Cellular Level
Acetylcholine derives from two constituents, choline, and an acetyl group, the latter derived from the coenzyme acetyl-CoA.[2] Choline is naturally present in foods such as egg yolks, liver, seeds of various vegetables, and legumes. Choline is also produced by the liver natively. Once choline is circulating in the plasma, it can readily cross the blood-brain barrier and be taken up by cholinergic nerve terminals via sodium-dependent uptake channels.[3][4] The rate-limiting step in acetylcholine production is the availability of acetate derived from mitochondrial acetyl-CoA and choline derived from the plasma directly and from reuptake from the synaptic cleft.
The synthesis of acetylcholine occurs in the terminal ends of axons. Choline acetyltransferase (CAT) is the enzyme that catalyzes the reaction of choline with acetyl-CoA to create a new molecule of acetylcholine. CAT is produced in the neuronal soma (body) and subsequently transported to the axon terminus via axoplasmic transport in which vesicles full of various proteins are “hitched” to actin filaments that span the length of the neuron for transport. Although localized mainly to the axon terminus, CAT is present throughout the neuron itself.[5][6]
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In the axon terminal, newly formed acetylcholine will be placed in vesicles with a minuscule number of free molecules still free in the cytosol. The vesicles are acidified via an energy-dependent pump (H-ATPase), which is utilized to create a gradient for acetylcholine to enter via vesicular acetylcholine transporter (VAChT), which exchanges one vesicular proton for one molecule of acetylcholine.[7]
The release of acetylcholine occurs when an action potential is relayed and reaches the axon terminus in which depolarization causes voltage-gated calcium channels to open and conduct an influx of calcium, which will allow the vesicles containing acetylcholine for release into the synaptic cleft. This release is highly dependent upon the SNARE protein system.[8][9] Synaptobrevin is often referred to as a “v” SNARE since it is in the vesicular membrane, and SNAP-25 along with syntaxin-1, often called “t” SNAREs since they are part of the presynaptic membrane, are different types of SNARE proteins that work together with calcium to perform vesicle membrane fusion and release. Importantly, synaptogamin is another vesicle-bound SNARE protein that will act as the calcium sensor for this system. Once the vesicle docks close enough to the presynaptic membrane, the cytosolic protein Munc18 will serve as an activating “clasp” that will attach synaptobrevin to SNAP-25 and syntaxin-1, bringing the vesicle and presynaptic membrane into close apposition as their free helical ends begin to twist around each other. The cytosolic protein complexin will then insert itself into this newly formed SNARE complex and prevent spontaneous fusion of the vesicle with the presynaptic membrane to prevent spontaneous fusion. When calcium is finally introduced into the cell after neuronal depolarization, it will bind synaptogamin and allow this molecule to bind to acidic phospholipids in the presynaptic membrane and displace the complexin molecules, which will then promote the fusion-block to be lifted. Only with the introduction of calcium into the cell can vesicular fusion to the presynaptic membrane be accomplished.[10] After completion of the fusion process, Ca-ATPase (PMCA) will pump calcium out of the neuron, and neuronal mitochondria will uptake calcium, both processes aiming to decrease intracellular calcium concentration. With the decrease in calcium, we see that synaptogamin will disassociate from the SNARE complex and that other SNARE proteins will be recruited to break down and recycle the constructed complex to get ready for the next round of vesicle fusion.[11] Once in the synaptic cleft, acetylcholine can bind either acetylcholine or muscarinic cholinergic receptors.
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There are two subtypes of nicotinic receptors, the muscular type (N1) and the neuronal type (N2). The muscular type is found specifically on the surface of muscle cells at the neuromuscular junction. The neuronal subtype is in the peripheral and central nervous systems. Specifically, N2 receptors are present in the adrenal medulla, on the postsynaptic cell bodies of neurons within the sympathetic and parasympathetic nervous systems, as well as in various locations in the brain such as the ventral tegmental area, hippocampus, prefrontal cortex, amygdala, and the nucleus accumbens.[12]
There are five different types of muscarinic receptors, M1, M2, M3, M4, and M5. All these subtypes are metabotropic receptors, contrasting them from the nicotinic type of acetylcholine receptors. Furthermore, each subtype is either stimulatory or inhibitory. Subtypes M1, M3, and M5 function through the phospholipase C second messenger pathway, while M2 and M4 function through a second messenger pathway that inhibits adenylate cyclase and prevents the formation of cAMP from ATP.[13] Generally, subtypes M1, M3, and M5 are stimulatory, and their G-alpha subunit of their GPCR will go on to activate downstream proteins while subtypes M2 and M4 are inhibitory with their G-alpha subunit going on to cause adenylate cyclase inhibition. All five subtypes of muscarinic receptors are present in the CNS, but M1-M4 can be found in a multitude of other organ systems as well. The M1 muscarinic receptor is in the cerebral cortex, salivary, and gastric glands. M2 receptors are present in smooth muscle as well as cardiac tissue. M3 receptors are in smooth muscle cells, particularly of the bronchioles, iris, bladder, and small intestines. M4 and M5 receptors have a less clear distribution but have been found in the hippocampus, substantia nigra, and other locations within the brain.[14][15]
Termination of acetylcholine action in the synaptic junction occurs when acetylcholine rapidly binds, then unbinds from its receptor in the target cell’s surface and gets subsequently cleaved by acetylcholinesterase into choline and acetate. Acetylcholinesterase is present in the synaptic cleft as a free molecule or GPI-linked protein on the surface of the postsynaptic cell surface.[16]
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