The structure of nicotinic acetylcholine receptor channels is revealed through electron microscope images. This reconstruction shows the receptor-channel pore and the contours of its surrounding five subunits as they would be seen from the perspective of the synaptic cleft. (Reproduced, with permission, from Nigel Unwin.)
In Part II, we examined how electrical signals are initiated and propagated within an individual neuron. We now turn to synaptic transmission, the process by which one nerve cell communicates with another. An average neuron forms and receives 1,000 to 10,000 synaptic connections, and the human brain contains at least 1011 neurons. Thus 1014 to 1015 synaptic connections are formed in the brain. There are 1,000-fold more synapses in one brain than the 100 billion stars in our galaxy! Fortunately, only a few basic mechanisms underlie synaptic transmission at these many connections.
With some exceptions, the synapse consists of three components: (1) the terminals of the presynaptic axon, (2) a target on the postsynaptic cell, and (3) a zone of apposition. Based on the structure of the apposition, synapses are categorized into two major groups: electrical and chemical. At electrical synapses, the presynaptic terminal and the postsynaptic cell are in very close apposition at regions termed gap junctions. The current generated by an action potential in the presynaptic neuron directly enters the postsynaptic cell through specialized bridging channels called gap junction channels, which physically connect the cytoplasm of the presynaptic and postsynaptic cells. At chemical synapses, a cleft separates the two cells, and the cells do not communicate through bridging channels. Rather, an action potential in the presynaptic cell leads to the release of a chemical transmitter from the nerve terminal. The transmitter diffuses across the synaptic cleft and binds to receptor molecules on the postsynaptic membrane, which regulates the opening and closing of ion channels in the postsynaptic cell. This leads to changes in the membrane potential of the postsynaptic neuron that can either excite or inhibit the firing of an action potential.
Receptors for transmitters can be classified into two major groups depending on how they control ion channels in the postsynaptic cell. One type, the ionotropic receptor, is an ion channel that opens when the transmitter binds. The second type, the metabotropic receptor, acts indirectly on ion channels by activating a biochemical second-messenger cascade within the postsynaptic cell. Both types of receptors can result in excitation or inhibition. The sign of the signal depends not on the identity of the transmitter but on the properties of the receptor with which the transmitter interacts. A single transmitter can produce several distinct effects by activating different types of receptors. Thus, receptor diversity permits a relatively small number of transmitters to produce a wide variety of synaptic actions. Most transmitters are low-molecular-weight molecules, but certain peptides also can act as messengers at synapses. The methods of electrophysiology, biochemistry, and molecular biology have been used to characterize the receptors in postsynaptic cells that respond to these various chemical messengers. These methods have also clarified how second-messenger pathways transduce signals within cells.
In this part of the book, we consider synaptic transmission in its most elementary forms. We first compare and contrast the two major classes of synapses, chemical and electrical (see Chapter 8). We then focus on a model chemical synapse in the peripheral nervous system, the neuromuscular junction between a presynaptic motor neuron and postsynaptic skeletal muscle fiber (see Chapter 9). Next we examine the principles of chemical synapses between neurons in the central nervous system, focusing on the postsynaptic cell and its integration of thousands of synaptic signals from multiple presynaptic inputs, which involve both ionotropic receptor-mediated signals (see Chapter 10) as well as metabotropic receptor-mediated signals (see Chapter 11). We then turn to the presynaptic terminal and consider the mechanisms by which neurons release transmitter from their presynaptic terminals, how transmitter release can be regulated by neural activity (see Chapter 12), and the chemical nature of the neurotransmitters (see Chapter 13). Because the molecular architecture of chemical synapses is complex, many diseases can affect chemical synaptic transmission (see Chapter 14). One disorder that we consider in detail in this section is myasthenia gravis, a disease that disrupts transmission at synapses between spinal motor neurons and skeletal muscle. Analysis of abnormalities in synaptic transmission associated with human disease is important clinically. At the same time clinical studies have provided critical insight into mechanisms that underlie normal synaptic function.