Acetylcholine

Acetylcholine (from Latin acetum = vinegar; Greek chole = bile), ACh for short, is a biogenic amine that plays a central role as a neurotransmitter in the autonomic nervous system. It controls vital functions such as breathing, blood pressure, heartbeat, digestion and metabolism. Curare, for example, which has become known as the poison of the arrow, clearly demonstrates the importance of acetylcholine: it blocks the acetylcholine receptors and thus blocks the entire peripheral nervous system.

Acetylcholine (ACh) is found both in the CNS and in the peripheral nervous system. Acetylcholine is formed by the enzyme choline acetyltransferase, an axoplasmic enzyme, from acetyl-CoA and choline. ACh is absorbed from the cytosol via a transporter integrated in the vesicle membrane into the neurosecretory storage vesicles of the motor nerve endings and stored. These storage vesicles contain 5,000 to 10,000 acetylcholine molecules. There are about 1 million storage vesicles per synapse.

During a nerve impulse ACh is released into the synaptic gap.

On the postsynaptic muscular endplate ACh activates the acetylcholine receptor (AChR), a glycoprotein with an MG of 300kDa. The receptor activation leads to the opening of an ion channel with depolarization of the motor endplate.

After binding to the acetylcholine receptor, ACh is rapidly cleaved by the enzyme acetylcholinesterase into choline and acetate, respectively, and thus inactivated. The enzyme acetylcholinesterase acts so efficiently and quickly that only a few acetylcholine molecules leave the synaptic cleft by diffusion. These molecules are then broken down by an unspecific cholinesterase (also known as buturylcholinesterase). This cholinesterase is produced in the liver, secreted by liver cells and is found ubiquitously dissolved in the extracellular fluid. This explains why acetylcholine, unlike norepinephrine, does not appear in circulating blood.

In addition, acetylcholine is found as a signalling substance in preganglionic sympathetic and in all parasympathetic neurons.

After γ-aminobutyric acid (GABA) and glycine, acetylcholine is one of the neurotransmitters most frequently found in the brain. Many cognitive processes are linked to acetylcholine as a messenger substance. In Alzheimer's disease there is a deficiency of acetylcholine due to the death of nerve cells that produce acetylcholine.

It seems to be proven that ACh plays a decisive role in learning processes. However, it is not clear whether acetylcholine also has an influence on the drive.

The effects of acetylcholine are mediated by 2 different receptor types:

• Muscarinic receptors
• nicotine receptors

Muscarinic receptors (named after an alkaloid of the fly agaric, Amanita muscaria): This type of receptor is a G-protein coupled receptor (metatropic receptors) that can be stimulated by the fungal toxin muscarin. Muscarinic receptors are also called "muscarinic acetylcholine receptors". Muscarinic receptors are divided into 5 subtypes (M1 - M5 receptors):

• M1 -receptors: They have exclusively neuronal functions
• M2 receptors: They are mainly found on heart muscle cells and on smooth muscle cells. On pacemaker cells of the right atrium, activation of this type of receptor leads to a shortening of the G1 protein-regulated action potential duration of the GIRGK channels and thus to a negatively inotropic effect.
• M3 receptors: They are mainly expressed on smooth muscle cells, exocrine gland cells and arterial vascular endothelia. Their presence on the vascular endothelium is a peculiarity in that vessels lack prasympathetic innervation.
• M4 receptors and M5 receptors: Their physiological significance is largely unknown. They are mainly expressed in the CNS.

Nicotine receptors: Nicotine receptors (nicotinic acetylcholine receptors) are receptors that can be stimulated by nicotine. The nicotine effect is mediated by this type of receptor. They are ion channel receptors. 2 subtypes of the nicotine receptor are known:

• NM-receptors: the index stands for "muscular type". They consist of several subunits (2 alpha1, one beta1, gamma, delta, epsilon subunit each) of which 5 always form the receptor channel. With this receptor type, the depolarization of the muscle cell proceeds slowly (end plate potential). An action potential of the muscle cell only occurs when the threshold potential for the fast, voltage-dependent Na+ channels is exceeded.
• NN receptors: the index stands for "neuronal type". There are numerous variants of these receptors, which are found in autonomous ganglia (transmission of excitation), in the adrenal medulla (nor-) adrenaline release and in the CNS (activation of the mesolimbic dopaminergic reward pathway, important role in thought and learning processes). These are ion channel receptors with high conductivity for Na+ and K+ ions.

In carotid sinus syndrome there is a malfunction between the carotid sinus located at the carotid bifurcation and the sinus node. Due to abnormal vagal function and hypersensitivity to acetylcholine, the hypersensitive baroreceptors located in the carotid sinus cause a slowing down of the polarization of the sinus node when stimulated (Gertsch 2008 / Gülker 1998).

Acetylcholine seems to play a pathogenetic role in certain forms of itching.

Parasympathomimetics: Parasympathomimetics are substances whose effect is caused by activation of muscarinic receptors. 2 substance classes are distinguished:

• Directly acting parasympathomimetics, which bind to the muscarinic receptor and activate it directly.
• Indirectly acting parasympathomimetics (cholinesterase inhibitors), which unfold their effect by increasing the synaptic acetylcholine concentration by inhibiting the breakdown of acetylcholine by inhibiting cholinesterase (see below cholinesterase inhibitors).

Direct acting parasympathomimetics: Clinically relevant are the substances carbachol, betanechol and pilocarpine. Carbachol, bethanechol are ester compounds of choline. Both substances cannot be broken down by cholinesterase. Pilocarpine is an alkaloid from South American plants and also cannot be broken down by cholinesterase. Carbachol is used in the treatment of acute glaucoma.

Indirectly acting parasympathomimetics (cholinesterase inhibitors): Some indirectly acting parasympathomimetics cause a temporary one and others cause an irreversible inhibition. Irreversible cholinesterase inhibitors are various organophosphoric acid esters, e.g. the insecticide parathion (E 605). Furthermore, the chemical warfare agents sarin and tabun, which in the smallest amounts cause a deadly overstimulation of the cholinergic synapses.

Botulinum toxin (the light chain of botulinum toxin is a zinc endopeptidase) blocks the exocytotic release of acetylcholine.

Acetylcholine and hornet stings: The proportion of acetylcholine in the venom of the hornet (Vespa crabro) is about five percent of the dry weight and is thus the highest concentration ever found in a living being. The hornet's sting is felt to be particularly painful due to this high concentration. The sting is no more toxic than that of other wasps or bees.

Acetylcholine and nettles: Well-known and feared are nettles because of the painful wheals (swelling) that develop in the skin after touching the stinging hairs. These stinging hairs are a protective mechanism against predators. The active ingredients of the stinging liquid are serotonin, histamine, acetylcholine and sodium formate.

The fresh plant juice of Urticae herba/folium contains acetylcholine as well as histamine, formic, acetic and butyric acid as well as other organic acids such as the rarely occurring caffeooleic acid; furthermore flavonoids, triterpenes, sterols (sterols), carotene, vitamin C and chlorophyll.

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