Porth's Essentials of Pathophysiology, 4e

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Organization and Control of Neural Function

C h a p t e r 3 4

Chemical SynapticTransmission The function of the nervous system relies on chemical substances that serve as synaptic messengers. These mes- sengers include neurotransmitters, neuromodulators, and neurotrophic or nerve growth factors. Neurotransmitters. Neurotransmitters are endogenous chemicals that facilitate the transmission of signals from one neuron to the next across synapses. There are many different ways to classify neurotransmitters, including by whether they produce excitatory or inhibitory effects on postsynaptic membranes and by their chemical structure. A neurotransmitter is classified as excitatory if it activates a receptor; for example, glutamate, the most common excitatory neurotransmitter in the brain, increases the probability that the target cell will fire an action potential. A neurotransmitter is classified as inhibitory if it inhibits a receptor; gamma aminobutyric acid (GABA) is the brain’s main inhibitory neurotrans- mitter. There are, however, other neurotransmitters for which both excitatory and inhibitory receptors exist; for example, acetylcholine is excitatory when it binds to a receptor at a myoneural junction, and it is inhibitory when it binds to a receptor at the sinoatrial node in the heart. Finally, some types of receptors activate complex metabolic pathways in the postsynaptic cell to produce effects that cannot appropriately be called either excit- atory or inhibitory. Receptors are named according to the type of neurotransmitter with which they interact. For example, a cholinergic receptor is a receptor that binds acetylcholine. In addition to function, neurotransmitters can be broadly categorized into three groups according to their chemical structure: (1) amino acids, (2) peptides, and (3) monoamines. Amino acids, such as glutamine, glycine, and GABA, serve as neurotransmitters at most CNS synapses. GABA mediates most synaptic inhibition in the CNS. Drugs such as the benzodiazepines (e.g., the tranquilizer diazepam) and the barbiturates exert their action by binding to their own distinct receptor on a GABA-operated ion channel. The drugs by themselves do not open the channel, but they change the effect that GABA has when it binds to the channel at the same time as the drug. Peptides are low–molecular-weight mol- ecules that are made up of two or more amino acids. Neuropeptides are peptides used by neurons to com- municate with each other. They include somatostatin, substance P, and opioid peptides such as endorphins and enkephalins, which are involved in pain sensation and perception (see Chapter 35). A monoamine is an amine molecule containing one amino group (−NH 2 group). All monoamines are derived from aromatic amino acids like phenylalanine, tyrosine, and tryptophan. Serotonin, dopamine, norepinephrine, and epinephrine are exam- ples in this category. Neuromodulators. Another class of messenger mole- cules, known as neuromodulators , also may be released from axon terminals. In contrast to neurotransmitters, neuromodulators do not directly activate ion-channel ( text continues on page 829 )

These vesicles  protect the neurotransmitters from enzyme destruction in the nerve terminal. There may be thousands of vesicles in a single terminal, each containing 10,000 to 100,000 transmitter molecules. Membrane depolarization due to arrival of an action potential causes the vesicles to move to the cell membrane and release their neurotrans- mitter molecules by fusion of the vesicular membrane with the outer cell membrane. Once a neurotransmitter has exerted its effects on the postsynaptic membrane, its rapid removal is neces- sary to maintain precise control of neural transmission. A released transmitter can : (1) be broken down into inactive substances by enzymes, (2) be taken back up into the presynaptic neuron in a process called reuptake , or (3) diffuse away into the intercellular fluid until its con- centration is too low to influence postsynaptic excitabil- ity. For example, acetylcholine is rapidly broken down by acetylcholinesterase into acetic acid and choline, with the choline being taken back into the presynaptic neuron for reuse in acetylcholine synthesis. The catecholamines are largely taken back into the neuron in an unchanged form for reuse. Catecholamines also can be degraded by enzymes, such as catechol- O -methyltransferase (COMT) in the synaptic space or monoamine oxidase (MAO) in the nerve terminals. Catechol- O -methyltransferase inhibitors and MAO inhibitors are used in the treat- ments of various conditions, such as Parkinson dis- ease, major depression, and anxiety (see the Autonomic Neurotransmission section for detail). Postsynaptic Potentials A neuron’s cell body and dendrites are covered by thou- sands of synapses, any or many of which can be active at any moment. Because of the interaction of this rich synap- tic input, each neuron resembles a little computer, in which circuits of many neurons interact with one another. It is the complexity of these interactions and the subtle inte- grations involved in excitatory and inhibitory responses that give rise to the nervous system’s intelligence. Neurotransmitters exert their actions through specific proteins, called receptors , embedded in the postsynap- tic membrane. These receptors are tailored precisely to match the size and shape of the transmitter. In each case, the interaction between a neurotransmitter and recep- tor causes the opening or closing of ion channels in the postsynaptic membrane, resulting in a transient, local change in the polarization of the postsynaptic mem- brane, called a postsynaptic potential . There are two types of postsynaptic potentials: excitatory and inhibi- tory. If opening of the ion channel results in a net gain of positive charge across the membrane, causing the potential to move close to zero, the membrane is said to be depolarized . This is called an excitatory postsynaptic potential , since it brings the resting potential closer to its firing threshold. If, on the other hand, opening of the ion channel results in a net gain of negative charge causing the potential to move further from zero, the membrane is said to be hyperpolarized . This is called an inhibitory postsynaptic potential , since it causes the resting mem- brane potential to move further from threshold.