Figure 713

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Mechanisms of action of lipid-insoluble messengers (noted as "first messengers" in this and subsequent figures). (a) Signal transduction mechanism in which the receptor complex itself contains an ion channel. (b) Signal transduction mechanism in which the receptor itself functions as an enzyme, usually a tyrosine kinase. (c) Signal transduction mechanism in which the receptor activates a JAK kinase in the cytoplasm. (d) Signal transduction mechanism involving G proteins.

Protein-PO4 + ADP

As described in Chapter 4, other enzymes do the reverse of protein kinases; that is, they dephosphory-late proteins. These enzymes, termed protein phosphatases, also participate in signal transduction pathways, but their roles are much less well understood than those of the protein kinases and will not be described here.

Receptors That Function as Ion Channels In the first type of plasma-membrane receptor listed in Table 7-4 (Figure 7-13a), the protein that acts as the receptor itself constitutes an ion channel, and activation of the receptor by a first messenger causes the channel to open. The opening results in an increase in the net diffusion across the plasma membrane of the ion or ions specific to the channel. As we shall see in Chapter 8, such a change in ion diffusion is usually associated with a change in the membrane potential, and this electric signal is often the essential event in the cell's response to the messenger. In addition, as described later in this chapter, when the channel is a calcium channel, its opening results in an increase, by diffusion, in the cytosolic calcium concentration, another essential event in the signal transduction pathway for many receptors.

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

Homeostatic Mechanisms and Cellular Communication CHAPTER SEVEN

Receptors That Function as Enzymes The receptors in the second category of plasma-membrane receptors listed in Table 7-4 (Figure 7-13b) have intrinsic enzyme activity. With one major exception (discussed below), the many receptors that possess intrinsic enzyme activity are all protein kinases. Of these, the great majority phosphorylate specifically the portions of proteins that contain the amino acid tyrosine; accordingly, they are termed tyrosine kinases. Keep in mind that (1) tyrosine kinases simply constitute one category of protein kinases, and that (2) the label does not denote any particular enzyme but is a generic term that defines the type of function—phosphorylating tyrosine groups—these protein kinases perform.

The sequence of events for receptors with intrinsic tyrosine kinase activity is as follows. The binding of a specific messenger to the receptor changes the conformation of the receptor so that its enzymatic portion, located on the cytoplasmic side of the plasma membrane, is activated. This results in autophosphorylation of the receptor; that is, the receptor phosphorylates its own tyrosine groups! The newly created phosphoty-rosines on the cytoplasmic portion of the receptor then serve as "docking" sites for cytoplasmic proteins that have a high affinity for those phosphotyrosines displayed by that particular receptor. The bound docking proteins then bind other proteins, which leads to a cascade of signaling pathways within the cell. The common denominator of these pathways is that, at one or more points in their sequences, they all involve activation of cytoplasmic proteins by phosphorylation.

The number of kinases that mediate these phos-phorylations can be very large, and their names constitute a veritable alphabet soup—RAF, MEK, MAPKK, and so on. In all this complexity, it is easy to lose track of the point that the end result of all these pathways is the activation or synthesis of molecules, usually proteins, that ultimately mediate the response of the cell to the messenger. The receptors with intrinsic tyrosine kinase activity all bind first messengers that influence cell proliferation and differentiation.

As stated above, there is one major exception to the generalization that plasma-membrane receptors with inherent enzyme activity function as protein ki-nases. In this exception, the receptor functions as a guanylyl cyclase to catalyse the formation, in the cytoplasm, of a molecule known as cyclic GMP (cGMP). In turn, cGMP functions as a second messenger to activate a particular protein kinase, cGMP-dependent protein kinase, which phosphorylates particular proteins that then mediate the cell's response to the original messenger. This signal transduction pathway is used by only a small number of messengers and should not be confused with the much more important cAMP system to be described in a later section.

(Also, we will see in Chapter 8 that in certain cells, guanylyl cyclase enzymes are present in the cytoplasm; in these cases, a first messenger—nitric oxide—diffuses into the cell and combines with the guanylyl cyclase there to trigger the formation of cGMP.)

Receptors that Interact with Cytoplasmic JAK Kinases To repeat, in the previous category, the receptor itself has intrinsic enzyme activity. In contrast, in the present category of receptors (Table 7-4 and Figure 7-13c), the enzymatic activity—again tyrosine kinase activity—resides not in the receptor but in a family of separate cytoplasmic kinases, termed JAK kinases, which are bound to the receptor. (The term "JAK" has several derivations, including "just another kinase.") In these cases, the receptor and its associated JAK kinase function as a unit; the binding of a first messenger to the receptor causes a conformational change in the receptor that leads to activation of the JAK kinase. Different receptors associate with different members of the JAK kinase family, and the different JAK kinases phosphorylate different target proteins, many of which act as transcription factors. The result of these pathways is the synthesis of new proteins, which mediate the cell's response to the first messenger.

Receptors that Interact with G Proteins The fourth category of plasma-membrane receptors in Table 7-4 (Figure 7-13d) is by far the largest, including hundreds of distinct receptors. Bound to the receptor is a protein located on the inner (cytosolic) surface of the plasma membrane and belonging to the family of proteins known as G proteins. The binding of a first messenger to the receptor changes the conformation of the receptor. This change causes one of the three subunits of the G protein to link up with still another plasmamembrane protein, either an ion channel or an enzyme. These ion channels and enzymes are termed plasmamembrane effector proteins since they mediate the next steps in the sequences of events leading to the cell's response.

In essence, then, a G protein serves as a switch to "couple" a receptor to an ion channel or an enzyme in the plasma membrane. The G protein may cause the ion channel to open, with resulting generation of electric signals or, in the case of calcium channels, changes in the cytosolic calcium concentration. Alternatively, the G protein may activate or inhibit the membrane enzyme with which it interacts; these are enzymes that, when activated, cause the generation, inside the cell, of second messengers.

There are three subfamilies of plasma-membrane G proteins, each with multiple distinct members, and a single receptor may be associated with more than one type of G protein. Moreover, some G proteins may

Vander et al.: Human Physiology: The Mechanism of Body Function, Eighth Edition

PART TWO Biological Control Systems couple to more than one type of plasma-membrane effector protein. Thus, a first-messenger-activated receptor, via its G-protein couplings, can call into action a variety of plasma-membrane effector proteins—ion channels and enzymes—which in turn induce a variety of cellular events.

To illustrate some of the major points concerning G proteins, plasma-membrane effector proteins, second messengers, and protein kinases, the next two sections describe the two most important effector-protein enzymes—adenylyl cyclase and phospholipase C— regulated by G proteins and the subsequent portions of the signal transduction pathways in which they participate.

Before doing so, however, we would like to emphasize that the plasma-membrane G proteins activated by receptors encompass only a subset of G proteins, a term that includes all those proteins that, regardless of location and function, share a particular chemical characteristic (the ability to bind certain guanine nucleotides). In contrast to G proteins coupled to receptors is a class of small (one-subunit), mainly cy-toplasmic G proteins (with names like Ras, Rho, and Rac). These G proteins play an important role in the signal transduction pathways from tyrosine kinase receptors, but they do not interact directly with either the receptor or membrane-bound effector molecules.

Adenylyl Cyclase and Cyclic AMP In this pathway, activation of the receptor (Figure 7-14) by the binding of the first messenger (for example, the hormone epi-nephrine) allows the receptor to activate its associated G protein, in this example known as Gs (the subscript s denotes "stimulatory"). This causes Gs to activate its effector protein, the membrane enzyme called adenylyl cyclase (also termed adenylate cyclase). The activated adenylyl cyclase, whose enzymatic site is located on the cytosolic surface of the plasma membrane, then catalyzes the conversion of some cytosolic ATP molecules to cyclic 3',5'-adenosine monophosphate, called simply cyclic AMP (cAMP) (Figure 7-15). Cyclic AMP then acts as a second messenger (Figure 7-14). It diffuses throughout the cell to trigger the sequences of events leading to the cell's ultimate response to the first messenger. The action of cAMP is eventually terminated by its breakdown to noncyclic AMP, a reaction catalyzed by the enzyme phosphodiesterase (Figure 7-15). This enzyme is also subject to physiological control so that the cellular concentration of cAMP can be changed either by altering the rate of its messenger-mediated generation or the rate of its phosphodiesterase-mediated breakdown.

What does cAMP actually do inside the cell? It binds to and activates an enzyme known as cAMP-dependent protein kinase (also termed protein

Extracellular fluid

First messenger

First messenger

Gs protein

Adenylyl cyclase

Adenylyl cyclase


Plasma membrane



Active cAMP-dependent ->- cAMP-dependent protein kinase protein kinase

Protein + ATP

Protein-PO4 + ADP


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Essentials of Human Physiology

Essentials of Human Physiology

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