Keywords
biogenic amines, chemical synapse, receptors, synaptic vesicle, neurotransmitter termination, ionotropic, metabotropic, glutamate, GABA, gap junction
Chapter Outline
There Are Five Steps in Conventional Chemical Synaptic Transmission, 44
Neurotransmitters Are Synthesized in Presynaptic Endings and in Neuronal Cell Bodies, 44
Neurotransmitters Are Packaged Into Synaptic Vesicles Before Release, 44
Presynaptic Endings Release Neurotransmitters Into the Synaptic Cleft, 44
Neurotransmitters Diffuse Across the Synaptic Cleft and Bind to Postsynaptic Receptors, 45
Neurotransmitter Action Is Terminated by Uptake, Degradation, or Diffusion, 45
Synaptic Transmission Can Be Rapid and Point-to-Point, or Slow and Often Diffuse, 46
Rapid Synaptic Transmission Involves Transmitter-Gated Ion Channels, 46
Slow Synaptic Transmission Usually Involves Postsynaptic Receptors Linked to G Proteins, 46
The Postsynaptic Receptor Determines the Effect of a Neurotransmitter, 47
The Size and Location of a Synaptic Ending Influence the Magnitude of Its Effects, 47
Synaptic Strength Can Be Facilitated or Depressed, 47
Medications and Toxins Can Have an Influence on the Amount of Neurotransmitter Released, 47
Messages Also Travel Across Synapses in a Retrograde Direction, 47
Most Neurotransmitters Are Small Amine Molecules, Amino Acids, or Neuropeptides, 47
Gap Junctions Mediate Direct Current Flow From One Neuron to Another, 48
In contrast to the way in which information travels within individual neurons as electrical signals, information is usually transmitted between neurons through the release of neurotransmitters at specialized junctions called synapses . And in contrast to unvarying, always-depolarizing action potentials, a wide variety of slow graded potentials may be produced at the synapses on an individual neuron—some depolarizing, some hyperpolarizing, some milliseconds in duration, others seconds, minutes, or even hours. This flexibility of a chemical (neurotransmitter mediated) synapse allows for advanced neuronal communication.
There Are Five Steps in Conventional Chemical Synaptic Transmission
The fundamental elements of a chemical synapse ( Fig. 8.1 ) are a presynaptic ending from which a neurotransmitter is released, a synaptic cleft across which it diffuses, and a postsynaptic element containing receptor molecules to which the neurotransmitter binds. Although the presynaptic ending is usually an axon terminal and the postsynaptic ending is usually a dendrite, any part of a neuron can be presynaptic to any part of another neuron. The essential processes at chemical synapses are presynaptic synthesis , packaging , and release of neurotransmitter; binding to postsynaptic receptors ; and termination of neurotransmitter action.
Neurotransmitters Are Synthesized in Presynaptic Endings and in Neuronal Cell Bodies
As described a little later, most neurotransmitters are either small molecules (e.g., amino acids) or peptides . Small-molecule transmitters are synthesized in presynaptic cytoplasm by soluble enzymes that arrived there by slow axonal transport. Peptide transmitters are synthesized in the cell body, loaded into vesicles, and shipped to presynaptic endings by fast axonal transport.
Neurotransmitters Are Packaged Into Synaptic Vesicles Before Release
Neurotransmitters are packaged for release from presynaptic endings in collections of synaptic vesicles . All presynaptic endings contain a complement of small vesicles , with specific transporters in their walls that pack them full of small-molecule transmitters. Many also contain some less numerous large vesicles containing peptides shipped from the cell body; one or more small-molecule transmitters are often added to the brew in these large vesicles. Small vesicles are located near the presynaptic membrane, whereas large vesicles are usually located a few millimeters farther away.
Presynaptic Endings Release Neurotransmitters Into the Synaptic Cleft
Neurotransmitter release is a secretory process triggered by an increase in presynaptic Ca 2+ concentration. The membranes of presynaptic terminals contain voltage-gated Ca 2+ channels that open when an action potential spreads into the terminal ( Fig. 8.2 ). Ca 2+ influx causes one or more vesicles to fuse with the presynaptic membrane and dump its neurotransmitter content into the synaptic cleft. Because small vesicles are close to the synaptic cleft, they are the first to release their contents. Because the large vesicles are farther away, release of their contents requires more Ca 2+ entry (hence, more presynaptic action potentials), and more time.
Medications Can Inhibit Neurotransmitter Release by Altering Voltage-Gated Ca 2+ Channel Function.
The control of voltage-gated Ca 2+ channels can dictate the amount of neurotransmitter release. There are several medications that are used to modulate these voltage-gated Ca 2+ channels. For example, medications used for chronic pain, such as gabapentin and pregabalin, reduce the number of these channels in the membrane, resulting in a decrease in the amount of calcium; there is therefore a reduction in the release of pain neurotransmitters. Likewise, the majority of the opioid narcotics (e.g., morphine, codeine, oxycodone, hydrocodone, oxycontin, hydromorphone, fentanyl, etc.) act indirectly via a G protein–coupled receptor (mu receptor) to block the function of the voltage-gated Ca 2+ channels from the intracellular side, again reducing calcium entry and reducing the release of pain neurotransmitters. Antiepileptic drugs such as ethosuximide, zonisamide, and trimethadione, used for absence seizures, also act by blocking voltage-gated Ca 2+ channels located in the thalamus to reduce neurotransmitter release.
Neurotransmitters Diffuse Across the Synaptic Cleft and Bind to Postsynaptic Receptors
The effects of neurotransmitters are mediated by receptors situated in or near postsynaptic membranes. Receptors for the transmitters found in small vesicles are mostly located right across the synaptic cleft, contributing to the rapid action of these transmitters. Receptors for peptides in large vesicles are often located outside the synaptic cleft, contributing to the slowness of large-vesicle effects.
Neurotransmitter Action Is Terminated by Uptake, Degradation, or Diffusion
A concerted effort is made to remove neurotransmitter soon after it is released so that the postsynaptic element will be prepared for subsequent releases. Besides simple diffusion of the neurotransmitter, several different mechanisms are used, with different kinds of synapses emphasizing different mechanisms. Most commonly, transmitter is taken back up by the presynaptic ending (reuptake) or taken up by nearby glial cells using selective transporters. All of the major neurotransmitters in the central nervous system (CNS), i.e., serotonin, norepinephrine, dopamine, glutamate and γ-aminobutyric acid (GABA), utilize selective transporters as a mechanism of termination. Yet, acetylcholine (another major neurotransmitter of the CNS) does not use a transporter for reuptake. Some neurotransmitters are terminated by degradation utilizing enzymes in the synaptic cleft. Common enzymes include monoamine oxidase (MAO), catechol- O -methyltransferase (COMT), and acetylcholinesterase. MAO will metabolize serotonin, norepinephrine, and dopamine whereas COMT only metabolizes norepinephrine and dopamine. Acetylcholinesterase is necessary for the inhibition of acetylcholine, since this neurotransmitter does not have a selective transporter for reuptake.
Medications Take Advantage of These Transporters and Enzymes.
Since neurotransmitter function is terminated by reuptake and/or enzymatic degradation, the inhibition of such transporters or enzymes would result in a longer transmitter function. In the case of severe depression, where CNS levels of serotonin and norepinephrine may be low, patients are treated with medications that block the reuptake of the neurotransmitter serotonin, as well as norepinephrine. Medications that selectively block the reuptake of serotonin are termed selective serotonin reuptake inhibitors (SSRIs) and include medications such as fluoxetine, paroxetine, sertraline, fluvoxamine, and citalopram. Medications that block the reuptake of serotonin and norepinephrine are termed either tricyclic antidepressants (TCAs) or serotonin and norepinephrine reuptake inhibitors (SNRIs), based on their chemical structure. TCAs include medications such as imipramine, amitriptyline, desipramine, and clomipramine as well as new-generation TCAs, such as bupropion, that include inhibiting the reuptake of some dopamine. SNRIs include medications such as venlafaxine and duloxetine.
As mentioned, a common way to terminate neurotransmission is by enzymatic metabolism. There are medications that will inhibit the enzymatic activity of MAO, resulting in elevated levels of serotonin, norepinephrine, and dopamine that are used for severe depression. Such inhibitors of MAOs include phenelzine, tranylcypromine, and selegiline. Medications that inhibit COMT, resulting in elevated levels of norepinephrine and dopamine, include tolcapone and entacapone, and are more often used for Parkinson’s disease. Finally, there are several medications that inhibit acetylcholinesterase for diseases such as myasthenia gravis and Alzheimer disease; these include neostigmine, pyridostigmine, edrophonium, donepezil, and rivastigmine.
Synaptic Transmission Can Be Rapid and Point-to-Point, or Slow and Often Diffuse
Postsynaptic responses to transmitter-binding can be either depolarizing or hyperpolarizing. Because depolarizing and hyperpolarizing events move the postsynaptic membrane closer to or farther from threshold, they are referred to respectively as excitatory postsynaptic potentials ( EPSPs ) and inhibitory postsynaptic potentials ( IPSPs ). Depending on the synapse and the transmitter, both EPSPs and IPSPs can be either fast (lasting a few milliseconds) or slow.
Rapid Synaptic Transmission Involves Transmitter-Gated Ion Channels
Fast EPSPs and IPSPs are produced by the binding of a neurotransmitter to a receptor that is itself a ligand-gated ion channel ( Fig. 8.3 ); because of the direct coupling to ion flow, these are also referred to as ionotropic receptors. The permeability change induced by the binding of transmitter determines the postsynaptic response. Some receptors become permeable to both Na + and Ca 2+ , causing depolarization (EPSP). Others become permeable to K + or Cl − , causing hyperpolarization (IPSP).
