同: neurotransmitters, defects in neurologic disease

WordNet

a neurochemical that transmits nerve impulses across a synapse

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/11/16 21:18:31」(JST)

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For an introduction to concepts and terminology used in this article, see Chemical synapse.

Neurotransmitters are endogenous chemicals that transmit signals from a neuron to a target cell across a synapse.^[1] Neurotransmitters are packaged into synaptic vesicles clustered beneath the membrane in the axon terminal, on the presynaptic side of a synapse. They are released into and diffuse across the synaptic cleft, where they bind to specific receptors in the membrane on the postsynaptic side of the synapse.^[2] Release of neurotransmitters usually follows arrival of an action potential at the synapse, but may also follow graded electrical potentials. Low level "baseline" release also occurs without electrical stimulation. Neurotransmitters are synthesized from plentiful and simple precursors, such as amino acids, which are readily available from the diet and which require only a small number of biosynthetic steps to convert.^[3]

1 Discovery
2 Identifying neurotransmitters
3 Types of neurotransmitters
- 3.1 Excitatory and inhibitory
4 Actions
5 Common neurotransmitters
6 Precursors of neurotransmitters
- 6.1 Dopamine precursors
- 6.2 Norepinephrine precursors
- 6.3 Serotonin precursors
7 Degradation and elimination
8 See also
9 References
10 External links

Discovery

Until the early 20th century, scientists assumed that the majority of synaptic communication in the brain was electrical. However, through the careful histological examinations of Ramón y Cajal (1852–1934), a 20 to 40 nm gap between neurons, known today as the synaptic cleft, was discovered. The presence of such a gap suggested communication via chemical messengers traversing the synaptic cleft, and in 1921 German pharmacologist Otto Loewi (1873–1961) confirmed that neurons can communicate by releasing chemicals. Through a series of experiments involving the vagus nerves of frogs, Loewi was able to manually slow the heart rate of frogs by controlling the amount of saline solution present around the vagus nerve. Upon completion of this experiment, Loewi asserted that sympathetic regulation of cardiac function can be mediated through changes in chemical concentrations. Furthermore, Otto Loewi is accredited with discovering acetylcholine (ACh)—the first known neurotransmitter.^[4] Some neurons do, however, communicate via electrical synapses through the use of gap junctions, which allow specific ions to pass directly from one cell to another.^[5]

Identifying neurotransmitters

The chemical identity of neurotransmitters is often difficult to determine experimentally. For example, it is easy using an electron microscope to recognize vesicles on the presynaptic side of a synapse, but it may not be easy to determine directly what chemical is packed into them. The difficulties led to many historical controversies over whether a given chemical was or was not clearly established as a transmitter. In an effort to give some structure to the arguments, neurochemists worked out a set of experimentally tractable rules. According to the prevailing beliefs of the 1960s, a chemical can be classified as a neurotransmitter if it meets the following conditions:

There are precursors and/or synthesis enzymes located in the presynaptic side of the synapse.
The chemical is present in the presynaptic element.
It is available in sufficient quantity in the presynaptic neuron to affect the postsynaptic neuron.
There are postsynaptic receptors and the chemical is able to bind to them.
A biochemical mechanism for inactivation is present.

Modern advances in pharmacology, genetics, and chemical neuroanatomy have greatly reduced the importance of these rules. A series of experiments that may have taken several years in the 1960s can now be done, with much better precision, in a few months. Thus, it is unusual nowadays for the identification of a chemical as a neurotransmitter to remain controversial for very long periods of time.

Types of neurotransmitters

There are many different ways to classify neurotransmitters. Dividing them into amino acids, peptides, and monoamines is sufficient for some classification purposes.

Major neurotransmitters:

Amino acids: glutamate,^[3] aspartate, D-serine, γ-aminobutyric acid (GABA), glycine
Monoamines and other biogenic amines: dopamine (DA), norepinephrine (noradrenaline; NE, NA), epinephrine (adrenaline), histamine, serotonin (SE, 5-HT)
Peptides: somatostatin, substance P, opioid peptides
Others: acetylcholine (ACh), adenosine, anandamide, nitric oxide, etc.

In addition, over 50 neuroactive peptides have been found, and new ones are discovered regularly. Many of these are "co-released" along with a small-molecule transmitter, but in some cases a peptide is the primary transmitter at a synapse. β-endorphin is a relatively well known example of a peptide neurotransmitter; it engages in highly specific interactions with opioid receptors in the central nervous system.

Single ions, such as synaptically released zinc, are also considered neurotransmitters by some,^[6] as are some gaseous molecules such as nitric oxide (NO), hydrogen sulfide (H₂S), and carbon monoxide (CO).^[7] These are not classical neurotransmitters by the strictest definition, however, because although they have all been shown experimentally to be released by presynaptic terminals in an activity-dependent way, they are not packaged into vesicles.

By far the most prevalent transmitter is glutamate, which is excitatory at well over 90% of the synapses in the human brain.^[3] The next most prevalent is GABA, which is inhibitory at more than 90% of the synapses that do not use glutamate. Even though other transmitters are used in far fewer synapses, they may be very important functionally—the great majority of psychoactive drugs exert their effects by altering the actions of some neurotransmitter systems, often acting through transmitters other than glutamate or GABA. Addictive drugs such as cocaine and amphetamine exert their effects primarily on the dopamine system. The addictive opiate drugs exert their effects primarily as functional analogs of opioid peptides, which, in turn, regulate dopamine levels.

Excitatory and inhibitory

Some neurotransmitters are commonly described as "excitatory" or "inhibitory". The only direct effect of a neurotransmitter is to activate one or more types of receptors. The effect on the postsynaptic cell depends, therefore, entirely on the properties of those receptors. It happens that for some neurotransmitters (for example, glutamate), the most important receptors all have excitatory effects: that is, they increase the probability that the target cell will fire an action potential. For other neurotransmitters, such as GABA, the most important receptors all have inhibitory effects (although there is evidence that GABA is excitatory during early brain development). There are, however, other neurotransmitters, such as acetylcholine, for which both excitatory and inhibitory receptors exist; and there are some types of receptors that activate complex metabolic pathways in the postsynaptic cell to produce effects that cannot appropriately be called either excitatory or inhibitory. Thus, it is an oversimplification to call a neurotransmitter excitatory or inhibitory—nevertheless it is so convenient to call glutamate excitatory and GABA inhibitory that this usage is seen very frequently.

Actions

Main article: Neuromodulation

As explained above, the only direct action of a neurotransmitter is to activate a receptor. Therefore, the effects of a neurotransmitter system depend on the connections of the neurons that use the transmitter, and the chemical properties of the receptors that the transmitter binds to.

Here are a few examples of important neurotransmitter actions:

Glutamate is used at the great majority of fast excitatory synapses in the brain and spinal cord. It is also used at most synapses that are "modifiable", i.e. capable of increasing or decreasing in strength. Modifiable synapses are thought to be the main memory-storage elements in the brain. Excessive glutamate release can lead to excitotoxicity causing cell death.
GABA is used at the great majority of fast inhibitory synapses in virtually every part of the brain. Many sedative/tranquilizing drugs act by enhancing the effects of GABA. Correspondingly glycine is the inhibitory transmitter in the spinal cord.
Acetylcholine is distinguished as the transmitter at the neuromuscular junction connecting motor nerves to muscles. The paralytic arrow-poison curare acts by blocking transmission at these synapses. Acetylcholine also operates in many regions of the brain, but using different types of receptors.
Dopamine has a number of important functions in the brain. It plays a critical role in the reward system, but dysfunction of the dopamine system is also implicated in Parkinson's disease and schizophrenia.
Serotonin is a monoamine neurotransmitter. Most is produced by and found in the intestine (approximately 90%), and the remainder in central nervous system neurons. It functions to regulate appetite, sleep, memory and learning, temperature, mood, behaviour, muscle contraction, and function of the cardiovascular system and endocrine system. It is speculated to have a role in depression, as some depressed patients are seen to have lower concentrations of metabolites of serotonin in their cerebrospinal fluid and brain tissue.^[8]
Substance P is an undecapeptide responsible for transmission of pain from certain sensory neurons to the central nervous system.

Neurons expressing certain types of neurotransmitters sometimes form distinct systems, where activation of the system affects large volumes of the brain, called volume transmission. Major neurotransmitter systems include the noradrenaline (norepinephrine) system, the dopamine system, the serotonin system and the cholinergic system.

Drugs targeting the neurotransmitter of such systems affect the whole system; this fact explains the complexity of action of some drugs. Cocaine, for example, blocks the reuptake of dopamine back into the presynaptic neuron, leaving the neurotransmitter molecules in the synaptic gap longer. Since the dopamine remains in the synapse longer, the neurotransmitter continues to bind to the receptors on the postsynaptic neuron, eliciting a pleasurable emotional response. Physical addiction to cocaine may result from prolonged exposure to excess dopamine in the synapses, which leads to the downregulation of some postsynaptic receptors. After the effects of the drug wear off, one might feel depressed because of the decreased probability of the neurotransmitter binding to a receptor. Prozac is a selective serotonin reuptake inhibitor (SSRI), which blocks re-uptake of serotonin by the presynaptic cell. This increases the amount of serotonin present at the synapse and allows it to remain there longer, hence potentiating the effect of naturally released serotonin.^[9] 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.

Diseases may affect specific neurotransmitter systems. 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.

A brief comparison of the major neurotransmitter systems follows:

Neurotransmitter systems
System	Origin ^[10]	Effects^[10]
Noradrenaline system	locus coeruleus	arousal reward
Noradrenaline system	Lateral tegmental field	arousal reward
Dopamine system	dopamine pathways: mesocortical pathway mesolimbic pathway nigrostriatal pathway tuberoinfundibular pathway	motor system, reward, cognition, endocrine, nausea
Serotonin system	caudal dorsal raphe nucleus	Increase (introversion), mood, satiety, body temperature and sleep, while decreasing nociception.
Serotonin system	rostral dorsal raphe nucleus
Cholinergic system	pontomesencephalotegmental complex	learning short-term memory arousal reward
	basal optic nucleus of Meynert
	medial septal nucleus

Common neurotransmitters

Category	Name	Abbreviation	Metabotropic	Ionotropic
Small: Amino acids	Aspartate		-	-
Neuropeptides	N-Acetylaspartylglutamate	NAAG	Metabotropic glutamate receptors; selective agonist of mGluR3	-
Small: Amino acids	Glutamate (glutamic acid)	Glu	Metabotropic glutamate receptor	NMDA receptor, Kainate receptor, AMPA receptor
Small: Amino acids	Gamma-aminobutyric acid	GABA	GABA_B receptor	GABA_A, GABA_A-ρ 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	Adrenergic receptor	-
Small: Monoamine (Phe/Tyr)	Epinephrine (adrenaline)	Epi	Adrenergic receptor	-
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: Diamine (His)	Histamine	H	Histamine receptor	-
PP: Gastrins	Gastrin		-	-
PP: Gastrins	Cholecystokinin	CCK	Cholecystokinin receptor	-
PP: Neurohypophyseals	Vasopressin	AVP	Vasopressin receptor	-
PP: Neurohypophyseals	Oxytocin	OT	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: Opioids	Corticotropin (adrenocorticotropic hormone)	ACTH	Corticotropin receptor	-
PP: Opioids	Dynorphin		-	-
PP: Opioids	Endorphin		-	-
PP: Opioids	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: Somatostatins	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	Soluble guanylyl cyclase	-
Gas	Carbon monoxide	CO	-	Heme bound to potassium channels
Other	Anandamide	AEA	Cannabinoid receptor	-
Other	Adenosine triphosphate	ATP	P2Y12	P2X receptor

Precursors of neurotransmitters

While intake of neurotransmitter precursors does increase neurotransmitter synthesis, evidence is mixed as to whether neurotransmitter release (firing) is increased. Even with increased neurotransmitter release, it is unclear whether this will result in a long-term increase in neurotransmitter signal strength, since the nervous system can adapt to changes such as increased neurotransmitter synthesis and may therefore maintain constant firing.^[11] Some neurotransmitters may have a role in depression, and there is some evidence to suggest that intake of precursors of these neurotransmitters may be useful in the treatment of mild and moderate depression.^[11]^[12]

Dopamine precursors

L-DOPA, a precursor of dopamine that crosses the blood–brain barrier, is used in the treatment of Parkinson's disease.

Norepinephrine precursors

For depressed patients where low activity of the neurotransmitter norepinephrine is implicated, there is only little evidence for benefit of neurotransmitter precursor administration. L-phenylalanine and L-tyrosine are both precursors for dopamine, norepinephrine, and epinephrine. These conversions require vitamin B6, vitamin C, and S-adenosylmethionine. A few studies suggest potential antidepressant effects of L-phenylalanine and L-tyrosine, but there is much room for further research in this area.^[11]

Serotonin precursors

Administration of L-tryptophan, a precursor for serotonin, is seen to double the production of serotonin in the brain. It is significantly more effective than a placebo in the treatment of mild and moderate depression.^[11] This conversion requires vitamin C.^[8] 5-hydroxytryptophan (5-HTP), also a precursor for serotonin, is also more effective than a placebo.^[11]

Degradation and elimination

A neurotransmitter must be broken down once it reaches the post-synaptic cell to prevent further excitatory or inhibitory signal transduction. For example, acetylcholine (ACh), an excitatory neurotransmitter, is broken down by acetylcholinesterase (AChE). Choline is taken up and recycled by the pre-synaptic neuron to synthesize more ACh. Other neurotransmitters such as dopamine are able to diffuse away from their targeted synaptic junctions and are eliminated from the body via the kidneys, or destroyed in the liver. Each neurotransmitter has very specific degradation pathways at regulatory points, which may be the target of the body's own regulatory system or recreational drugs.

References

^ "Neurotransmitter" at Dorland's Medical Dictionary
^ Elias, L. J, & Saucier, D. M. (2005). Neuropsychology: Clinical and Experimental Foundations. Boston: Pearson
^ ^a ^b ^c Robert Sapolsky (2005). "Biology and Human Behavior: The Neurological Origins of Individuality, 2nd edition". The Teaching Company. "see pages 13 & 14 of Guide Book"
^ Saladin, Kenneth S. Anatomy and Physiology: The Unity of Form and Function. McGraw Hill. 2009 ISBN 0-07-727620-5
^ "Junctions Between Cells". http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/J/Junctions.html. Retrieved 2010-11-22.
^ Kodirov,Sodikdjon A., Shuichi Takizawa, Jamie Joseph, Eric R. Kandel, Gleb P. Shumyatsky, and Vadim Y. Bolshakov. Synaptically released zinc gates long-term potentiation in fear conditioning pathways. PNAS, October 10, 2006. 103(41): 15218-23. doi:10.1073/pnas.0607131103
^ Nitric oxide and other gaseous neurotransmitters
^ ^a ^b University of Bristol. "Introduction to Serotonin". http://www.chm.bris.ac.uk/motm/serotonin/depression.htm. Retrieved 2009-10-15.
^ Yadav, V. et al (2008). "Lrp5 Controls Bone Formation by Inhibiting Serotonin Synthesis in the Duodenum". Cell 135 (5): 825–837. doi:10.1016/j.cell.2008.09.059. PMC 2614332. PMID 19041748. //www.ncbi.nlm.nih.gov/pmc/articles/PMC2614332/.
^ ^a ^b Rang, H. P. (2003). Pharmacology. Edinburgh: Churchill Livingstone. pp. 474 for noradrenaline system, page 476 for dopamine system, page 480 for serotonin system and page 483 for cholinergic system.. ISBN 0-443-07145-4.
^ ^a ^b ^c ^d ^e Meyers, Stephen (2000). "Use of Neurotransmitter Precursors for Treatment of Depression". Alternative Medicine Review 5 (1): 64–71. PMID 10696120. http://www.thorne.com/altmedrev/.fulltext/5/1/64.pdf.
^ Van Praag, HM (1981). "Management of depression with serotonin precursors". Biol Psychiatry 16 (3): 291–310. PMID 6164407.

External links

Wikimedia Commons has media related to: Neurotransmitter

Molecular Expressions Photo Gallery: The Neurotransmitter Collection
Brain Neurotransmitters
Endogenous Neuroactive Extracellular Signal Transducers
Neurotransmitter at the US National Library of Medicine Medical Subject Headings (MeSH)
neuroscience for kids website
brain explorer website
wikibooks cellular neurobiology

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Related Pictures

★リンクテーブル★

リンク元	「神経伝達物質」「ニューロトランスミッター」「neuromessenger」
拡張検索	「vesicular neurotransmitter transport protein」「neurotransmitter agent」「plasma membrane neurotransmitter transport protein」「neurotransmitter uptake inhibitor」「uptake inhibitor of neurotransmitter」

「神経伝達物質」

Structure of a typical chemical synapse
	Postsynaptic; density Voltage-; gated Ca++; channel Synaptic; vesicle Reuptake; pump Receptor Neurotransmitter Axon terminal Synaptic cleft Dendrite

　　[★]

英: neurotransmitter (SP)
同: ニューロトランスミッター、化学的伝達物質化学伝達物質 chemical transmitter、伝達物質 transmitter

概念

シナプス前ニューロンからシナプス後ニューロンへ興奮性もしくは抑制性の情報を伝える化学物質。

作用の方向で分類

興奮性

アセチルコリン

グルタミン酸

抑制性

GABA

グリシン

部位で分類

中枢神経	末梢神経
中枢神経	遠心性	求心性
グルタミン酸	アセチルコリン	サブスタンスP
GABA	ノルエピネフリン	CGRP
グリシン	(エピネフリン)
ドーパミン
エピネフリン
セロトニン
アセチルコリン
ヒスタミン
エンドルフィン
ノシセプチン