The concentration of Ca2+ in the cytoplasm is kept very low by the action of active transport carriers—calcium pumps—in the plasma membrane. Through the action of these pumps, the concentration of calcium is about 10,000 times lower in the cytoplasm than in the extracellular fluid. In addition, the endoplasmic reticulum (chapter 3) of many cells contains calcium pumps that actively transport Ca2+ from the cytoplasm into the cisternae of the endoplasmic reticulum. The steep concentration gradient for Ca2+ that results allows various stimuli to evoke a rapid, though brief, diffusion of Ca2+ into the cytoplasm, which can serve as a signal in different control systems.
At the terminal boutons of axons, for example, the entry of Ca2+ through voltage-regulated Ca2+ channels in the plasma membrane serves as a signal for the release of neurotransmitters (chapter 7; see fig. 7.21). Similarly, when muscles are stimulated to contract, Ca2+ couples electrical excitation of the muscle cell to the mechanical processes of contraction (see chapter 12). Additionally, it is now known that Ca2+ serves as a part of a second-messenger system in the action of a number of hormones.
When epinephrine stimulates its target organs, it must first bind to adrenergic receptor proteins in the membrane of its target cells. As discussed in chapter 9, there are two types of adrenergic receptors—alpha and beta (see fig. 9.10). Stimulation of the beta-adrenergic receptors by epinephrine results in activation of adenyl-ate cyclase and the production of cAMP. Stimulation of alpha-adrenergic receptors by epinephrine, in contrast, activates the target cell via the Ca2+ second-messenger system (see fig. 11.10).
The binding of epinephrine to its alpha-adrenergic receptor activates, via a G-protein intermediate, an enzyme in the plasma membrane known as phospholipase C. The substrate of this enzyme, a particular membrane phospholipid, is split by the active enzyme into inositol triphosphate (IP3) and another derivative, diacylglycerol (DAG). Both derivatives serve as second messengers, but the action of IP3 is somewhat better understood and will be discussed in this section.
The IP3 leaves the plasma membrane and diffuses through the cytoplasm to the endoplasmic reticulum. The membrane of the endoplasmic reticulum contains receptor proteins for IP3, so that the IP3 is a second messenger in its own right, carrying the hormone's message from the plasma membrane to the endoplas-mic reticulum. Binding of IP3 to its receptors causes specific Ca2+ channels to open, so that Ca2+ diffuses out of the endoplas-mic reticulum and into the cytoplasm (fig. 11.9).
As a result of these events, there is a rapid and transient rise in the cytoplasmic Ca2+ concentration. This signal is augmented, through mechanisms that are incompletely understood, by the opening of Ca2+ channels in the plasma membrane. This may be due to the action of yet a different (and currently unknown) messenger sent from the endoplasmic reticulum to the plasma membrane. The Ca2+ that enters the cytoplasm binds to a protein called calmodulin. Once Ca2+ binds to calmodulin, the now-active calmodulin in turn activates specific protein kinase enzymes (those that add phosphate groups to proteins) that modify the actions of other enzymes in the cell (fig. 11.10). Activation of specific calmodulin-dependent enzymes is analogous to the activation of enzymes by cAMP-dependent protein kinase. The steps of the Ca2+ second-messenger system are summarized in table 11.5.
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This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.