The summary provided will be further elaborated in subsequent sections. It is important to note that certain types of neurotransmitters, such as neuropeptides and gaseous neurotransmitters like nitric oxide, as well as the discovery of metabotropic receptors, have necessitated modifications to the basic understanding. Unlike ionotropic receptors, which typically contain the ion channel within themselves, metabotropic receptors are not associated with ion channels. Instead, they are coupled to G proteins that initiate second messenger cascades capable of influencing ion channels. The distinctions between classic and peptide transmitters are outlined in Table 6.1. More information on the properties of peptide and gaseous transmitters can be found in the relevant parts of this chapter, while metabotropic receptors are discussed in the Receptors section.

The entry of calcium serves as the signal for transmitter release. Depolarization of the presynaptic membrane caused by an action potential results in the opening of voltage-gated calcium channels. This enables calcium to enter the terminal and trigger transmitter release. However, calcium only enters the terminal if there is a favorable electrochemical gradient. The direction of ion flow through open channels is determined by the combination of concentration and voltage gradients. The extracellular concentration of calcium is higher compared to the intracellular concentration, favoring entry into the terminal. However, during the peak of the action potential, the membrane potential is positive, creating a voltage gradient that opposes the entry of calcium due to its positive charge. As a result, only a small amount of calcium enters the terminal at the peak of the action potential. While the membrane is highly permeable to calcium, the overall driving force is minimal. By using a voltage clamp, it is possible to experimentally set the membrane potential to be positive and equal to the Nernst equilibrium potential for calcium. In such cases, no calcium enters the terminal despite the calcium channels being open, resulting in no transmitter release and no postsynaptic response. This potential is referred to as the suppression potential. However, if the membrane potential is rapidly made negative again, either due to the end of the action potential or adjustment of the voltage clamp, calcium rushes into the terminal due to the large driving force that arises instantaneously upon repolarization. The high membrane permeability to calcium, which remains elevated as the calcium channels take several milliseconds to close in response to the new membrane potential, leads to transmitter release and a subsequent postsynaptic response.

The storage and release of neurotransmitters are fundamental aspects of synaptic transmission. These questions were initially addressed through two observations. The first observation involved the use of electron microscopy, which revealed the presence of small round or irregularly shaped organelles called synaptic vesicles in presynaptic terminals. The second observation was made through recordings of postsynaptic responses at the neuromuscular junction. Under normal conditions, an action potential in a motor neuron causes a significant depolarization in the postsynaptic muscle, known as an end plate potential (EPP). This EPP is analogous to an excitatory postsynaptic potential (EPSP) in a neuron. However, when the extracellular concentration of calcium is low, the amplitude of the EPP decreases. This reduction occurs because the presynaptic calcium current is reduced, leading to a smaller rise in intracellular calcium. The release of transmitter is proportional to the concentration of calcium. In this scenario, the EPP fluctuates among discrete values.
The succeeding sections will amplify specific points of this summary. However, it is worth mentioning at this point that some of the nonclassic types of neurotransmitters (e.g., neuropeptides and gaseous neurotransmitters such as nitric oxide) and the discovery of metabotropic receptors have required modifications of several aspects of this basic conception. (Whereas an ionotropic receptor usually contains the ion channel as an integral part of itself, a metabotropic receptor does not contain an ion channel but instead is coupled to a G protein that initiates second messenger cascades that can ultimately affect ion channels.) Some of the differences between classic and peptide transmitters are listed in
Table 6.1 . More details on the properties of peptide and gaseous transmitters are provided in the relevant parts of the section of this chapter, and metabotropic receptors are covered in the Receptors section.
Calcium Entry Is the Signal for Transmitter Release
Depolarization of the presynaptic membrane by the action potential causes voltage-gated Ca++ channels to open, which makes it possible for Ca++ to flow into the terminal and trigger the release of transmitter. However, Ca++ will enter the terminal only if there is a favorable electrochemical gradient to do so. Recall that it is the combination of the concentration and voltage gradients that determines the direction of ion flow through open channels. Extracellular [Ca++] is high relative to intracellular [Ca++], which favors entry into the terminal; however, during the peak of the action potential, the membrane potential is positive, and the voltage gradient opposes the entry of Ca++ because of its positive charge. Thus, at the peak of the action potential, relatively little Ca++ enters the terminal because although the membrane is highly permeable to Ca++ , the overall driving force is small. In fact, by using a voltage clamp, one can experimentally make the membrane potential positive and equal to the Nernst equilibrium potential for Ca++ . If this is done, no Ca++ will enter the terminal despite Ca++ channels being open, and as a result no transmitter is released and no postsynaptic response is observed. This voltage is known as the suppression potential. If the membrane potential is rapidly made negative again (because of either the end of the action potential or by adjusting the voltage clamp), Ca++ rushes into the terminal as a result of the large driving force (which arises instantaneously on repolarization) and the high membrane permeability to Ca++ (which remains high because it takes the Ca++ channels several milliseconds to close in response to the new membrane potential), thereby resulting in release of transmitter and a postsynaptic response (
Fig. 6.4 •Fig. 6.3 IPSPsandEPSPsrecordedwithamicroelectrodeinacatspinalmotorneuroninresponsetostimulationofappropriateperipheralafferentfibers.Fortytracesaresuperimposed.NotethattheseIPSPsarehyperpolarizing,butinsomecasesIPSPscanbedepolarizing—seetextforanexplanation.(RedrawnfromCurtisDR,EcclesJC.J Physiol 1959;145:529.)
Synaptic Vesicles and the Quantal Nature of Transmitter Release
How neurotransmitter is stored and how it is released are questions fundamental to synaptic transmission. Answering these questions began with two observations. The first was the discovery of small round or irregularly shaped organelles known as synaptic vesicles in presynaptic terminals by electron microscopy (see
Figs. 6.1B 6.2 ). The second observation came from recordings of postsynaptic responses at the neuromuscular junction. Normally an action potential in a motor neuron causes a large depolarization in the postsynaptic muscle, termed an end plate potential (EPP), which is equivalent to an EPSP in a neuron. However, under conditions of low extracellular [Ca++], the EPP amplitude is reduced (because the presynaptic Ca++ current is reduced, leading to a smaller rise in intracellular [Ca++], and transmitter release is proportional to [Ca++]). In this condition, the EPP is seen to fluctuate among discrete values (