Figure 717

The variety of cellular responses induced by cAMP is due mainly to the fact that activated cAMP-dependent protein kinase can phosphorylate many different proteins, activating them or inhibiting them. In this figure, the protein kinase is shown phosphorylating eight different proteins—a microtubular protein, an ATPase, an ion channel, a protein in the endoplasmic reticulum, a protein involved in DNA synthesis, and three enzymes.

Not mentioned so far is the fact that receptors for some first messengers, upon activation by their messengers, cause adenylyl cyclase to be inhibited, resulting in less, rather than more, generation of cAMP. This occurs because these receptors are associated with a different G protein, known as Gi (the subscript i denotes "inhibitory''), and activation of Gi causes inhibition of adenylyl cyclase. The result is to decrease the concentration of cAMP in the cell and, thereby, to decrease the phosphorylation of key proteins inside the cell.

Phospholipase C, Diacylglycerol, and Inositol Trisphosphate In this system, the relevant G protein (termed Gq), activated by a first-messenger-bound receptor, activates a plasma-membrane effector enzyme called phospholipase C. This enzyme catalyzes the breakdown of a plasma-membrane phospholipid known as phosphatidylinositol bisphosphate, abbreviated PIP2, to diacylglycerol (DAG) and inositol trisphosphate (IP3) (Figure 7-18). Both DAG and IP3 then function as second messengers but in very different ways.

DAG activates a particular protein kinase known as protein kinase C, which then phosphorylates a large number of other proteins, leading to the cell's response.

IP3, in contrast to DAG, does not exert its second messenger role by directly activating a protein kinase. Rather, IP3, after entering the cytosol, binds to calcium channels on the outer membranes of the endoplasmic reticulum and opens them. Because the concentration of calcium is much higher in the endoplasmic reticu-lum than in the cytosol, calcium diffuses out of this organelle into the cytosol, significantly increasing cy-tosolic calcium concentration. This increased calcium concentration then continues the sequence of events leading to the cell's response to the first messenger. We will pick up this thread in a later section.

Control of Ion Channels by G Proteins A comparison of Figures 7-13d and 7-17 emphasizes one more important feature of G-protein function—its ability to both directly and indirectly gate ion channels. As shown in Figure 7-13d and described earlier, an ion channel can be the effector protein for a G protein. This situation is known as direct G-protein gating of plasmamembrane ion channels because the G protein interacts directly with the channel (the term "gating" denotes control of the opening or closing of a channel). All the events occur in the plasma membrane and are independent of second messengers. Now look at Figure 7-17, and you will see that cAMP-dependent protein kinase can phosphorylate a plasma-membrane ion channel, thereby causing it to open. Since, as we have seen, the sequence of events leading to activation of cAMP-dependent protein kinase proceeds through a G protein, it should be clear that the opening of this channel is indirectly dependent on that G protein. To generalize, the indirect gating of ion channels by G proteins utilizes a second-messenger pathway for the opening (or closing) of the channel. Not just cAMP-dependent protein kinase but protein kinases involved in other signal transduction pathways can participate in reactions leading to such indirect gating. Table 7-5 summarizes the three ways we have described by which receptor activation by a first messenger leads to opening or closing of ion channels.

Calcium as a Second Messenger The calcium ion (Ca2+) functions as a second messenger in a great variety of cellular responses to stimuli, both chemical (first messenger) and electrical. The physiology of calcium as a second messenger requires an analysis of two broad questions: (1) How do stimuli cause the

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

II. Biological Control Systems

7. Homeostatic Mechanisms and Cellular Communication

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Homeostatic Mechanisms and Cellular Communication CHAPTER SEVEN

TABLE 7-5 Summary of Mechanisms by Which Receptor Activation Influences Channels cytosolic calcium concentration to increase? (2) How does the increased calcium concentration elicit the cells' responses? Note that, for simplicity, our two questions are phrased in terms of an increase in cytosolic concentration. There are, in fact, first messengers that elicit a decrease in cytosolic calcium concentration and therefore a decrease in calcium's second-messenger effects. Now for the answer to the first question.

The regulation of cytosolic calcium concentration is described in Chapter 6. In brief, by means of active-transport systems in the plasma membrane and cell organelles, Ca2+ is maintained at an extremely low concentration in the cytosol. Accordingly, there is always a large electrochemical gradient favoring diffusion of calcium into the cytosol via calcium channels in both the plasma membrane and endoplasmic retic-ulum. A stimulus to the cell can alter this steady state by influencing the active-transport systems and/or the ion channels, resulting in a change in cytosolic calcium concentration.

The most common ways that receptor activation by a first messenger increases the cytosolic Ca2+ concentration have already been presented in this chapter and are summarized in the top part of Table 7-6.

1. The ion channel is part of the receptor.

2. A G protein directly gates the channel.

3. A G protein gates the channel indirectly via a second messenger.

The previous paragraph dealt with receptor-initiated sequences of events. This is a good place, however, to emphasize that there are calcium channels in the plasma membrane that are opened directly by an electric stimulus to the membrane (Chapter 6). Calcium can act as a second messenger, therefore, in response not only to chemical stimuli acting via receptors, but to electric stimuli acting via voltage-gated calcium channels as well. Moreover, extracellular calcium entering the cell via these channels can, in certain cells, bind to calcium-sensitive channels in the en-doplasmic reticulum and open them. In this manner,

First messenger

Extracellular fluid

First messenger

G protein


Phospholipase C

G protein


Endoplasmic reticulum

Inactive protein kinase C

Plasma membrane

Active protein kinase C

Intracellular fluid


Protein + ATP Protein-PO4 + ADP


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