Neurons synthesize and store specific chemicals called neurotransmitters which are released at the terminal following the arrival of an electrical impulse.
For example, acetylcholine 1 neurons synthesize acetylcholine by a series of enzymatic reactions that takes place in the neuron terminal. Acetylcholine is stored in the terminal in small sacs, or vesicles. When an electrical impulse originating in the cell body travels down the axon to the terminal, it triggers the release of acetylcholine from the vesicles into the space between neurons the synapse 2 Figure 5.
Acetylcholine neurons also innervate tissues such as muscles and other organs. When acetylcholine is released from the axon terminals, it binds to specific proteins called acetylcholine receptors 3 on neighboring neurons or on other types of cells, like muscles. In the case of a muscle, it causes muscle contraction; this occurs in smooth muscle, like the intestines and the bronchioles of the lung, and in skeletal muscle.
In sweat, salivary and tear glands, acetylcholine causes secretion. In the heart, acetylcholine slows conduction of electrical impulses and thus decreases the heart rate it can also increase heart rate indirectly via the sympathetic nervous system 5. In the brain, acetylcholine affects the firing rate of neurons and participates in memory and learning, motor control, and wakefulness.
So depending on the location of the acetylcholine receptors, acetylcholine has many actions throughout the body. Definitions: 1 a neurotransmitter stored in vesicles of nerve terminals; it is found in neurons within the central nervous system, the somatic nervous system, the parasympathetic nervous system and the sympathetic nervous system.
They are usually located on cell membranes and elicit a function once bound. As is the case for all nerve terminal proteins, CAT is produced in the cholinergic cell body and transported down the axon to the nerve endings. Both CAT and ACh may be found throughout the neuron, but their highest concentration is in axon terminals. The rate-limiting steps in ACh synthesis are the availability of choline and acetyl-CoA.
During increased neuronal activity the availability of acetyl-CoA from the mitochondria is upregulated as is the uptake of choline into the nerve ending from the synaptic cleft. As will be described later, the inactivation of ACh is converted by metabolism to choline and acetic acid.
Consequently much of the choline used for ACh synthesis comes from the recycling of choline from metabolized ACh. Another source is the breakdown of the phospholipid, phosphatidylcholine.
One of the strategies to increase ACh neurotransmission is the administration of choline in the diet. However, this has not been effective, probably because the administration of choline does not increase the availability of choline in the CNS. The majority of the ACh in nerve endings is contained in clear as viewed in the electron microscope um vesicles. A small amount is also free in the cytosol. Vesicle-bound ACh is not accessible to degradation by acetylcholinesterase see below.
The uptake of ACh into storage vesicle occurs through an energy-dependent pump that acidifies the vesicle. No useful pharmacological agents are available to modify cholinergic function through interaction with the storage of ACh. Interestingly, the gene for VAChT is contained on the first intron of the choline acetyltransferase gene. This proximity implies the two important cholinergic proteins are probably regulated coordinately. You will recall that the miniature endplate potentials and the quantal release in response to action potentials at the neuromuscular junction are due to the release of packets of ACh from individual storage vesicles Chapter 5.
Many toxins are known that interfere with these processes and are effective in preventing ACh secretion. The examples in Figure There are two broad classes of cholinergic receptors: nicotinic and muscarinic. This classification is based on two chemical agents that mimic the effects of ACh at the receptor site nicotine and muscarine.
ACh binds to the two a subunits. The bottom half shows the molecular structure of each a subunit of the nicotinic receptor based on cDNA derived amino acid sequence. A funnel-shaped internal ion channel is surrounded by the five subunits. Muscarinic receptors, classified as G protein coupled receptors GPCR , are located at parasympathetic autonomically innervated visceral organs, on the sweat glands and piloerector muscles and both post-synaptically and pre-synaptically in the CNS see Table I.
The muscarinic receptor is composed of a single polypeptide. Because each of these regions of the protein is markedly hydrophobic, they span the cell membrane seven times as depicted in Figure The fifth internal loop and the carboxyl-terminal tail of the polypeptide receptor are believed to be the site of the interaction of the muscarinic receptor with G proteins see right. The site of agonist binding is a circular pocket formed by the upper portions of the seven membrane-spanning regions.
ACh has excitatory actions at the neuromuscular junction, at autonomic ganglion, at certain glandular tissues and in the CNS. It has inhibitory actions at certain smooth muscles and at cardiac muscle. The biochemical responses to stimulation of muscarinic receptor involve the receptor occupancy causing an altered conformation of an associated GTP-binding protein G protein.
In response to the altered conformation of the muscarinic receptor, the a subunit of the G protein releases bound guanosine diphosphate GDP and simultaneously binds guanosine triphosphate GTP. This hydrolysis terminates the action of the G protein. The rate of hydrolysis of the GTP thus dictates the length of time the G protein remains activated. Inhibition of Adenylate Cyclase: The muscarinic receptor, through interaction with an inhibitory GTP-binding protein, acts to inhibit adenylyl cyclase.
Reduced cAMP production leads to reduced activation of cAMP-dependent protein kinase , reduced heart rate, and contraction strength. As shown in Figure The DAG activates protein kinase C not shown.
Cellular responses are influenced by PKC's phosphorylation of target proteins. This conductance increase increases the resting membrane potential in myocardial and other cell membranes leading to inhibition.
ACh binds only briefly to the pre- or postsynaptic receptors. Following dissociation from the receptor, the ACh is rapidly hydrolyzed by the enzyme acetylcholinesterase AChE as shown in Figure This enzyme has a very high catalysis rate, one of the highest known in biology. AChE is synthesized in the neuronal cell body and distributed throughout the neuron by axoplasmic transport. AChE exists as alternatively spliced isoforms that vary in their subunit composition.
The variation at the NMJ is a heteromeric protein composed of four subunits coupled to a collagen tail that anchors the multi-subunit enzyme to the cell membrane of the postsynaptic cell Figure This four-subunit form is held together by sulfhydryl bonds and the tail anchors the enzyme in the extracellular matrix at the NMJ.
Other isoforms are homomeric and freely soluble in the cytoplasm of the presynaptic cell. In addition, other cholinesterases exist throughout the body, which are also able to metabolize acetylcholine. These are termed pseudocholinesterases. Drugs that inhibit ACh breakdown are effective in altering cholinergic neurotransmission.
In fact, the irreversible inhibition of AChE by isopropylfluoroesters are so toxic that they can be incompatible with life—inhibiting the muscles for respiration. This inhibition is produced because ACh molecules accumulate in the synaptic space, keep the receptors occupied, and cause paralysis.
Two notable examples are insecticides and the gases used in biological warfare. The mechanism of action of these irreversible inhibitors of AChE is that they carbamylate the AChE, rendering it inactive. The carbamylation inactivates both the acetyl and choline binding domains.
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