Figure 718

Mechanism by which an activated receptor stimulates the enzymatically mediated breakdown of PIP2 to yield of IP3 and DAG. IP3 then causes the release of calcium ions from the endoplasmic reticulum, and DAG activates a particular protein kinase known as protein kinase C.

PART TWO Biological Control Systems

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

PART TWO Biological Control Systems

TABLE 7-6 Calcium as a Second Messenger

Extracellular fluid

Common mechanisms by which stimulation of a cell leads to an increase in cytosolic Ca2+ concentration:

1. Receptor activation a. Plasma-membrane calcium channels open in response to a first messenger; the receptor itself may contain the channel, or the receptor may activate a G protein that opens the channel via a second messenger.

b. Calcium is released from the endoplasmic reticulum; this is mediated by second messengers, particularly IP3 and calcium entering from the extracellular fluid.

c. Active calcium transport out of the cell is inhibited by a second messenger.

2. Opening of voltage-sensitive calcium channels

Major mechanisms by which an increase in cytosolic

Ca2+ concentration induces the cell's responses:

1. Calcium binds to calmodulin. On binding calcium, the calmodulin changes shape, which allows it to activate or inhibit a large variety of enzymes and other proteins. Many of these enzymes are protein kinases.

2. Calcium combines with calcium-binding intermediary proteins other than calmodulin. These proteins then act in a manner analogous to calmodulin.

3. Calcium combines with and alters response proteins directly, without the intermediation of any specific calcium-binding protein.

a small amount of extracellular calcium entering the cell can function as a second messenger to release a much larger amount of calcium from the endoplasmic reticulum. This is termed "calcium-induced calcium release." Thus, depending on the cell and the signal— first messenger or an electrical impulse—the major second messenger that releases calcium from the en-doplasmic reticulum can be either IP3 or calcium itself (item 1b in the top of Table 7-6).

Now we turn to the question of how the increased cytosolic calcium concentration elicits the cells' responses (bottom of Table 7-6). The common denominator of calcium's actions is its ability to bind to various cytosolic proteins, altering their conformation and thereby activating their function. One of the most important of these is a protein found in virtually all cells and known as calmodulin (Figure 7-19). On binding with calcium, calmodulin changes shape, and this allows calcium-calmodulin to activate or inhibit a large variety of enzymes and other proteins, many of which are protein kinases. Activation or inhibition of calmodulin-dependent protein kinases leads, via phosphorylation, to activation or inhibition of proteins involved in the cell's ultimate responses to the first messenger.

First messenger




Intracellular fluid

I Ca2+ entry via plasma-membrane Ca2+ channels and/or

I Ca2+ release from endoplasmic reticulum

T Cytosolic Ca2+

nactive ^ > Active Ca-t calmodulin

Inactive calmodulin


Active calmodulin-dependent calmodulin-dependent j protein kinase protein kinase


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