Signaling Molecules

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Neurotransmitters vary greatly in their composition. Acetylcholine, the biogenic amines, and some amino acids form the so-called classical neurotransmitters (because they were first to be discovered and studied extensively; see Sec. 6.3.1). Other neurotransmitters are the neuropeptides and neurosteroids (see Sec. 6.3.2). Finally, recent research has revealed that neurons can also release gaseous transmitters such as nitric oxide or carbon monoxide to affect nearby nerve cells. They constitute the third class of neurotransmitters called unconventional transmitters.

Figure 6.7 The synapse. The axonal terminal from the presynaptic neuron and the dendritic membrane from the postsynaptic neuron form the synapse. The neurotransmitter is released from the presynaptic terminal, diffuses through the synaptic cleft, and binds to receptors located on the membrane of the postsynaptic neuron. (Public domain figure produced by Goodlett, C.R. and Horn, K.H. Mechanisms of alcohol-induced damage to the developing nervous system. Alcohol Res. Health. 2001;25(3):175-184, and displayed at National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health, http:// www.niaaa.nih.gov/Resources/GraphicsGallery/Neuroscience/synapse.htm.)

Signal-emitting Signal-receiving neuron neuron

Figure 6.7 The synapse. The axonal terminal from the presynaptic neuron and the dendritic membrane from the postsynaptic neuron form the synapse. The neurotransmitter is released from the presynaptic terminal, diffuses through the synaptic cleft, and binds to receptors located on the membrane of the postsynaptic neuron. (Public domain figure produced by Goodlett, C.R. and Horn, K.H. Mechanisms of alcohol-induced damage to the developing nervous system. Alcohol Res. Health. 2001;25(3):175-184, and displayed at National Institute on Alcohol Abuse and Alcoholism of the National Institutes of Health, http:// www.niaaa.nih.gov/Resources/GraphicsGallery/Neuroscience/synapse.htm.)

For a substance secreted by a nerve cell to qualify as a neurotransmitter, it must have the following characteristics:

■ The presynaptic neuron must contain the appropriate mechanism for synthesis and secretion of the neurotransmitter.

■ Presynaptic nerve terminals must release the neurotransmitter in a form identifiable by biochemical or pharmacological techniques.

■ The effects of the neurotransmitter on the postsynaptic cell must reproduce the effects obtained by stimulation of the presynaptic neuron.

■ Competitive antagonists as well as inhibitors of synthesis must block the effects of the presynaptic stimulation.

■ Finally, there must be synaptic mechanisms, such as enzymatic inac-tivation or reuptake, to terminate the effects of the neurotransmitter.

The process of chemical transmission includes several steps: the synthesis, the storage, and the active release of the neurotransmitter, as well as the interaction of the neurotransmitter with postsynaptic receptors and the termination of this process. These steps are explained in the following discussion of the classical neurotransmitter acetylcholine (ACh) and illustrated in Fig. 6.8. ACh is also the transmitter at the synapse between nerve cells, and cardiac and voluntary muscle cells (neuromuscular junction) in mammals. Neurons using ACh as a neu-rotransmitter are termed cholinergic.

The first step in chemical transmission involves the synthesis of the neurotransmitter. As for all classical neurotransmitters, synthesis of ACh takes place in the presynaptic terminal far away from the nerve cell body: the enzyme choline acetyltransferase (ChAt in Fig. 6.8) transfers the acetyl group from acetyl-coenzyme A to choline. The required

Figure 6.8 Cholinergic synapse. Acetylcholine (ACh) is synthesized by choline acetyltransferase (ChAt) in the presy-naptic membrane. After release into the synaptic cleft, ACh binds to the cholinergic receptor (AChR). The effect of ACh is terminated by the enzyme acetylcholinesterase (AChE). Ac = acetic acid; AcCoA = acetyl-coenzyme A; C = choline transporter; Ch+ = choline; CL = citrate lyase; OxAc = oxaloac-etate; Pyr = pyruvate.

Figure 6.8 Cholinergic synapse. Acetylcholine (ACh) is synthesized by choline acetyltransferase (ChAt) in the presy-naptic membrane. After release into the synaptic cleft, ACh binds to the cholinergic receptor (AChR). The effect of ACh is terminated by the enzyme acetylcholinesterase (AChE). Ac = acetic acid; AcCoA = acetyl-coenzyme A; C = choline transporter; Ch+ = choline; CL = citrate lyase; OxAc = oxaloac-etate; Pyr = pyruvate.

agents for this reaction are compartmentalized within the presynaptic terminal: acetyl-coenzyme A (AcCoA) exists within the mitochondria whereas choline (Ch+) and ChAt are cytoplasmic. Thus, the synthesis of ACh within the presynaptic terminal can be controlled by the rate at which AcCoA is released from the mitochondria or by the availability of Ch+ within the cytoplasm.

The next step in chemical transmission is the storage of the neuro-transmitter. The vesicular cholinergic transporter is responsible for the translocation of the newly synthesized acetylcholine into presynaptic vesicles where it is protected from degradation by enzymes. As for all classical neurotransmitters, the synaptic vesicles are small in diameter (~50 nm), and they are arranged in a predetermined spatial arrangement in the presynaptic terminal for quick release.

The following step, the active release of neurotransmitter into the synaptic cleft, occurs when repetitive firing of the neurons occurs. The transmitter release is regulated by extracellular stimulation of the presynaptic neuron. The presynaptic neuron generates depolarizing signals, which travel along the axon to its presynaptic terminals triggering fusion of the synaptic vesicles with the presynaptic cell membrane and the release of the neurotransmitter into the synaptic cleft (for a discussion on secretion, see Sec. 6.4).

In the next step, the neurotransmitter interacts with receptors on the postsynaptic as well as the presynaptic membrane. Membrane receptors include ionotropic receptors and G-protein-coupled receptors (GPCRs) (see Sec. 6.1). In the case of ACh, there are two types of cholin-ergic receptors: nicotinic and muscarinic. These differ in their mechanism since nicotinic receptors are ionotropic and muscarinic receptors are GPCRs. Nicotinic and muscarinic receptors have different distributions in the body and subserve different functions; furthermore, each type of receptors can be differentiated into different subtypes. For example, the muscarinic cholinergic receptors include five different subtypes numbered M1 to M5, differentiated by function as well as by distribution in the body. M1 cholinergic receptors modulate signaling in brain areas such as the cortex and the hippocampus. M2 cholinergic receptors are involved in tremor and hypothermia. M3 cholinergic receptors mediate gland secretion, contraction of smooth muscle, and pupil dilation. M4 cholinergic receptors modulate the activity of the neurotransmitter dopamine in brain motor functions. Finally, M5 cholinergic receptors control the muscle tone of cerebral blood vessels. Thus, the existence of different receptor types and subtypes increases the versatility of the same neurotransmitter, in our example ACh, in triggering and modulating different physiological functions.

The last step is the termination of the action of the released neuro-transmitter. This must occur because continuous stimulation of the postsynaptic cell could threaten its survival. Passive and active mechanisms of transmitter termination exist. The passive termination occurs when the neurotransmitter diffuses away from the receptor and becomes diluted into the extracellular fluid to insignificant concentrations. The cell membrane on the pre- and the postsynaptic cells also contain active mechanisms to terminate the action of the released neurotransmitter. In the case of ACh, termination is primarily by the action of the membrane enzyme acetylcholinesterase (AChE in Fig. 6.8) secreted into the synaptic cleft where it exerts its effect on the neurotransmitter. Acetylcholinesterase breaks down ACh into acetic acid (Ac) and choline (Ch+). Choline is transported back into the presynaptic terminal by the action of the choline transporter (C in Fig. 6.8), to be stored and reused in neurotransmitter synthesis. As its name indicates, the choline transporter is a specialized membrane protein, which binds to choline and shuttles it back into the presynaptic terminal in a sodium-dependent process. Termination of the neurotransmitter action ends the process of synaptic transmission.

Electrophysiological studies of nerve cells have revealed that communication is not limited to active periods (i.e., periods of active stimulation by the presynaptic neuron), but appears to be ongoing at all times. Recordings during inactive periods at the neuromuscular junction show that the synapse is not silent. Instead, small (1 mV) electrical signals termed miniature end-plate potentials can be continuously detected (Fig. 6.9). The mechanism that generates miniature end-plate potentials remains unclear. The amount of ACh necessary to generate a miniature end-plate potential is termed a quantum. The most commonly accepted model posits that each quantum is the result of the interaction of one synaptic vesicle with a fusion pore located on the

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Figure 6.9 Miniature end-plate potentials recordings. Each upward deflection represents one miniature endplate potential. (Reproduced with permission from Purves, D., Augustine, G.J., Fitzpatrick, D., Hall, W.C., Lamantia, A.-S., McNamara, J.O. and Williams, S.M. Neuroscience, 3rd ed., 2004, Sinauer Associates, Inc.)

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Figure 6.9 Miniature end-plate potentials recordings. Each upward deflection represents one miniature endplate potential. (Reproduced with permission from Purves, D., Augustine, G.J., Fitzpatrick, D., Hall, W.C., Lamantia, A.-S., McNamara, J.O. and Williams, S.M. Neuroscience, 3rd ed., 2004, Sinauer Associates, Inc.)

presynaptic membrane and subsequent release of the content of this single synaptic vesicle.

However, another model for quantal release also exists whereby arrays of synaptic vesicles docked to the nerve terminal membrane by a complex of fusion pores synchronously release ACh to generate a quantum. In Fig. 6.10a, the presynaptic terminal of a frog neuromuscular junction has been processed by the freeze-fracture technique. The electron micrograph image on the left of Fig. 6.10a shows an unstimulated presynaptic terminal. The dots in the picture represent particles that are thought to be calcium channels. The electron micrograph image on the right shows a terminal stimulated by an action potential. The dimple-like structures in the picture represent the fusion pores by which the synaptic vesicles fuse with the presynaptic membrane. Figure 6.106 is the schematic drawing of synaptic vesicles interacting with the presy-naptic membrane to form such fusion pores. In the schematic, calcium channels are symbolized as cylinders integrated in the presynaptic terminal membrane. Based on freeze-fracture and other studies, a new model of transmitter release is developed, which proposes that miniature end-plate potentials caused by the simultaneous fusion of several synaptic vesicles may not be dismissed as "background noise" but may constitute a low level of intercellular communication with potential physiological significance. Moreover, the model takes into account the existence of subminiature end-plate potentials (less than 1 mV), which may be the result of partial transmitter release from a single

Figure 6.10 Fusion pore. (a) The left scanning electron micrograph shows the synaptic side of an inactive presynaptic membrane. After depolarization and transmitter release, fusion pores are visible in the right scanning electron micrograph. (b) The drawing shows how synaptic vesicles interact with the presynaptic membrane to form fusion pores through which neurotransmitter is released. (Left figure reproduced with permission from Heuser, J.E., Reese, T.S., Dennis, M.J., Jan, Y. and Jan, L. (1979). Synaptic vesicle exocytosis captured by quick freezing and correlated with quantal transmitter release. J. Cell Biology. 81: 281. Right figure reproduced with permission from Purves, D., Augustine, G.J., Fitzpatrick, D., Hall, W.C., Lamantia, A.-S., McNamara, J.O. and Williams, S.M. Neuroscience, 3rd ed., 2004, Sinauer Associates, Inc.)

Figure 6.10 Fusion pore. (a) The left scanning electron micrograph shows the synaptic side of an inactive presynaptic membrane. After depolarization and transmitter release, fusion pores are visible in the right scanning electron micrograph. (b) The drawing shows how synaptic vesicles interact with the presynaptic membrane to form fusion pores through which neurotransmitter is released. (Left figure reproduced with permission from Heuser, J.E., Reese, T.S., Dennis, M.J., Jan, Y. and Jan, L. (1979). Synaptic vesicle exocytosis captured by quick freezing and correlated with quantal transmitter release. J. Cell Biology. 81: 281. Right figure reproduced with permission from Purves, D., Augustine, G.J., Fitzpatrick, D., Hall, W.C., Lamantia, A.-S., McNamara, J.O. and Williams, S.M. Neuroscience, 3rd ed., 2004, Sinauer Associates, Inc.)

fusion pore complex representing another degree of low-level intercellular communication.

6.3.1 Classical transmitters

The classical transmitters are ACh, the biogenic amines, or products of intermediary glucose metabolism such as the amino acids g-aminobutyric acid (GABA), glutamate, or aspartate. The term biogenic amine refers to a group of biologically active amines, which serve as neurotransmit-ters. They include the catecholamines: dopamine, norepinephrine, and epinephrine. The last two names have replaced the older nomenclature of noradrenaline and adrenaline. Another important biogenic amine is 5-hydroxytryptamine or serotonin.

In Sec. 6.3, the formation of ACh by the enzyme choline acetyltrans-ferase (ChAt) was presented. However, synthesis of classical transmitters can also occur by sequential action of different enzymes. For example, the first step in the synthesis of the catecholamines begins with the conversion of the amino acid phenylalanine to tyrosine by the enzyme phenylalanine hydroxylase (Fig. 6.11). Breakdown of proteins eaten during a meal provides for the major source of phenylalanine. Next, tyrosine is accumulated in the nerve cell and converted by the enzyme tyrosine hydroxylase to 3,4-dihydroxyphenylalanine (DOPA). The latter is in turn rapidly converted to dopamine by the enzyme aromatic amino acid decarboxylase (AADC). Thus, nerve cells, which use dopamine as a neurotransmitter, manufacture only the enzymes tyrosine hydroxylase and AADC. These cells are referred to as dopaminergic neurons. Noradrenergic neurons, which utilize norepinephrine as a neurotrans-mitter also manufacture the enzyme dopamine-fi-hydroxylase (DBH) to convert dopamine to norepinephrine. Finally, adrenergic neurons synthesize the enzyme phenylethanolamine N-methyltransferase (PNMT) for the conversion of norepinephrine to epinephrine. Thus, the sequential action of enzymes contained within the same nerve cell can synthesize the specific neurotransmitter required for intercellular communication.

Synthesis of classical transmitters occurs in presynaptic axon terminals, near the site of neurotransmitter release. Because of this, characteristic synthetic enzymes for the classical neurotransmitters can be found in axonal terminals. For example, the enzymes tryptophan hydroxylase (converts the amino acid tryptophan to 5-hydroxytrypto-phan) and AADC (also converts 5-hydroxytryptamine to serotonin) are localized in the cytoplasm near terminal endings. This distribution of synthetic enzymes has been exploited to identify the type of neuro-transmitter used by a nerve cell. Figure 6.12 shows dopaminergic neurons that are identified in culture by the presence of fluorescently labeled

Phenylalanine

Phenylalanine

HO CH

Figure 6.11 Catecholamine synthetic pathway. A series of synthetic enzymes converts phenylalanine to the bioactive catecholamines dopamine, norepinephrine, and epinephrine. AADC = aromatic acid decarboxylase; DBH = dopamine-b-hydroxylase; PNMT = phenyletha-nolamine N-methyl transferase.

HO CH

Figure 6.11 Catecholamine synthetic pathway. A series of synthetic enzymes converts phenylalanine to the bioactive catecholamines dopamine, norepinephrine, and epinephrine. AADC = aromatic acid decarboxylase; DBH = dopamine-b-hydroxylase; PNMT = phenyletha-nolamine N-methyl transferase.

tyrosine hydroxylase, required for the synthesis of DOPAfrom tyrosine as can be seen in Fig. 6.11. Clinical Box 6.1 presents an example how cells can be labeled in vivo with fluorescent markers and the diagnostic value of fluorescent tagging.

Release of classical transmitters is elicited by depolarization of the nerve cell and is calcium-dependent (see Sec. 6.4). Termination of the action of classical neurotransmitters is performed either by the action of enzymes and/or by reuptake mechanisms. The action of AChE, which is the primary mode of transmitter termination for ACh, has already been discussed in Sec. 6.3. For the catecholamines, the enzymes

Figure 6.12 Dopamine neurons identified by tyrosine hydroxylase labeling and imaged by a red fluorescence tag. (Reproduced with permission from Bannon, M.J. Wayne State University School of Medicine, and displayed at http://serotonin.med.wayne.edu/mbannon/.)

Figure 6.12 Dopamine neurons identified by tyrosine hydroxylase labeling and imaged by a red fluorescence tag. (Reproduced with permission from Bannon, M.J. Wayne State University School of Medicine, and displayed at http://serotonin.med.wayne.edu/mbannon/.)

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