Intracellular Signaling After Hormone Receptor Activation

Almost without exception, a hormone affects its target tissues by first forming a hormone-receptor complex. This alters the function of the receptor itself, and the activated receptor initiates the hormonal effects. To explain this, let us give a few examples of the different types of interactions.

Ion Channel-Linked Receptors. Virtually all the neuro-transmitter substances, such as acetylcholine and norepinephrine, combine with receptors in the postsy-naptic membrane. This almost always causes a change in the structure of the receptor, usually opening or closing a channel for one or more ions. Some of these ion channel-linked receptors open (or close) channels for sodium ions, others for potassium ions, others for calcium ions, and so forth. The altered movement of these ions through the channels causes the subsequent effects on the postsynaptic cells. Although a few hormones may exert some of their actions through activation of ion channel receptors, most hormones that open or close ions channels do this indirectly by coupling with G protein-linked or enzyme-linked receptors, as discussed next.

G Protein-Linked Hormone Receptors. Many hormones activate receptors that indirectly regulate the activity of target proteins (e.g., enzymes or ion channels) by coupling with groups of cell membrane proteins called heterotrimeric GTP-binding proteins (G proteins) (Figure 74-4). There are more than 1000 known G protein-coupled receptors, all of which have seven transmembrane segments that loop in and out of the cell membrane. Some parts of the receptor that protrude into the cell cytoplasm (especially the cytoplas-mic tail of the receptor) are coupled to G proteins that include three (i.e., trimeric) parts—the a, b, and g sub-units. When the ligand (hormone) binds to the extracellular part of the receptor, a conformational change occurs in the receptor that activates the G proteins and induces intracellular signals that either (1) open or close cell membrane ion channels or (2) change the activity of an enzyme in the cytoplasm of the cell.

The trimeric G proteins are named for their ability to bind guanosine nucleotides. In their inactive state, the a, b, and g subunits of G proteins form a complex that binds guanosine diphosphate (GDP) on the a subunit. When the receptor is activated, it undergoes a conformational change that causes the GDP-bound trimeric G protein to associate with the cytoplasmic part of the receptor and to exchange GDP for guano-sine triphosphate (GTP). Displacement of GDP by GTP causes the a subunit to dissociate from the trimeric complex and to associate with other intracel-lular signaling proteins; these proteins, in turn, alter the activity of ion channels or intracellular enzymes such as adenylyl cyclase or phospholipase C, which alters cell function.

The signaling event is rapidly terminated when the hormone is removed and the a subunit inactivates itself by converting its bound GTP to GDP; then the a subunit once again combines with the b and g sub-units to form an inactive, membrane-bound trimeric G protein.

Some hormones are coupled to inhibitory G proteins (denoted Gi proteins), whereas others are coupled to stimulatory G proteins (denoted Gs proteins). Thus, depending on the coupling of a hormone receptor to an inhibitory or stimulatory G protein, a hormone can either increase or decrease the activity of intracellular enzymes. This complex system of cell membrane G proteins provides a vast array of potential cell responses to different hormones in the various target tissues of the body.

Enzyme-Linked Hormone Receptors. Some receptors, when activated, function directly as enzymes or are closely associated with enzymes that they activate. These enzyme-linked receptors are proteins that pass through the membrane only once, in contrast to the seven-transmembrane G protein-coupled receptors. Enzyme-linked receptors have their hormone-binding site on the outside of the cell membrane and their catalytic or enzyme-binding site on the inside. When the hormone binds to the extracellular part of the receptor, an enzyme immediately inside the cell membrane is activated (or occasionally inactivated). Although many enzyme-linked receptors have intrinsic enzyme activity, others rely on enzymes that are closely associated with the receptor to produce changes in cell function.

One example of an enzyme-linked receptor is the leptin receptor (Figure 74-5). Leptin is a hormone

Hormone

Receptor

Extracellular fluid

Cytoplasm

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Essentials of Human Physiology

Essentials of Human Physiology

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.

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