A synapse is a site where information is transmitted from one cell to another. The information can be transmitted either electrically (electrical synapse) or via a chemical transmitter (chemical synapse).
Types of Synapses
Electrical synapses allow current to flow from one excitable cell to the next via low resistance pathways between the cells called gap junctions. Gap junctions are found in cardiac muscle and in some types of smooth muscle and account for the very fast conduction in these tissues. For example, rapid cell-to-cell conduction occurs in cardiac ventricular muscle, in the uterus, and in the bladder, allowing cells in these tissues to be activated simultaneously and ensuring that contraction occurs in a coordinated manner.
In chemical synapses, there is a gap between the presynaptic cell membrane and the postsynaptic cell membrane, known as the synaptic cleft. Information is transmitted across the synaptic cleft via a neurotransmitter, a substance that is released from the presynaptic terminal and binds to receptors on the postsynaptic terminal.
The following sequence of events occurs at chemical synapses: An action potential in the presynaptic cell causes Ca2+ channels to open. An influx of Ca2+ into the presynaptic terminal causes the neurotransmitter, which is stored in synaptic vesicles, to be released by exocytosis. The neurotransmitter diffuses across the synaptic cleft, binds to receptors on the postsynaptic membrane, and produces a change in membrane potential on the postsynaptic cell.
The change in membrane potential on the postsynaptic cell membrane can be either excitatory or inhibitory, depending on the nature of the neurotransmitter released from the presynaptic nerve terminal. If the neurotransmitter is excitatory, it causes depolarization of the postsynaptic cell; if the neurotransmitter is inhibitory, it causes hyperpolarization of the postsynaptic cell.
In contrast to electrical synapses, neurotransmission across chemical synapses is unidirectional (from presynaptic cell to postsynaptic cell). The synaptic delay is the time required for the multiple steps in chemical neurotransmission to occur.
Neuromuscular Junction—Example of a Chemical Synapse
Motoneurons are the nerves that innervate muscle fibers. A motor unit comprises a single motoneuron and the muscle fibers it innervates. Motor units vary considerably in size: A single motoneuron may activate a few muscle fibers or thousands of muscle fibers. Predictably, small motor units are involved in fine motor activities (e.g., facial expressions), and large motor units are involved in gross muscular activities (e.g., quadriceps muscles used in running).
Sequence of Events at the Neuromuscular Junction
The synapse between a motoneuron and a muscle fiber is called the neuromuscular junction (Fig. 1-16). An action potential in the motoneuron produces an action potential in the muscle fibers it innervates by the following sequence of events: The numbered steps correlate with the circled numbers in Figure 1-16.
Figure 1–16 Sequence of events in neuromuscular transmission. 1, Action potential travels down the motoneuron to the presynaptic terminal. 2, Depolarization of the presynaptic terminal opens Ca2+ channels, and Ca2+ flows into the terminal. 3, Acetylcholine (ACh) is extruded into the synapse by exocytosis. 4, ACh binds to its receptor on the motor end plate. 5, Channels for Na+ and K+ are opened in the motor end plate. 6, Depolarization of the motor end plate causes action potentials to be generated in the adjacent muscle tissue. 7, ACh is degraded to choline and acetate by acetylcholinesterase (AChE); choline is taken back into the presynaptic terminal on an Na+-choline cotransporter.
Video: Chemical synaptic transmission
1. Action potentials are propagated down the motoneuron, as described previously. Local currents depolarize each adjacent region to threshold. Finally, the presynaptic terminal is depolarized, and this depolarization causes voltage-gated Ca2+ channels in the presynaptic membrane to open.
2. When these Ca2+ channels open, the Ca2+ permeability of the presynaptic terminal increases, and Ca2+ flows into the terminal down its electrochemical gradient.
3. Ca2+ uptake into the terminal causes release of the neurotransmitter acetylcholine (ACh), which has been previously synthesized and stored in synaptic vesicles. To release ACh, the synaptic vesicles fuse with the plasma membrane and empty their contents into the synaptic cleft by exocytosis.
ACh is formed from acetyl coenzyme A (acetyl CoA) and choline by the action of the enzyme choline acetyltransferase (Fig. 1-17). ACh is stored in vesicles with ATP and proteoglycan for subsequent release. On stimulation, the entire content of a synaptic vesicle is released into the synaptic cleft. The smallest possible amount of ACh that can be released is the content of one synaptic vesicle (one quantum), and for this reason, the release of ACh is said to be quantal.
Figure 1–17 Synthesis and degradation of acetylcholine.
4. ACh diffuses across the synaptic cleft to the postsynaptic membrane. This specialized region of the muscle fiber is called the motor end plate, which contains nicotinic receptors for ACh. ACh binds to the α subunits of the nicotinic receptor and causes a conformational change. It is important to note that the nicotinic receptor for ACh is an example of a ligand-gated ion channel: It also is an Na+ and K+channel. When the conformational change occurs, the central core of the channel opens, and the permeability of the motor end plate to both Na+ and K+ increases.
5. When these channels open, both Na+ and K+ flow down their respective electrochemical gradients, Na+ moving into the end plate and K+ moving out, each ion attempting to drive the motor end plate potential to its equilibrium potential. Indeed, if there were no other ion channels in the motor end plate, the end plate would depolarize to a value about halfway between the equilibrium potentials for Na+ and K+, or approximately 0 mV. (In this case, zero is not a “magic number”—it simply happens to be the value about halfway between the two equilibrium potentials.) In practice, however, because other ion channels that influence membrane potential are present in the end plate, the motor end plate only depolarizes to about −50 mV, which is the end plate potential (EPP). The EPP is not an action potential but is simply a local depolarization of the specialized motor end plate.
The content of a single synaptic vesicle produces the smallest possible change in membrane potential of the motor end plate, the miniature end plate potential (MEPP). MEPPs summate to produce the full-fledged EPP. The spontaneous appearance of MEPPs proves the quantal nature of ACh release at the neuromuscular junction.
Each MEPP, which represents the content of one synaptic vesicle, depolarizes the motor end plate by about 0.4 mV. An EPP is a multiple of these 0.4 mV units of depolarization. How many such quanta are required to depolarize the motor end plate to the EPP? Because the motor end plate must be depolarized from its resting potential of −90 mV to the threshold potential of −50 mV, it must, therefore, depolarize by 40 mV. Depolarization by 40 mV requires 100 quanta (because each quantum or vesicle depolarizes the motor end plate by 0.4 mV).
6. Depolarization of the motor end plate (the EPP) then spreads by local currents to adjacent muscle fibers, which are depolarized to threshold and fire action potentials. Although the motor end plate itself cannot fire action potentials, it depolarizes sufficiently to initiate the process in the neighboring “regular” muscle cells. Action potentials are propagated down the muscle fiber by a continuation of this process.
7. The EPP at the motor end plate is terminated when ACh is degraded to choline and acetate by acetylcholinesterase (AChE) on the motor end plate. Approximately 50% of the choline is returned to the presynaptic terminal by Na+-choline cotransport, to be used again in the synthesis of new ACh.
Agents That Alter Neuromuscular Function
Several agents interfere with normal activity at the neuromuscular junction, and their mechanisms of action can be readily understood by considering the steps involved in neuromuscular transmission (Table 1-3; see Fig. 1-16).
Table 1–3 Agents Affecting Neuromuscular Transmission
ACh, Acetylcholine; AChE, acetylcholinesterase; EPP, end plate potential.
Botulinus toxin blocks the release of ACh from presynaptic terminals, causing total blockade of neuromuscular transmission, paralysis of skeletal muscle, and, eventually, death from respiratory failure.
Curare competes with ACh for the nicotinic receptors on the motor end plate, decreasing the size of the EPP. When administered in maximal doses, curare causes paralysis and death. D-Tubocurarine, a form of curare, is used therapeutically to cause relaxation of skeletal muscle during anesthesia. A related substance, α-bungarotoxin, binds irreversibly to ACh receptors. Binding of radioactive α-bungarotoxin has provided an experimental tool for measuring the density of ACh receptors on the motor end plate.
AChE inhibitors (anticholinesterases) such as neostigmine prevent degradation of ACh in the synaptic cleft, and they prolong and enhance the action of ACh at the motor end plate. AChE inhibitors can be used in the treatment of myasthenia gravis, a disease characterized by skeletal muscle weakness and fatigability, in which ACh receptors are blocked by antibodies (Box 1-4).
BOX 1–4 Clinical Physiology: Myasthenia Gravis
DESCRIPTION OF CASE. An 18-year-old college woman comes to the student health service complaining of progressive weakness. She reports that occasionally her eyelids “droop” and that she tires easily, even when completing ordinary daily tasks such as brushing her hair. She has fallen several times while climbing a flight of stairs. These symptoms improve with rest. The physician orders blood studies, which reveal elevated levels of antibodies to ACh receptors. Nerve stimulation studies show decreased responsiveness of skeletal muscle on repeated stimulation of motoneurons. The woman is diagnosed with myasthenia gravis and is treated with the drug pyridostigmine. After treatment, she reports a return of muscle strength.
EXPLANATION OF CASE. This young woman has classic myasthenia gravis. In the autoimmune form of the disease, antibodies are produced to ACh receptors on the motor end plates of skeletal muscle. Her symptoms of severe muscle weakness (eye muscles; arms and legs) are explainable by the presence of antibodies that block ACh receptors. Although ACh is released in normal amounts from the terminals of motoneurons, binding of ACh to its receptors on the motor end plates is impaired. Because ACh cannot bind, depolarization of the motor end plate (end plate potential, EPP) will not occur and normal action potentials cannot be generated in the skeletal muscle. Muscle weakness and fatigability ensue.
TREATMENT. Treatment of the patient with myasthenia gravis depends on a clear understanding of the physiology of the neuromuscular junction. Because this patient’s condition improved with the administration of pyridostigmine (a long-acting acetylcholinesterase [AChE] inhibitor), the success of the treatment confirmed the diagnosis of myasthenia gravis. AChE on the motor end plate normally degrades ACh (i.e., AChE terminates the action of ACh). By inhibiting the ACh-degradative enzyme with pyridostigmine, ACh levels in the neuromuscular junction are maintained at a high level, prolonging the time available for ACh to activate its receptors on the motor end plate. Thus, a more normal EPP in the muscle fiber can be produced even though many of the ACh receptors are blocked by antibodies.
Hemicholinium blocks choline reuptake into presynaptic terminals, thus depleting choline stores from the motoneuron terminal and decreasing the synthesis of ACh.
Types of Synaptic Arrangements
There are several types of relationships between the input to a synapse (the presynaptic element) and the output (the postsynaptic element): one-to-one, one-to-many, or many-to-one.
One-to-one synapses. The one-to-one synapse is illustrated by the neuromuscular junction (see Fig. 1-16). A single action potential in the presynaptic cell, the motoneuron, causes a single action potential in the postsynaptic cell, the muscle fiber.
One-to-many synapses. The one-to-many synapse is uncommon, but it is found, for example, at the synapses of motoneurons on Renshaw cells of the spinal cord. An action potential in the presynaptic cell, the motoneuron, causes a burst of action potentials in the postsynaptic cells. This arrangement causes amplification of activity.
Many-to-one synapses. The many-to-one synapse is a very common arrangement in the nervous system. In these synapses, an action potential in the presynaptic cell is insufficient to produce an action potential in the postsynaptic cell. Instead, many presynaptic cells converge on the postsynaptic cell, these inputs summate, and the sum of the inputs determines whether the postsynaptic cell will fire an action potential.
Synaptic Input—Excitatory and Inhibitory Postsynaptic Potentials
The many-to-one synaptic arrangement is a common configuration in which many presynaptic cells converge on a single postsynaptic cell, with the inputs being either excitatory or inhibitory. The postsynaptic cell integrates all the converging information, and if the sum of the inputs is sufficient to bring the postsynaptic cell to threshold, it will then fire an action potential.
Excitatory Postsynaptic Potentials
Excitatory postsynaptic potentials (EPSPs) are synaptic inputs that depolarize the postsynaptic cell, bringing the membrane potential closer to threshold and closer to firing an action potential. EPSPs are produced by opening Na+and K+ channels, similar to the nicotinic ACh receptor. The membrane potential is driven to a value approximately halfway between the equilibrium potentials for Na+ and K+, or 0 mV, which is a depolarized state. Excitatory neurotransmitters include ACh, norepinephrine, epinephrine, dopamine, glutamate, and serotonin.
Inhibitory Postsynaptic Potentials
Inhibitory postsynaptic potentials (IPSPs) are synaptic inputs that hyperpolarize the postsynaptic cell, taking the membrane potential away from threshold and farther from firing an action potential. IPSPs are produced by opening Cl− channels. The membrane potential is driven toward the Cl− equilibrium potential (approximately −90 mV), which is a hyperpolarized state. Inhibitory neurotransmitters are γ-aminobutyric acid (GABA) and glycine.
Integration of Synaptic Information
The presynaptic information that arrives at the synapse may be integrated in one of two ways, spatially or temporally.
Spatial summation occurs when two or more presynaptic inputs arrive at a postsynaptic cell simultaneously. If both inputs are excitatory, they will combine to produce greater depolarization than either input would produce separately. If one input is excitatory and the other is inhibitory, they will cancel each other out. Spatial summation may occur, even if the inputs are far apart on the nerve cell body, because EPSPs and IPSPs are conducted so rapidly over the cell membrane.
Temporal summation occurs when two presynaptic inputs arrive at the postsynaptic cell in rapid succession. Because the inputs overlap in time, they summate.
Other Phenomena That Alter Synaptic Activity
Facilitation, augmentation, and post-tetanic potentiation are phenomena that may occur at synapses. In each instance, repeated stimulation causes the response of the postsynaptic cell to be greater than expected. The common underlying mechanism is believed to be an increased release of neurotransmitter into the synapse, possibly caused by accumulation of Ca2+ in the presynaptic terminal. Long-term potentiation occurs in storage of memories and involves both increased release of neurotransmitter from presynaptic terminals and increased sensitivity of postsynaptic membranes to the transmitter.
Synaptic fatigue may occur where repeated stimulation produces a smaller than expected response in the postsynaptic cell, possibly resulting from the depletion of neurotransmitter stores from the presynaptic terminal.
The transmission of information at chemical synapses involves the release of a neurotransmitter from a presynaptic cell, diffusion across the synaptic cleft, and binding of the neurotransmitter to specific receptors on the postsynaptic membrane to produce a change in membrane potential.
The following criteria are used to formally designate a substance as a neurotransmitter: The substance must be synthesized in the presynaptic cell; the substance must be released by the presynaptic cell on stimulation; and, if the substance is applied exogenously to the postsynaptic membrane at physiologic concentration, the response of the postsynaptic cell must mimic the in vivo response.
Neurotransmitter substances can be grouped into the following categories: acetylcholine, biogenic amines, amino acids, and neuropeptides (Table 1-4).
Table 1–4 Classification of Neurotransmitter Substances
The role of acetylcholine (ACh) as a neurotransmitter is vitally important for several reasons. ACh is the only neurotransmitter that is utilized at the neuromuscular junction. It is the neurotransmitter released from all preganglionic and most postganglionic neurons in the parasympathetic nervous system and from all preganglionic neurons in the sympathetic nervous system. It is also the neurotransmitter that is released from presynaptic neurons of the adrenal medulla.
Figure 1-17 illustrates the synthetic and degradative pathways for ACh. In the presynaptic terminal, choline and acetyl CoA combine to form ACh, catalyzed by choline acetyltransferase. When ACh is released from the presynaptic nerve terminal, it diffuses to the postsynaptic membrane, where it binds to and activates nicotinic ACh receptors. AChE is present on the postsynaptic membrane, where it degrades ACh to choline and acetate. This degradation terminates the action of ACh at the postsynaptic membrane. Approximately one half of the choline that is released from the degradation of ACh is taken back into the presynaptic terminal to be reutilized for synthesis of new ACh.
Norepinephrine, Epinephrine, and Dopamine
Norepinephrine, epinephrine, and dopamine are members of the same family of biogenic amines: They share a common precursor, tyrosine, and a common biosynthetic pathway (Fig. 1-18). Tyrosine is converted to L-dopa by tyrosine hydroxylase, and L-dopa is converted to dopamine by dopa decarboxylase. If dopamine β-hydroxylase is present in small dense-core vesicles of the nerve terminal, dopamine is converted to norepinephrine. If phenylethanolamine-N- methyltransferase (PNMT) is present (with S- adenosylmethionine as the methyl donor), then norepinephrine is methylated to form epinephrine.
Figure 1–18 Synthesis and degradation of dopamine, norepinephrine, and epinephrine. COMT, Catechol-O-methyltransferase; MAO, monoamine oxidase.
The specific neurotransmitter secreted depends on which portion, or portions, of the enzymatic pathway are present in a particular type of nerve or gland. Thus, dopaminergic neurons secrete dopamine because the presynaptic nerve terminal contains tyrosine hydroxylase and dopa decarboxylase, but not the other enzymes. Adrenergic neurons secrete norepinephrine because they contain dopamine β-hydroxylase, in addition to tyrosine hydroxylase and dopa decarboxylase, but not PNMT. The adrenal medulla contains the complete enzymatic pathway; therefore, it secretes primarily epinephrine.
The degradation of dopamine, norepinephrine, and epinephrine to inactive substances occurs via two enzymes: catechol-O- methyltransferase (COMT) and monoamine oxidase (MAO). COMT, a methylating enzyme, is not found in nerve terminals, but it is distributed widely in other tissues including the liver. MAO is located in presynaptic nerve terminals and catalyzes oxidative deamination. If a neurotransmitter is to be degraded by MAO, there must be reuptake of the neurotransmitter from the synapse.
Each of the biogenic amines can be degraded by MAO alone, by COMT alone, or by both MAO and COMT (in any order). Thus, there are three possible degradative products from each neurotransmitter, and typically these products are excreted in the urine (see Fig. 1-18). The major metabolite of norepinephrine is normetanephrine. The major metabolite of epinephrine is metanephrine. Both norepinephrine and epinephrine are degraded to 3-methoxy-4-hydroxymandelic acid (VMA).
Serotonin, another biogenic amine, is produced from tryptophan in serotonergic neurons in the brain and in the gastrointestinal tract (Fig. 1-19). Following its release from presynaptic neurons, serotonin may be returned intact to the nerve terminal, or it may be degraded in the presynaptic terminal by MAO to 5-hydroxyindoleacetic acid. Additionally, serotonin serves as the precursor to melatonin in the pineal gland.
Figure 1–19 Synthesis and degradation of serotonin. MAO, Monoamine oxidase.
Histamine, a biogenic amine, is synthesized from histidine, catalyzed by histidine decarboxylase. It is present in neurons of the hypothalamus, as well as in nonneural tissue such as mast cells of the gastrointestinal tract.
Glutamate, an amino acid, is the major excitatory neurotransmitter in the central nervous system. It plays a significant role in the spinal cord and cerebellum. There are four subtypes of glutamate receptors. Three of the subtypes are ionotropic receptors, or ligand-gated ion channels including the NMDA (N-methyl-D-aspartate) receptor that is widely distributed throughout the central nervous system. A fourth subtype comprises metabotropic receptors, which are coupled via heterotrimeric guanosine triphosphate (GTP)–binding proteins (G proteins) to ion channels.
Glycine, an amino acid, is an inhibitory neurotransmitter that is found in the spinal cord and brain stem. Its mechanism of action is to increase Cl− conductance of the postsynaptic cell membrane. By increasing Cl− conductance, the membrane potential is driven closer to the Cl− equilibrium potential. Thus, the postsynaptic cell membrane is hyperpolarized or inhibited.
γ-Aminobutyric Acid (GABA)
γ-Aminobutyric acid (GABA) is an amino acid and an inhibitory neurotransmitter that is distributed widely in the central nervous system in GABAergic neurons. GABA is synthesized from glutamic acid, catalyzed by glutamic acid decarboxylase, an enzyme that is unique to GABAergic neurons (Fig. 1-20). Following its release from presynaptic nerves and its action at the postsynaptic cell membrane, GABA can be either recycled back to the presynaptic terminal or degraded by GABA transaminase to enter the citric acid cycle. Unlike the other amino acids that serve as neurotransmitters (e.g., glutamate and glycine), GABA does not have any metabolic functions (i.e., it is not incorporated into proteins).
Figure 1–20 Synthesis and degradation of γ-aminobutyric acid (GABA).
The two types of GABA receptors on postsynaptic membranes are the GABAA and the GABAB receptors. The GABAA receptor is directly linked to a Cl− channel and thus is ionotropic. When stimulated, it increases Cl−conductance and, thus, hyperpolarizes (inhibits) the postsynaptic cell. The GABAA receptor is the site of action of benzodiazepines and barbiturates in the central nervous system. The GABABreceptor is coupled via a G protein to a K+ channel and thus is metabotropic. When stimulated, it increases K+ conductance and hyperpolarizes the postsynaptic cell.
Huntington disease is associated with GABA deficiency. The disease is characterized by hyperkinetic choreiform movements related to a deficiency of GABA in the projections from the striatum to the globus pallidus. The characteristic uncontrolled movements are, in part, attributed to lack of GABA-dependent inhibition of neural pathways.
Nitric oxide (NO) is a short-acting inhibitory neurotransmitter in the gastrointestinal tract and the central nervous system. In presynaptic nerve terminals, the enzyme NO synthase converts arginine to citrulline and NO. Then, NO, a permeant gas, simply diffuses from the presynaptic terminal to its target cell (instead of the usual packaging of neurotransmitter in synaptic vesicles and release by exocytosis). In addition to serving as a neurotransmitter, NO also functions in signal transduction of guanylyl cyclase in a variety of tissues including vascular smooth muscle (see Chapter 4).
There is a long and growing list of neuropeptides that function as neuromodulators, neurohormones, and neurotransmitters (see Table 1-4 for a partial list).
Neuromodulators are substances that act on the presynaptic cell to alter the amount of neurotransmitter released in response to stimulation. Alternatively, a neuromodulator may be cosecreted with a neurotransmitter and alter the response of the postsynaptic cell to the neurotransmitter.
Neurohormones, like other hormones, are released from secretory cells (in these cases, neurons) into the blood to act at a distant site.
In several instances, neuropeptides are copackaged and cosecreted from presynaptic vesicles along with the classical neurotransmitters. For example, vasoactive intestinal peptide (VIP) is stored and secreted with ACh, particularly in neurons of the gastrointestinal tract. Somatostatin, enkephalin, and neurotensin are secreted with norepinephrine. Substance P is secreted with serotonin.
In contrast to classical neurotransmitters, which are synthesized in presynaptic nerve terminals, neuropeptides are synthesized in the nerve cell body. As occurs in all protein synthesis, the cell’s DNA is transcribed into specific messenger RNA, which is translated into polypeptides on the ribosomes. Typically, a preliminary polypeptide containing a signal peptide sequence is synthesized first. The signal peptide is removed in the endoplasmic reticulum, and the final peptide is delivered to secretory vesicles. The secretory vesicles are then moved rapidly down the nerve by axonal transport to the presynaptic terminal, where they become the synaptic vesicles.
Adenosine triphosphate (ATP) and adenosine function as neuromodulators in the autonomic and central nervous systems. For example, ATP is synthesized in the sympathetic neurons that innervate vascular smooth muscle. It is costored and cosecreted with the “regular” neurotransmitter of these neurons, norepinephrine. When stimulated, the neuron releases both ATP and norepinephrine and both transmitters cause contraction of the smooth muscle; in fact, the ATP-induced contraction precedes the norepinephrine-induced contraction.