About Acetylcholine
Acetylcholine plays a major role in cognitive function and memory formation as well as motor control. It was the first neurotransmitter to be identified. Acetylcholine allows neurons to communicate with each other. This neurotransmitter is released by the axon terminals in response to a nerve impulse. In relation to motor function, the release of acetylcholine will cause a change in the muscle cell and elicit a contraction of the muscle, producing movement.
The synthesis, storage, and release of ACh follow a similar life cycle in all
cholinergic synapses, including those at skeletal neuromuscular junctions,
preganglionic sympathetic and parasympathetic terminals, postganglionic
parasympathetic varicosities, postganglionic sympathetic varicosities
innervating sweat glands in the skin, and in the CNS
The neurochemical events that underlie cholinergic neurotransmission are summarized in following figure. Two enzymes,
1. choline acetyltransferase and
2. AChE,
are involved in ACh synthesis and degradation, respectively.
synthesis, storage, and release of acetylcholine (ACh) and
receptors on which ACh acts
Choline Acetyltransferase. Choline acetyltransferase catalyzes the final step in the synthesis of ACh¾the acetylation of choline with acetyl coenzyme A (CoA)
Acetyl CoA for this reaction is derived from pyruvate via the multistep pyruvate dehydrogenase reaction or is synthesized by acetate thiokinase, which catalyzes the reaction of acetate with ATP to form an enzyme-bound acyladenylate (acetyl AMP). In the presence of CoA, transacetylation and synthesis of acetyl CoA proceed .
Choline acetyltransferase, like other protein constituents of the neuron, is synthesized within the perikaryon and then is transported along the length of the axon to its terminal. Axonal terminals contain a large number of mitochondria, where acetyl CoA is synthesized. Choline is taken up from the extracellular fluid into the axoplasm by active transport. The final step in the synthesis occurs within the cytoplasm, following which most of the ACh is sequestered within synaptic vesicles. Although moderately potent inhibitors of choline acetyltransferase exist, they have no therapeutic utility in part because the uptake of choline is the rate-limiting step in ACh biosynthesis.
Choline Transport. Transport of choline from the plasma into neurons is accomplished by distinct high- and low-affinity transport systems. The high-affinity system (Km = 1 to 5 mM) is unique to cholinergic neurons, is dependent on extracellular Na+, and is inhibited by hemicholinium. Plasma concentrations of choline approximate 10 mM; thus, the concentration of choline does not limit its availability to cholinergic neurons. Much of the choline formed from AChE-catalyzed hydrolysis of ACh is recycled into the nerve terminal. The cloning of the high-affinity choline transporter found in presynaptic terminals reveals a sequence and structure differing from those of other neurotransmitter transporters but similar to that of the Na+-dependent glucose transporter family
Storage of ACh. After its synthesis from choline, ACh is taken up by the storage vesicles principally at the nerve terminals. The vesicles are transported anterogradely from the cell body via the microtubules, with little ACh incorporation taking place during this process.
There appear to be two types of vesicles in cholinergic terminals: electron-lucent vesicles (40 to 50 nm in diameter) and dense-cored vesicles (80 to 150 nm). The core of the vesicles contains both ACh and ATP, at an estimated ratio of 10:1, which are dissolved in the fluid phase with metal ions (Ca2+ and Mg2+) and a proteoglycan called vesiculin. Vesiculin is negatively charged and is thought to sequester the Ca2+ or ACh. It is bound within the vesicle, with the protein moiety anchoring it to the vesicular membrane. In some cholinergic terminals there are peptides, such as VIP, that act as cotransmitters at some junctions. The peptides usually are located in the dense-cored vesicles. Vesicular membranes are rich in lipids, primarily cholesterol and phospholipids, as well as protein. The proteins include ATPase, which is ouabain-sensitive and thought to be involved in proton pumping and in vesicular inward transport of Ca2+. Other proteins include protein kinase (involved in phosphorylation mechanisms of Ca2+ uptake), calmodulin, atractyloside-binding protein (which acts as an ATP carrier), and synapsin (which is thought to be involved with exocytosis).
Release of Acetylcholine. Fatt and Katz recorded at the motor end plate of skeletal muscle and observed the random occurrence of small (0.1 to 3.0 mV) spontaneous depolarizations at a frequency of approximately 1 Hz. The magnitude of these mepps is considerably below the threshold required to fire a muscle action potential (AP); that they are due to the release of ACh is indicated by their enhancement by neostigmine (an anti-ChE agent) and their blockade by D -tubocurarine (a competitive antagonist that acts at nicotinic receptors). These results led to the hypothesis that ACh is released from motor nerve endings in constant amounts, or quanta. The likely morphological counterpart of quantal release was discovered shortly thereafter in the form of synaptic vesicles by De Robertis and Bennett. Most of the storage and release properties of ACh originally investigated in motor end plates apply to other fast-responding synapses. When an AP arrives at the motor nerve terminal, there is a synchronous release of 100 or more quanta (or vesicles) of ACh.
Acetylcholinesterase (AChE). For ACh to serve as a neurotransmitter in the motor system and at other neuronal synapses, it must be removed or inactivated within the time limits imposed by the response characteristics of the synapse. At the neuromuscular junction, immediate removal is required to prevent lateral diffusion and sequential activation of adjacent receptors. Modern biophysical methods have revealed that the time required for hydrolysis of ACh at the neuromuscular junction is less than a millisecond. The Km of AChE for ACh is approximately 50 to 100 mM. Choline has only 10-3 to 10-5 the potency of ACh at the neuromuscular junction.
Reference: Goodman-Gilman The Pharmacological Basis Of Therapeutics 11th edition
The neurochemical events that underlie cholinergic neurotransmission are summarized in following figure. Two enzymes,
1. choline acetyltransferase and
2. AChE,
are involved in ACh synthesis and degradation, respectively.
Choline Acetyltransferase. Choline acetyltransferase catalyzes the final step in the synthesis of ACh¾the acetylation of choline with acetyl coenzyme A (CoA)
Acetyl CoA for this reaction is derived from pyruvate via the multistep pyruvate dehydrogenase reaction or is synthesized by acetate thiokinase, which catalyzes the reaction of acetate with ATP to form an enzyme-bound acyladenylate (acetyl AMP). In the presence of CoA, transacetylation and synthesis of acetyl CoA proceed .
Choline acetyltransferase, like other protein constituents of the neuron, is synthesized within the perikaryon and then is transported along the length of the axon to its terminal. Axonal terminals contain a large number of mitochondria, where acetyl CoA is synthesized. Choline is taken up from the extracellular fluid into the axoplasm by active transport. The final step in the synthesis occurs within the cytoplasm, following which most of the ACh is sequestered within synaptic vesicles. Although moderately potent inhibitors of choline acetyltransferase exist, they have no therapeutic utility in part because the uptake of choline is the rate-limiting step in ACh biosynthesis.
Choline Transport. Transport of choline from the plasma into neurons is accomplished by distinct high- and low-affinity transport systems. The high-affinity system (Km = 1 to 5 mM) is unique to cholinergic neurons, is dependent on extracellular Na+, and is inhibited by hemicholinium. Plasma concentrations of choline approximate 10 mM; thus, the concentration of choline does not limit its availability to cholinergic neurons. Much of the choline formed from AChE-catalyzed hydrolysis of ACh is recycled into the nerve terminal. The cloning of the high-affinity choline transporter found in presynaptic terminals reveals a sequence and structure differing from those of other neurotransmitter transporters but similar to that of the Na+-dependent glucose transporter family
Storage of ACh. After its synthesis from choline, ACh is taken up by the storage vesicles principally at the nerve terminals. The vesicles are transported anterogradely from the cell body via the microtubules, with little ACh incorporation taking place during this process.
There appear to be two types of vesicles in cholinergic terminals: electron-lucent vesicles (40 to 50 nm in diameter) and dense-cored vesicles (80 to 150 nm). The core of the vesicles contains both ACh and ATP, at an estimated ratio of 10:1, which are dissolved in the fluid phase with metal ions (Ca2+ and Mg2+) and a proteoglycan called vesiculin. Vesiculin is negatively charged and is thought to sequester the Ca2+ or ACh. It is bound within the vesicle, with the protein moiety anchoring it to the vesicular membrane. In some cholinergic terminals there are peptides, such as VIP, that act as cotransmitters at some junctions. The peptides usually are located in the dense-cored vesicles. Vesicular membranes are rich in lipids, primarily cholesterol and phospholipids, as well as protein. The proteins include ATPase, which is ouabain-sensitive and thought to be involved in proton pumping and in vesicular inward transport of Ca2+. Other proteins include protein kinase (involved in phosphorylation mechanisms of Ca2+ uptake), calmodulin, atractyloside-binding protein (which acts as an ATP carrier), and synapsin (which is thought to be involved with exocytosis).
Release of Acetylcholine. Fatt and Katz recorded at the motor end plate of skeletal muscle and observed the random occurrence of small (0.1 to 3.0 mV) spontaneous depolarizations at a frequency of approximately 1 Hz. The magnitude of these mepps is considerably below the threshold required to fire a muscle action potential (AP); that they are due to the release of ACh is indicated by their enhancement by neostigmine (an anti-ChE agent) and their blockade by D -tubocurarine (a competitive antagonist that acts at nicotinic receptors). These results led to the hypothesis that ACh is released from motor nerve endings in constant amounts, or quanta. The likely morphological counterpart of quantal release was discovered shortly thereafter in the form of synaptic vesicles by De Robertis and Bennett. Most of the storage and release properties of ACh originally investigated in motor end plates apply to other fast-responding synapses. When an AP arrives at the motor nerve terminal, there is a synchronous release of 100 or more quanta (or vesicles) of ACh.
Acetylcholinesterase (AChE). For ACh to serve as a neurotransmitter in the motor system and at other neuronal synapses, it must be removed or inactivated within the time limits imposed by the response characteristics of the synapse. At the neuromuscular junction, immediate removal is required to prevent lateral diffusion and sequential activation of adjacent receptors. Modern biophysical methods have revealed that the time required for hydrolysis of ACh at the neuromuscular junction is less than a millisecond. The Km of AChE for ACh is approximately 50 to 100 mM. Choline has only 10-3 to 10-5 the potency of ACh at the neuromuscular junction.
Reference: Goodman-Gilman The Pharmacological Basis Of Therapeutics 11th edition