Acetylcholine
Acetylcholine
Acetylcholine is a highly active neurotransmitter that diffuses across the synapse, the narrow gap between nerve cells, and plays an important role in connecting nerves to each other.
By the early 1900s, scientists had a reasonably clear idea of the anatomy of the nervous system. They knew that individual nerve cells—neurons— form the basis of that system. They also knew that neurological messages travel in minute electrical signals along the length of a neuron and then pass from the axons, which carry electrical impulses from the cell to the dendrites of another, which receive these impulses.
The mechanism by which the nerve message travels across the synapse between two adjacent neurons was unknown until British neurologist Thomas R. Elliott (1877–1961) suggested in 1903 that a chemical compound might carry the impulse. Elliott assumed that adrenalin might be this chemical messenger or neurotransmitter, as it is known today.
Nearly two decades passed before evidence confirming Elliott’s hypothesis was obtained. In 1921 German-American pharmacologist Otto Loewi (1873-1961) devised a way to test the idea. After earning his medical degree from the University of Strasbourg in 1896, Loewi then taught and did research in London, Vienna, and Graz, Austria. With the rise of Adolf Hitler (1889-1945), Loewi left Germany first for England and then emigrated to the United States in 1940, where he became a faculty member at the New York University College of Medicine.
In his 1921 experiment, Loewi found that when he stimulated the nerves attached to a frog’s heart, they secreted at least two chemical substances. One he thought was adrenalin, while the second he named vagusstoffe, after the vagus nerve, which branches into the heart.
Soon news of Loewi’s discovery reached other scientists in the field, among them English physiologist Henry Dale (1875-1968). Dale earned a medical degree from Cambridge in 1909. After a short academic career at St. Bartholomew’s Hospital in London and at University College London, he joined the physiological research laboratories at the pharmaceutical firm of Burroughs Wellcome. Except for the war years, Dale remained at Burroughs Wellcome until 1960. He died in Cambridge on July 23, 1968.
While attending a conference in Heidelberg in 1907, Dale became interested in the ergot fungus and the chemicals it secretes. By 1914, he had isolated a compound from ergot that produces effects on organs similar to those produced by nerves. He called the compound acetylcholine. When Dale heard of Loewi’s discovery of vagusstoffe seven years later, he suggested that it was identical to acetylcholine. For their discoveries, Loewi and Dale shared the 1936 Nobel Prize in physiology or medicine.
Unraveling the exact mechanism by which acetylcholine carries messages across the synapse has occupied countless neurologists since the Loewi-Dale discovery. Some of the most important work was done by Australian physiologist John Carew Eccles (1903–1997) and German-British physiologist Bernard Katz (1911–2003). Eccles developed a method for inserting microelectrodes into adjacent cells and then studying the chemical and physical changes that occur when a neurotransmitter passes through the synapse. Katz discovered that neurotransmitters like acetylcholine are released in tiny packages of a few thousand molecules. He also characterized the release of these packages in resting and active neurons. Eccles and Katz received Nobel Prizes in physiology or medicine in 1963 and 1970, respectively.
The biochemical action of acetylcholine is now well understood. Depending on its concentration, it exerts two different physiological effects. Injecting small amounts reduces blood pressure (by dilating blood vessels, or vasodilation), slows the heartbeat, and increases both smooth muscle contraction and exocrine gland secretions. These effects are collectively known as the “muscarinic effects” because they mimic those of the Amanita mushroom toxin muscarine. Acetylcholine levels rise with atropine administration, causing a rise in blood pressure similar to that produced by nicotine. This effect is therefore known as the “nicotinic effect” of acetylcholine.
See also Nerve impulses and conduction of impulses; Neuroscience.
Acetylcholine
Acetylcholine
Acetylcholine is a highly active neurotransmitter acting as a chemical connection between nerves (neu rons). Acetylcholine diffuses across the narrow gap between nerve cells, known as the synapse and thus, plays an important role in connecting nerves to each other.
By the early 1900s, scientists had a reasonably clear idea of the anatomy of the nervous system . They knew that individual nerve cells—neurons—formed the basis of that system. They also knew that nerve messages traveled in the form of minute electrical signals along the length of a neuron and then passed from the axon of one cell to the dendrites of a nearby cell.
One major problem remained, however, to understand the mechanism by which the nerve message travels across the narrow gap—the synapse—between two adjacent neurons. The British neurologist, Thomas R. Elliott (1877–1961), suggested in 1903 that the nerve message is carried from one cell to another by means of a chemical compound. Elliott assumed that adrenalin might be this chemical messenger or, neurotransmitter, as it is known today.
Nearly two decades passed before evidence relating to Elliott's hypothesis was obtained. Then, in 1921, the German-American pharmacologist, Otto Loewi (1873–1961), devised a method for testing the idea. Born in Frankfurt-am-Main, Germany, in 1873, Loewi received his medical degree from the University of Strasbourg in 1896 and then taught and did research in London, England, Vienna, Austria, and Graz, Austria. With the rise of Adolf Hitler (1889–1945), Loewi left Germany first for England and then, in 1940, the United States where he became a faculty member at the New York University College of Medicine.
In his 1921 experiment, Loewi found that when he stimulated the nerves attached to a frog's heart , they secreted at least two chemical substances. One substance he thought was adrenalin, while the second he named vagusstoffe, after the vagus nerve in the heart.
Soon news of Loewi's discovery reached other scientists in the field, among them the English physiologist Henry Dale (1875–1968). Dale earned a medical degree from Cambridge in 1909. After a short academic career at St. Bartholomew's Hospital in London and at University College, London, Dale joined the Physiological Research Laboratories at the pharmaceutical firm of Burroughs Wellcome. Except for the war years, Dale remained at Burroughs Wellcome until 1960. He died in Cambridge on July 23, 1968.
While attending a conference in Heidelberg, Germany, in 1907, Dale became interested in the fungus ergot and the chemicals it secretes. By 1914, Dale had isolated a compound from ergot that produces effects on organs similar to those produced by nerves. He called the compound acetylcholine. When Dale heard of Loewi's discovery of vagusstoffe seven years later, he suggested that it was identical to the acetylcholine he had discovered earlier. For their discoveries, Loewi and Dale shared the 1936 Nobel Prize for physiology or medicine.
Unraveling the exact mechanism by which acetylcholine carries messages across the synapse has occupied the energies of countless neurologists since the Loewi-Dale discovery. Some of the most important work has been done by the Australian physiologist, John Carew Eccles (1903–1997), and the German-British physiologist, Bernard Katz (1911-). Eccles developed a method for inserting microelectrodes into adjacent cells and then studying the chemical and physical changes that occur when a neurotransmitter passes through the synapse. Katz discovered that neurotransmitters like acetylcholine are released in tiny packages of a few thousand molecules each. He also characterized the release of these packages in resting and active neurons. For their work on neurotransmitters, Eccles and Katz each received a Nobel Prize for physiology or medicine in 1963 and 1970, respectively.
The biochemical action of acetylcholine is now well understood. Depending on its concentration , it exerts two different physiological effects. Injection of small amounts into a human patient produces a fall in blood pressure (due to the dilation of blood vessels, or vasodilation), slowing of the heartbeat, increased contraction of smooth muscle in many organs and copious secretion from exocrine glands . These effects are collectively known as the "muscarinic effects" of acetylcholine, as they parallel the physiological effects of the mushroom amanita toxin, Muscarin. The rise in acetylcholine following atropine administration causes a rise in blood pressure similar to that produced by nicotine . This effect is therefore known as the "nicotinic effect" of acetylcholine.
See also Nerve impulses and conduction of impulses; Neuroscience
acetylcholine
When a nerve action potential reaches and invades the nerve terminal, a shower of acetylcholine vesicles is released into the junction (synapse) between the nerve terminal and the ‘effector’ cell which the nerve activates. This may be another nerve cell or a muscle or gland cell. Thus electrical signals are converted to chemical signals, allowing messages to be passed between nerve cells or between nerve cells and non-nerve cells. This process is termed ‘chemical neurotransmission’ and was first demonstrated, for nerves to the heart, by the German pharmacologist Loewi in 1921. Chemical transmission involving acetylcholine is known as ‘cholinergic’.
Acetylcholine acts as a transmitter between motor nerves and the fibres of skeletal muscle at all neuromuscular junctions. At this type of synapse, the nerve terminal is closely apposed to the cell membrane of a muscle fibre at the so-called motor end plate. On release, acetylcholine acts almost instantly, to cause a sequence of chemical and physical events (starting with depolarization of the motor endplate) which cause contraction of the muscle fibre. This is exactly what is required for voluntary muscles in which a rapid response to a command is required. The action of acetylcholine is terminated rapidly, in around 10 milliseconds; an enzyme (cholinesterase) breaks the transmitter down into choline and an acetate ion. The choline is then available for re-uptake into the nerve terminal.
These same principles apply to cholinergic transmission at sites other than neuromuscular junctions, although the structure of the synapses differs. In the autonomic nervous system these include nerve-to-nerve synapses at the relay stations (ganglia) in both the sympathetic and the parasympathetic divisions, and the endings of parasympathetic nerve fibres on non-voluntary (smooth) muscle, the heart, and glandular cells; in response to activation of this nerve supply, smooth muscle contracts (notably in the gut), the frequency of heart beat is slowed, and glands secrete. Acetylcholine is also an important transmitter at many sites in the brain at nerve-to-nerve synapses.
To understand how acetylcholine brings about a variety of effects in different cells it is necessary to understand membrane receptors. In post-synaptic membranes (those of the cells on which the nerve fibres terminate) there are many different sorts of receptors and some are receptors for acetylcholine. These are protein molecules that react specifically with acetylcholine in a reversible fashion. It is the complex of receptor combined with acetylcholine which brings about a biophysical reaction, resulting in the response from the receptive cell. Two major types of acetylcholine receptors exist in the membranes of cells. The type in skeletal muscle is known as ‘nicotinic’; in glands, smooth muscle, and the heart they are ‘muscarinic’; and there are some of each type in the brain. These terms are used because nicotine mimics the action of acetylcholine at nicotinic receptors, whereas muscarine, an alkaloid from the mushroom Amanita muscaria, mimics the action of acetylcholine at the muscarinic receptors.
Alan W. Cuthbert
See also autonomic nervous system; neurotransmitters.
Acetylcholine
Acetylcholine
Acetylcholine is the neurotransmitter produced by neurons referred to as cholinergic neurons. In the peripheral nervous system acetylcholine plays a role in skeletal muscle movement, as well as in the regulation of smooth muscle and cardiac muscle. In the central nervous system acetylcholine is believed to be involved in learning, memory, and mood.
Acetylcholine is synthesized from choline and acetyl coenzyme A through the action of the enzyme choline acetyltransferase and becomes packaged into membrane-bound vesicles . After the arrival of a nerve signal at the termination of an axon, the vesicles fuse with the cell membrane, causing the release of acetylcholine into the synaptic cleft . For the nerve signal to continue, acetylcholine must diffuse to another nearby neuron or muscle cell, where it will bind and activate a receptor protein.
There are two main types of cholinergic receptors, nicotinic and muscarinic. Nicotinic receptors are located at synapses between two neurons and at synapses between neurons and skeletal muscle cells. Upon activation a nicotinic receptor acts as a channel for the movement of ions into and out of the neuron, directly resulting in depolarization of the neuron. Muscarinic receptors, located at the synapses of nerves with smooth or cardiac muscle, trigger a chain of chemical events referred to as signal transduction.
For a cholinergic neuron to receive another impulse, acetylcholine must be released from the receptor to which it has bound. This will only happen if the concentration of acetylcholine in the synaptic cleft is very low. Low synaptic concentrations of acetylcholine can be maintained via a hydrolysis reaction catalyzed by the enzyme acetylcholinesterase. This enzyme hydrolyzes acetylcholine into acetic acid and choline. If acetylcholinesterase activity is inhibited, the synaptic concentration of acetylcholine will remain higher than normal. If this inhibition is irreversible, as in the case of exposure to many nerve gases and some pesticides, sweating, bronchial constriction, convulsions, paralysis, and possibly death can occur. Although irreversible inhibition is dangerous, beneficial effects may be derived from transient (reversible) inhibition. Drugs that inhibit acetylcholinesterase in a reversible manner have been shown to improve memory in some people with Alzheimer's disease.
see also Neurotransmitters.
Jennifer L. Powers
Bibliography
Whittaker, V. (1990). "The Contribution of Drugs and Toxins to Understanding of Cholinergic Function." Trends in Physiological Sciences 11:8–13.
Internet Resources
Basic Neuropharmacology. "The Chemistry of the Nervous System." Available from <http://www.ptd.neu.edu/neuroanatomy/cyberclass>.
King, Michael W. "Biochemistry of Neurotransmitters." Available from <http://web.indstate.edu/thcme/mwking>.
Acetylcholine
ACETYLCHOLINE
Acetylcholine (ACh) is a major Neurotransmitter in the central and peripheral nervous systems. It is the ester of acetate and choline, formed by the enzyme choline acetyl transferase, from choline and acetyl-CoA. This was the first substance (ca. 1906) to meet the criteria of identification for a neurotransmitter. Later, acetylcholine was shown to be the general neurotransmitter for the neuromuscular junctions. In all vertebrate species, it is the major neurotransmitter for all autonomic ganglia and the neurotransmitter between parasympathetic ganglia and their target cells. Acetylcholine neurotransmission occurs widely within the central nervous system. Collections of Neurons arising within the brain—the medulla, the pons, or the anterior diencephalon—innervate a wide set of cortical and subcortical targets; some of these circuits are destroyed in Alzheimer's disease.
(See also: Scopolomine and Atropine )
BIBLIOGRAPHY
Cooper, J. R., Bloom, F. E., & Roth, R. H. (1996). The biochemical basis of neuropharmacology, 7th ed. New York: Oxford University Press.
Floyd Bloom
acetylcholine
acetylcholine
acetylcholine
a·ce·tyl·cho·line / əˌsētlˈkōˌlēn; ˌasitl-/ • n. Biochem. a compound that occurs throughout the nervous system, in which it functions as a neurotransmitter.