Neurotransmitter
| Structure of a typical chemical synapse |
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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 on the presynaptic side of a synapse, and are released into the synaptic cleft, where they bind to receptors in the membrane on the postsynaptic side of the synapse. 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.[2]
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[edit] 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 control 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.[3] 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.[4]
[edit] 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.
[edit] 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,[2] 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)
- 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[5], as are some gaseous molecules such as nitric oxide (NO) and carbon monoxide (CO). 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.[2] 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.
[edit] 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