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CHEMICAL SYNAPTIC TRANSMISSION can be divided into four steps: (1) synthesis and storage of a transmitter substance, (2) release of the transmitter, (3) interaction of the transmitter with receptors at the postsynaptic membrane, and (4) removal of the transmitter from the synapse. In the previous chapters, we considered steps 2 and 3. We now turn to the initial and final steps of chemical synaptic transmission: the synthesis and storage of transmitter molecules and their removal from the synaptic cleft after synaptic action.

A Chemical Messenger Must Meet Four Criteria to Be Considered a Neurotransmitter

Before considering the biochemical processes involved in synaptic transmission, it is important to make clear what is meant by a chemical transmitter. The concept is empirical and has changed over the years with increased understanding of synaptic transmission and a corresponding expansion of signaling agents. The concept that a released chemical could act as a transmitter was introduced by the British physician George Oliver and his colleague Edward Albert Schaefer, who in 1894 reported that injection of an adrenal gland extract increases blood pressure (Sir Henry Dale claimed that Oliver discovered this by injecting the extract into his own son). The constituent responsible was independently identified by three laboratories in 1897, and competing claims for priority provide one reason that this transmitter has 38 different names in the Merck Index, including adrenaline (as it was obtained from the adrenal gland) and epinephrine.

Experiments reported in 1904 by Thomas Elliott, a student in the lab of the physiologist John Langley, are generally credited as the first report of chemical neurotransmission. Elliott concluded that “adrenaline might then be the chemical stimulant liberated on each occasion when the impulse arrives at the periphery.” Not incidentally, Elliott also proposed as early as 1914 that nerves could accumulate transmitter by an uptake system, suggesting that adrenal gland signaling might “depend on what could be picked up from the circulating blood and stored in its nerve endings,” although uptake mechanisms were not demonstrated until more than 40 years later.

In 1913, Arthur Ewins, working with Henry Dale, discovered acetylcholine (ACh) as a component of the ergot fungus. In 1921, Otto Loewi demonstrated that stimulation of the vagus nerve terminals in frog hearts released “vagustoff,” which was later shown to be ACh. Dale and Loewi later shared the Nobel Prize in 1946. The terms cholinergic and adrenergic were introduced to indicate that a neuron makes and releases ACh or norepinephrine (or epinephrine), respectively, the two substances first recognized as neurotransmitters. The term catecholaminergic, encompassing dopamine and the adrenergic transmitters, was derived from one of many natural sources, the catechu tree of India. Since that time, many other substances have been identified as transmitters.

The first secretory vesicles shown to accumulate and release neurotransmitters were the chromaffin vesicles of the adrenal gland, named in 1902 by ...

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