Synthesis of Acetylcholine | Nervous System | Animals

After reading this article we will learn about the synthesis of Acetylcholine (Ach).  

Acetylcholine (Ach) is the neurotransmitter at parasympathetic neuro-effector junctions, all autonomic ganglia, adrenal medulla, somatic neuromuscular junctions, and CNS. Synthesis, Storage and Release of Ach: Ach is synthesized in the cholinergic nerve endings.

After a reaction among acetate, coenzyme A and ATP, acetyl CoA is formed within the mitochondria and released into the cytoplasm. Choline enters into the axoplasm by active transport through the axonal membrane.

Choline acetyltransferase or choline acetylase, which is present in the axonal terminal, helps in acetylation of choline with acetyl CoA to form Ach. The transport of choline from the extracellular fluid into neuron is directly proportional to the concentration of extracellular Na⁺ and is inhibited by hemicholinium.

After synthesis, Ach is transported into the synaptic vesicles where it is stored till an action potential (AP) renders its release into the synaptic cleft by exocytosis. Vesamicol inhibits this transport and release systems.

When an action potential arrives at the motor or cholinergic nerve terminal, depo­larization of the area opens the voltage-gated Ca²⁺ channels on the axonal membrane, through which Ca²⁺ enters into the axoplasm and helps in fusion of vesicles with axonal membrane, resulting in extrution of a larger quantity of Ach.

The release of Ach can be inhibited by excess Mg²⁺, botulinus toxin, or procaine. Black widow spider venom’ causes release of excessive amounts of Ach followed by blockade of release.

Action and destruction of Ach:

To elicit a response, Ach binds with the available cholinergic receptors on the postsynaptic membrane. There are mainly two types of cholinergic receptors-nicotinic and muscarinic. These are again having subtypes like nicotinic N_m (on skeletal muscle cell) and N_n (neuronal) and muscarinic M₁, M₂, M₃, M₄ and M₅ receptors.

Nicotinic receptors are ligand-gated ion channels, having 5 subunits (α, α₁,β, γ and δ) surrounding the internal channel. Ach binds with α subunits of the receptor which leads to conformational change (opening of the channel) in receptor protein to form a pore in its axis. Na⁺ enters inside the cell through this channel and cause depolarization and excitation (contraction of skeletal muscle, firing of postganglionic neurons, or secretion of catecholamine from adrenal medulla).

M₁ receptors (neuronal) are excitatory in nature and found mainly in autonomic ganglia (produce late EPSP), CNS and gastric glands (for histamine and acid secre­tion). M₂ receptors (cardiac) exert inhibitory effects and predominate in heart (cause decrease in heart rate and force of contraction), and also on the presynaptic mem­branes of peripheral and central neurons (decrease NE release).

M₃ receptors produce excitatory responses and mainly present in smooth muscles (for contraction of bron­chial, GIT, uterine, and eye smooth muscles and relaxation of vascular smooth mus­cles) and glands (stimulate secretion of salivary, bronchial, lacrimal and sweat glands). M₄ receptors are also appeared to be found in smooth muscles and salivary glands. All five subtypes of muscarinic receptors are also located in CNS.

The basic functions of muscarinic receptors are mediated by the membrane bound G-proteins. The M₁, M₃ and M₅ receptors activate a G-protein (G q/11) which in term stimulates membrane bound phospholipase C (enzyme) activity resulting in hydrolysis of membranous phospholipids to form inositol triphosphate (IP₃) and diacylglycerol (DAG).

IP₃ causes release of Ca²⁺ from the endoplasmic reticulum into cytosol and Ca²⁺ mediated responses are thus produced (as contraction of smooth muscle and secretion of glands). DAG activates protein kinase C and Ca²⁺ for further response.

M₃ receptors, located on endothelial cells of blood vessels, stimulate nitric oxide (NO) (previously recognised as Endothelium dependent relaxing factor (EDRF)) release from the cells. NO then diffuses to the vascular smooth muscle to cause relaxation by stimulating cytosolic guanylyl cyclase enzyme.

M₂ and M₄ receptors interact with distinct group of G-proteins (Gi and Go) to inhibit the adenylyl cyclase, to activate receptor operated K⁺ channels (in heart), and to suppress the activity of voltage-gated Ca²⁺ channels in some cells. The former two effects are responsible for the negative chronotropic and ionotropic Reponses of Ach in the heart.

After release from the pre-junctional membrane (before or after binding with the receptors), Ach is rapidly hydrolysed by the enzyme cholinesterase to acetate and choline. Choline is reentered into the nerve endings and used for the synthesis of Ach.

Mainly two types of cholinesterases exist in the body:

(i) Aceylcholinesterase (AChE) or true cholinesterase and

(ii) Butyrylcholinesterase (BuChE) or Pseudo cholinesterase.

The former enzyme is distributed to all cholinergic junctions, RBC-and gray matter. The rate of ACh hydrolysis by AChE is very fast. It can also hydrolyse methacholine. Physotigmine has more selectivity for this enzyme. BuChE, present in plasma, liver, intestine and white matter, can slowly hydrolyse ACh but not methacholine. It is more selectively inhibited by organophosphorous Compounds.