fatty acid oxidation.


2. Storage of acetylcholine in vesicles: The acetylcholine is packaged into presynaptic vesicles by an active transport process coupled to the efflux of protons. The mature vesicle contains not only acetylcholine but also adenosine triphosphate (ATP) and proteoglycan. 

[Note: ATP has been suggested to be a cotransmitter acting at prejunctional purinergic receptors to inhibit the release of acetylcholine or norepinephrine.] Cotransmission from autonomic neurons is the rule rather than the exception. This means that most synaptic vesicles will contain the primary neurotransmitter, here acetylcholine, as well as a cotransmitter that will increase or decrease the effect of the primary neurotransmitter. The neurotransmitters in vesicles will appear as bead-like structures, known as varicosities, along the nerve terminal of the presynaptic neuron.


3. Release of acetylcholine: When an action potential propagated by the action of voltage-sensitive sodium channels arrives at a nerve ending, voltage-sensitive calcium channels on the presynaptic membrane open, causing an increase in the concentration of intracellular calcium. Elevated calcium levels promote the fusion of synaptic vesicles with the cell membrane and release of their contents into the synaptic space. This release can be blocked by botulinum toxin. In contrast, the toxin in black widow spider venom causes all the acetylcholine stored in synaptic vesicles to empty into the synaptic gap.


4. Binding to the receptor: Acetylcholine released from the synaptic vesicles diffuses across the synaptic space, and it binds to either of two postsynaptic receptors on the target cell or to presynaptic receptors in the membrane of the neuron that released the acetylcholine. The postsynaptic cholinergic receptors on the surface of the effector organs are divided into two classes—muscarinic and nicotinic.


Binding to a receptor leads to a biologic response within the cell, such as the initiation of a nerve impulse in a postganglionic fiber or activation of specific enzymes in effector cells as mediated by second-messenger molecules. 


5. Degradation of acetylcholine: The signal at the postjunctional effector site is rapidly terminated, because acetylcholinesterase cleaves acetylcholine to choline and acetate in the synaptic cleft.

[Note: Butyrylcholinesterase, sometimes called pseudocholinesterase, is found in the plasma, but it does not play a significant role in termination of acetylcholine's effect in the synapse


6. Recycling of choline: Choline may be recaptured by a sodium-coupled, high-affinity uptake system that transports the molecule back into the neuron, where it is acetylated into acetylcholine that is stored until released by a subsequent action potential.


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