Neurotransmitter

Chemical structure of D-aspartic acid, a common amino acid neurotransmitter.

A neurotransmitter is a chemical that relays information across the gap (synapse) between one neuron (nerve cell) and an adjacent neuron or muscle cell. The neurotransmitter is released by the axon terminal end of one neuron, in response to an electrical impulse, and travels across the microscopic synapse in milliseconds to the dendrites of the adjacent neuron, where it is recognized by a receptor site. The neurotransmitter either stimulates a continuation of the electrical impulse in the adjoining neuron or inhibites its continuation. Examples of neurotransmitters include acetylcholine, dopamine, serotonin, and nitric oxide.

Types

Neurotransmitters are used to relay, amplify, and modulate electrical signals between a neuron and another cell. According to the prevailing beliefs of the 1960s, a chemical can be classified as a neurotransmitter if it meets the following conditions:

• It is synthesized endogenously, that is, within the presynaptic neuron;
• It is available in sufficient quantity in the presynaptic neuron to exert an effect on the postsynaptic neuron;
• Externally administered, it must mimic the endogenously-released substance; and
• A biochemical mechanism for inactivation must be present.

However, there are other materials, such as the zinc ion, that are neither synthesized nor catabolized (i.e., degraded) and are considered neurotransmitters by some. Thus, the old definitions are being revised.

There are hundreds of known neurotransmitters. There are many different ways to classify these neurotransmitters. Often, dividing them into amino acids, peptides, and monoamines is sufficient for many purposes.

Some more precise divisions are as follows:

• Various "small-molecule neurotransmitters" are known:
  • acetylcholine
  • monoamines (norepinephrine, dopamine, and serotonin)
  • 3 or 4 amino acids, depending on exact definition used: (primarily glutamic acid, gamma aminobutyric acid, aspartic acid, and glycine)
  • Purines, (Adenosine, adenosine triphosphate or ATP, Guanosine triphosphate, and their derivatives)
  • Fatty acids are also receiving attention as the potential endogenous cannabinoid.
• Over 50 neuroactive peptides (vasopressin, somatostatin, neurotensin, etc.) have been found, among them hormones such as luteinizing hormone (LH) or insulin that have specific local actions in addition to their long-range signalling properties.
• Single ions, such as synaptically-released zinc, are also considered neurotransmitters by some.

The major "workhorse" neurotransmitters of the brain are glutamic acid (=glutamate) and amma-aminobutyric acid (GABA).

Discovery and mechanism of action

The structure of a typical neuron includes four main components (from left to right): dendrites, cell body (or soma), axon, and axon terminal.

Austrian scientist Otto Loewi discovered the first transmitter in 1921 during research with the vagus nerve of frog hearts (Chamberlin and Narins 2005). He named this chemical "vagusstoff" but it is now known as acetylcholine.

Most neurons are composed of four main components: a soma, or cell body, which contains the nucleus; one or more dendritic trees that typically receive input; an axon that carries an electric impulse; and an axon terminal that often functions to transmit signals to other cells.

Neurotransmitters are manufactured in a neuron's cell body. They are then transported to the axon terminal, where small-molecule neurotransmitter molecules are usually packaged in small, membrane-bound bags called vesicles. Nitric oxide is an exception, not being contained within a vesicle, but released from the neuron shortly after it is manufactured (Chamberlin and Narins 2005).

When an action potential travels to the synapse, the rapid depolarization causes calcium ion channels to open. Calcium then stimulates the transport of vesicles to the synaptic membrane; the vesicle and cell membrane fuse, leading to the release of the packaged neurotransmitter, a mechanism called exocytosis.

The neurotransmitters then diffuse across the synaptic cleft to bind to receptors on the dendrites of an adjacent neuron. A receptor is a transmembrane protein, with part of the protein on the inside surface of the neuron membrane, part on the outside surface, and the rest spanning the membrane (Chamberlin and Narins 2005). Receptors can bind to neurotransmitters, although not all neurotransmitters can bind to all receptors, as there is selectivity in the process. The receptors are broadly classified into ionotropic and metabotropic receptors. Ionotropic receptors are ligand-gated ion channels that open or close through neurotransmitter binding. Metabotropic receptors, which can have a diverse range of effects on a cell, transduct the signal by secondary messenger systems, or G-proteins.

Neuroactive peptides are usually packaged into dense-core vesicles and are released through a similar, but metabolically distinct, form of exocytosis used for small-molecule synaptic vesicles.

Post-synaptic effect

When a receptor recognizes a neurotransmitter it can result in either depolarization, a response that stimulates the release of the neurotransmitter from the terminal end of the neuron, thus continuing the electrical impulse, or it can result in hyperpolarization, which makes this release less likely (Chamberlin and Narins 2005).

A neurotransmitter's effect is determined by its receptor. For example, GABA can act on both rapid or slow inhibitory receptors (the GABA-A and GABA-B receptor respectively). Many other neurotransmitters, however, may have excitatory or inhibitory actions depending on which receptor they bind to.

Neurotransmitters, thus, may cause either excitatory or inhibitory post-synaptic potentials. That is, they may help the initiation of a nerve impulse in the receiving neuron, or they may discourage such an impulse by modifying the local membrane voltage potential. In the central nervous system, combined input from several synapses is usually required to trigger an action potential. Glutamate is the most prominent of excitatory transmitters; GABA and glycine are well-known inhibitory neurotransmitters.

Many neurotransmitters are removed from the synaptic cleft by neurotransmitter transporters in a process called reuptake (or often simply 'uptake'). Without reuptake, the molecules might continue to stimulate or inhibit the firing of the postsynaptic neuron. Cells termed astrocytes can remove neurotransmitters from the area. Some, such as norepinephrine, dopamine, and serotonin can be reabsorbed into the neuron's terminal region (Chamberlin and Narins 2005).

Another mechanism for removal of a neurotransmitter is digestion by an enzyme. For example, at cholinergic synapses (where acetylcholine is the neurotransmitter), the enzyme acetylcholinesterase breaks down the acetylcholine.

Neuroactive peptides are often removed from the cleft by diffusion, and eventually broken down by proteases.

Specificity

While some neurotransmitters (glutamate, GABA, glycine) are used very generally throughout the central nervous system, others can have more specific effects, such as on the autonomic nervous system (by both pathways in the sympathetic nervous system and the parasympathetic nervous system) and the action of others are regulated by distinct classes of nerve clusters that can be arranged in familiar pathways around the brain. For example, serotonin is released specifically by cells in the brainstem, in an area called the raphe nuclei, but travels around the brain along the medial forebrain bundle activating the cortex, hippocampus, thalamus, hypothalamus, and cerebellum. Also, it is released in the Caudal serotonin nuclei, so as to have effect on the spinal cord. In the peripherial nervous system (such as in the gut wall), serotonin regulates vascular tone. Dopamine classically modulates two systems: the brain's reward mechanism, and movement control.

Some neurotransmitter/neuromodulators like zinc not only can modulate the sensitivity of a receptor to other neurotransmitters (allosteric modulation) but can even penetrate specific, gated channels in post-synaptic neurons, thus entering the post-synaptic cells. This "translocation" is another mechanism by which synaptic transmitters can affect postsynaptic cells.

Diseases may affect specific neurotransmitter pathways. For example, Parkinson's disease is at least in part related to failure of dopaminergic cells in deep-brain nuclei, for example the substantia nigra. Treatments potentiating the effect of dopamine precursors have been proposed and effected, with moderate success.

Examples of neurotransmitter effects

Some examples of neurotransmitter action:

• Acetylcholine - voluntary movement of the muscles
• Norepinephrine - wakefulness or arousal
• Dopamine - voluntary movement and motivation, certain addictions
• Serotonin - memory, mood and emotions (anxiety, depression), wakefulness, sleep and temperature regulation
• GABA (gamma aminobutyric acid) - inhibition of motor neurons
• Glycine - spinal reflexes and motor behaviour
• Neuromodulators - sensory transmission, especially pain

It is important to appreciate that it is the receptor that dictates the neurotransmitter's effect.

Drugs targeting neurotransmitter systems

Various drugs either mimic the effects of naturally ocurring neurotransmitters or impact aspects of the system.

For example, heroin and codeine mimic the pain-regulating endorphins, filling their receptors to accomplish their effects (Chamberlin and Narins 2005). Caffeine consumption blocks the effect of adenosine, a transmitter that inhibits brain activity, and thus the consumer of caffeine experiences wakefullness (Chamberin and Narins 2005). Cocaine blocks the reuptake of dopamine, leaving these neurotransmitters in the synaptic gap longer. Prozac is a serotonin reuptake inhibitor, hence potentiating its effect. AMPT prevents the conversion of tyrosine to L-DOPA, the precursor to dopamine; reserpine prevents dopamine storage within vesicles; and deprenyl inhibits monoamine oxidase (MAO)-B and thus increases dopamine levels.

Common neurotransmitters

Category	Name	Abbreviation	Metabotropic	Ionotropic
Small: Amino acids	Aspartate		-	-
Small: Amino acids	Glutamate (glutamic acid)	Glu	Metabotropic glutamate receptor	NMDA receptor, Kainate receptor, AMPA receptor
Small: Amino acids	Gamma-aminobutyric acid	GABA	GABAB receptor	GABAA receptor, GABAC receptor
Small: Amino acids	Glycine	Gly	-	Glycine receptor
Small: Acetylcholine	Acetylcholine	Ach	Muscarinic acetylcholine receptor	Nicotinic acetylcholine receptor
Small: Monoamine (Phe/Tyr)	Dopamine	DA	Dopamine receptor	-
Small: Monoamine (Phe/Tyr)	Norepinephrine (noradrenaline)	NE	-	-
Small: Monoamine (Phe/Tyr)	Epinephrine (adrenaline)	Epi	-	-
Small: Monoamine (Phe/Tyr)	Octopamine		-	-
Small: Monoamine (Phe/Tyr)	Tyramine		-
Small: Monoamine (Trp)	Serotonin (5-hydroxytryptamine)	5-HT	Serotonin receptor, all but 5-HT3	5-HT3
Small: Monoamine (Trp)	Melatonin	Mel	Melatonin receptor	-
Small: Monoamine (His)	Histamine	H	Histamine receptor	-
PP: Gastrins	Gastrin		-	-
PP: Gastrins	Cholecystokinin	CCK	Cholecystokinin receptor	-
PP: Neurohypophyseals	Vasopressin		Vasopressin receptor	-
PP: Neurohypophyseals	Oxytocin		Oxytocin receptor	-
PP: Neurohypophyseals	Neurophysin I		-	-
PP: Neurohypophyseals	Neurophysin II		-	-
PP: Neuropeptide Y	Neuropeptide Y	NY	Neuropeptide Y receptor	-
PP: Neuropeptide Y	Pancreatic polypeptide	PP	-	-
PP: Neuropeptide Y	Peptide YY	PYY	-	-
PP: Opiods	Corticotropin (adrenocorticotropic hormone)	ACTH	Corticotropin receptor	-
PP: Opiods	Dynorphin		-	-
PP: Opiods	Endorphin		-	-
PP: Opiods	Enkephaline		-	-
PP: Secretins	Secretin		Secretin receptor	-
PP: Secretins	Motilin		Motilin receptor	-
PP: Secretins	Glucagon		Glucagon receptor	-
PP: Secretins	Vasoactive intestinal peptide	VIP	Vasoactive intestinal peptide receptor	-
PP: Secretins	Growth hormone-releasing factor	GRF	-	-
PP: Somtostatins	Somatostatin		Somatostatin receptor	-
SS: Tachykinins	Neurokinin A		-	-
SS: Tachykinins	Neurokinin B		-	-
SS: Tachykinins	Substance P		-	-
PP: Other	Bombesin		-	-
PP: Other	Gastrin releasing peptide	GRP	-	-
Gas	Nitric oxide	NO	-	-
Gas	Carbon monoxide	CO	-	-
Other	Anandamide		-	-
Other	Adenosine triphosphate	ATP	P2Y12	P2X receptor

See also

• Neuron
• Nervous system

References

ISBN links support NWE through referral fees

• Chamberlin, S. L., and B. Narins. 2005. The Gale Encyclopedia of Neurological Disorders. Detroit: Thomson Gale. ISBN 078769150X.
• Hucho, Ferdinand. 1993. Neurotransmitter Receptors. New Comprehensive Biochemistry, v. 24. Amsterdam [Netherlands]: Elsevier. ISBN 0444899030.
• King, M. W. 2006. Biochemistry of nerve transmission. Indiana University School of Medicine. Retrieved June 14, 2007.

External links

• Molecular Expressions Photo Gallery: The Neurotransmitter Collection. Retrieved June 14, 2007.
• Brain Neurotransmitters. Retrieved June 14, 2007.
• Endogenous Neuroactive Extracellular Signal Transducers. Retrieved June 14, 2007.

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