There are certain universal characteristics of chemical messenger systems illustrated in Figure 8.8. Signaling generally follows the following sequence: (a) the chemical messenger is secreted from a specifi c cell in response to a stimulus; (b) the mes- senger diffuses or is transported through blood or other extracellular fl uid to the target cell; (c) a molecule in the target cell, termed a receptor, (a plasma membrane receptor or intracellular receptor) specifi cally binds the messenger; (d) binding of the messenger to the receptor elicits a response; (e) the signal ceases and is termi- nated. Chemical messengers elicit their response in the target cell without being metabolized by the cell.
An additional feature of chemical messenger systems is that the specifi city of the response is dictated by the type of receptor and its location. Generally, each receptor binds only one specifi c chemical messenger, and each receptor initiates a charac- teristic signal transduction pathway that will ultimately activate or inhibit certain processes in the cell. Only certain cells, the target cells, carry receptors for that mes- senger and are capable of responding to its message.
The means of signal termination is an exceedingly important aspect of cell sig- naling, and failure to terminate a message contributes to several diseases, such as cancer.
Lotta T. (see Chapter 6) was given colchicine, a drug that is frequently used to treat gout in its initial stages.
One of colchicine’s actions is to prevent phago- cytic activity by binding to dimers of the α- and β-subunits of tubulin. When the tubulin dimer- colchicine complexes bind to microtubules, further polymerization of the microtubule is inhibited, depolymerization predominates, and the microtubules disassemble. Microtubules are necessary for vesicular movement of urate crystals during phagocytosis and release of mediators that activate the infl ammatory re- sponse. Thus, colchicine diminishes the infl am- matory response, swelling, and pain caused by formation of the urate crystals.
Ann R.’s fasting is accompanied by high levels of the endocrine hor- mone glucagon, which is secreted in response to low blood glucose levels. It enters the blood and acts on the liver to stimulate a number of pathways, including the release of glucose from glycogen stores (glycogenoly- sis) (see Chapter 1). The specifi city of its ac- tion is determined by the location of receptors.
Although liver parenchymal cells have gluca- gon receptors, skeletal muscle and many other tissues do not. Therefore, glucagon cannot stimulate glycogenolysis in these tissues.
1
2
SECRETION
DIFFUSION/RECEPTOR BINDING
SIGNAL TRANSDUCTION
RESPONSE Stimulus
Chemical messengers
Plasma membrane receptor
Target cell Intracellular
receptor
Secretory cell
3 DIFFUSION
FIG. 8.8. General features of chemical messengers. (1) Secretion of chemical message.
(2) Binding of message to cell surface receptor. (3) Diffusion of a hydrophobic message across the plasma membrane and binding to an intracellular receptor.
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A. General Features of Chemical Messenger Systems Applied to the Nicotinic Acetylcholine Receptor
The individual steps involved in cell signaling by chemical messengers are illustrated with acetylcholine (ACh), a neurotransmitter that acts on nicotinic acetylcholine receptors on the plasma membrane of certain muscle cells. This system exhibits the classical features of chemical messenger release and specifi city of response.
Neurotransmitters are secreted from neurons in response to an electrical stimulus called the action potential (a voltage difference across the plasma membrane caused by changes in Na⫹ and K⫹ gradients that is propagated along a nerve). The neurotrans- mitters diffuse across a synapse to another excitable cell, where they elicit a response (Fig. 8.9). Acetylcholine is the neurotransmitter at neuromuscular junctions, where it transmits a signal from a motor nerve to a muscle fi ber that elicits contraction of the fi ber. Prior to release, acetylcholine is sequestered in vesicles clustered near an active zone in the presynaptic membrane. This membrane also has voltage-gated Ca2⫹
channels, which open when the action potential reaches them, resulting in an infl ux of Ca2⫹. Ca2⫹ triggers fusion of the vesicles with the plasma membrane and acetyl- choline is released into the synaptic cleft. Thus, the chemical messenger is released from a specifi c cell in response to a specifi c stimulus. The mechanism of vesicle fu- sion with the plasma membrane is common to the release of many second messengers.
Acetylcholine diffuses across the synaptic cleft to bind to the nicotinic acetyl- choline receptor on the plasma membrane of the muscle cells. The subunits of the receptor are assembled around a channel, which has a funnel-shaped opening in the center. As acetylcholine binds to one of the subunits of the receptor, a conforma- tional change opens the narrow portion of the channel (the gate), allowing Na⫹ to diffuse in and K⫹ to diffuse out (a uniform property of most receptors is that signal transduction begins with conformational changes in the receptor). The change in ion concentration activates a sequence of events that eventually triggers the cellular response–contraction of the fi ber.
Acetylcholine works on two differ- ent types of receptors: nicotinic and muscarinic. Nicotinic receptors (for which nicotine is an activator) are found at the neuromuscular junction of skeletal muscle cells as well as in the parasympathetic ner- vous system. Muscarinic receptors (for which muscarine, a mushroom toxin, is an activa- tor) are found at the neuromuscular junction of cardiac and smooth muscle cells as well as in the sympathetic nervous system. Curare (a paralyzing agent) is an inhibitor of nicotinic acetylcholine receptors, whereas atropine is an inhibitor of muscarinic acetylcholine recep- tors. Atropine may be used under conditions in which acetylcholinesterase has been inac- tivated by various nerve gases or chemicals such that atropine will block the effects of the excess acetylcholine present at the synapse.
Synaptic vesicle (ACh) Presynaptic membrane Synaptic cleft Postsynaptic membrane Ca2+ channel Junctional fold Voltage-gated Na+ channel
Presynaptic nerve terminal
ACh synaptic vesicles
ACh
receptors Muscle cell
FIG. 8.9. Acetylcholine receptors at the neuromuscular junction. A motor nerve terminates in several branches; each branch terminates in a bulb-shaped structure called the presynaptic bouton. Each bouton synapses with a region of the muscle fi ber that contains junctional folds.
At the crest of each fold, there is a high concentration of acetylcholine receptors, which are gated ion channels.
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CHAPTER 8 ■ CELL STRUCTURE AND SIGNALING BY CHEMICAL MESSENGERS 123
Once acetylcholine secretion stops, the message is rapidly terminated by ace- tylcholinesterase, an enzyme located on the postsynaptic membrane that cleaves acetylcholine. It is also terminated by diffusion of acetylcholine away from the syn- apse. Rapid termination of message is a characteristic of systems requiring a rapid response from the target cell.
B. Endocrine, Paracrine, and Autocrine Actions
The actions of chemical messengers are often classifi ed as endocrine, paracrine, or autocrine (Fig. 8.10). Each endocrine hormone (e.g., insulin) is secreted by a specifi c cell type (generally in an endocrine gland), enters the blood, and exerts its actions on specifi c target cells, which may be some distance away. In contrast to endocrine hormones, paracrine actions are those carried out on nearby cells and the location of the cells plays a role in specifi city of the response. Synaptic trans- mission by acetylcholine and other neurotransmitters (sometimes called neurocrine signaling) is an example of paracrine signaling. Acetylcholine activates only those acetylcholine receptors located across the synaptic cleft from the signaling nerve, not every muscle cell with acetylcholine receptors. Paracrine actions are also very important in limiting the immune response to a specifi c location in the body, a fea- ture that helps prevent the development of autoimmune disease. Autocrine actions involve a messenger acting on the cell from which it is secreted or on nearby cells that are the same type as the secreting cells.
C. Types of Chemical Messengers
There are three types of major signaling systems in the body employing chemical messengers: the nervous system, the endocrine system, and the immune system.
The major properties of these messengers are summarized in Table 8.1. It is im- portant to realize that each of the hundreds of chemical messengers has its own specifi c receptor, which will usually bind no other messenger. There are also some
A.Endocrine
B.Paracrine
C.Autocrine
Hormone secreted into blood
Secretory cell
Target sites on same cell
Receptor Hormone or other chemical messenger
Target cells
Interstitial fluid
Adjacent target cell
Blood vessel
FIG. 8.10. Endocrine (A), paracrine (B), and autocrine (C) actions of hormones and other chemical messengers.
Mia S. was tested with an inhibitor of acetylcholinesterase, edrophonium chlo- ride, administered intravenously. After this drug inactivates acetylcholinesterase, acetylcholine that is released from the nerve terminal accumulates in the synaptic cleft. Even though Mia expresses fewer acetylcholine receptors on her muscle cells (due to the autoantibody-induced degradation of receptors) by increasing the local concentration of acetylcholine, these receptors have a higher probability of being occupied and activated.
Therefore, acute intravenous administration of this short-acting drug briefl y improves muscu- lar weakness in patients with myasthenia gravis.
Table 8.1 Types of Chemical Messengers
System Types of Messengers Examples of Messengers Nervous (neurotransmitters act
as messengers)
Biogenic amines Neuropeptides
Acetylcholine
γ-Aminobutyric acid (GABA) Endorphins
Neuropeptide-Y Endocrine (molecule secreted by
one organ but acts at another organ)
Polypeptide Catecholamines Steroid hormones
(lipophilic)
Insulin Glucagon Epinephrine Dopamine Estrogen Cortisol Immune (alters gene transcrip-
tion in target cells)
Cytokines Interleukins
Colony-stimulating factors Interferons
Eicosanoids (control cellular function in response to injury)
Primarily 20 carbon lipids
Prostaglandins Leukotrienes Growth factors (goes across all
systems)
Proteins Platelet-derived growth factor (PDGF)
Epidermal growth factor (EGF)
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compounds normally considered hormones that are more diffi cult to categorize. For example, retinoids, which are derivatives of vitamin A (also called retinol) and vita- min D (which is also derived from cholesterol), are usually classifi ed as hormones, although they are not synthesized in endocrine cells.