There are many kinds of chemical signals. Some ligands are hydrophobic (nonpolar) and can diffuse through membranes, whereas others cannot. Physical signals such as light also vary in their ability to penetrate cells and tissues. Correspondingly, a receptor can be classified by its location in the cell, which largely depends on the nature of its signal (Figure 7.4):

In complex eukaryotes such as mammals and higher plants, there are three well-studied categories of cell membrane receptors that are grouped according to their functions: ion channels, protein kinase receptors, and G protein-coupled receptors.

ION CHANNELS As you saw in Key Concept 6.3, the cell membranes of many types of cells have gated ion channels that allow ions such as Na⁺, K⁺, Ca²⁺, or Cl^– to enter or leave the cell. The gate-opening mechanism is an alteration in the three-dimensional shape of the channel protein upon interaction with a signal; thus these proteins function as *receptors. Each type of ion channel responds to a specific signal, including sensory stimuli such as light, sound, and electric charge differences across the cell membrane, as well as chemical ligands such as hormones and neurotransmitters.

The acetylcholine receptor, located in the cell membrane of skeletal muscle cells, is an example of an ion channel. This protein is a sodium channel that binds the ligand acetylcholine, which is a neurotransmitter—a chemical signal released from nerve cells (Figure 7.5). When two molecules of acetylcholine bind to the channel, it opens for about a thousandth of a second. That is enough time for Na⁺, which is more concentrated outside the cell than inside, to rush into the cell, moving in response to both concentration and electric potential gradients. The change in Na⁺ concentration in the cell initiates a series of events that result in muscle contraction.

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PROTEIN KINASE RECEPTORS Some eukaryotic receptor proteins, called protein kinases, catalyze the phosphorylation (adding phosphate) of themselves or other proteins, thus changing their shapes and therefore their functions.

Phosphorylation is a reaction that is especially important in biology. Of the estimated 21,000 genes that code for proteins in humans, more than 500 of them encode protein kinases. When you think of all the functions that make up a person, this is indeed an impressive number. The three amino acids that are phosphorylated are therefore worth knowing:

The receptor for insulin is an example of a protein kinase receptor. Insulin is a protein hormone made by the pancreas. Its receptor has two copies each of two different polypeptide subunits called α and β (Figure 7.6). When insulin binds to the receptor, the receptor becomes activated and is able to phosphorylate itself and certain cytoplasmic proteins that are appropriately called insulin-response substrates. These proteins then initiate many cellular responses, including the insertion of glucose transporters (see Figure 6.12) into the cell membrane.

G PROTEIN-COUPLED RECEPTORS A third category of eukaryotic cell membrane receptors is the G protein-coupled receptors, also referred to by the more impressive sounding name seven-transmembrane domain receptors. These receptors have many roles, including light detection in the mammalian retina (photoreceptors), detection of odors (olfactory receptors), and regulation of mood and behavior (such as mating in mammals and even single-celled yeasts). The receptors that bind the hormones oxytocin and vasopressin, which affect mating behavior in voles (see the opening story), are G protein-coupled receptors.

The seven-transmembrane domains of the receptor protein pass through the phospholipid bilayer and are separated by short loops that extend either outside or inside the cell. Ligand binding on the extracellular side of the receptor changes the shape of its cytoplasmic region, exposing a site that binds to a mobile membrane protein called a G protein. The G protein is partially inserted into the lipid bilayer and partially exposed on the cytoplasmic surface of the membrane.

Many G proteins have three polypeptide subunits and can bind three different types of molecules (Figure 7.7A):

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When the G protein binds to an activated receptor protein, GDP is exchanged for GTP (Figure 7.7B). At the same time, the ligand is usually released from the extracellular side of the receptor. GTP binding causes a conformational change in the G protein. The GTP-bound subunit then separates from the rest of the G protein, diffusing in the plane of the phospholipid bilayer until it encounters an effector protein to which it can bind. An effector protein is just what its name implies: it causes an effect in the cell. The binding of the GTP-bearing G protein subunit activates the effector—which may be an enzyme or an ion channel—thereby causing changes in cell function (Figure 7.7C).

After activation of the effector protein, the GTP bound to the G protein is hydrolyzed to GDP. The now inactive G protein subunit separates from the effector protein and diffuses in the membrane to collide with and bind to the other two G protein subunits. When the three components of the G protein are reassembled, the protein is capable of binding again to an activated receptor. After binding, the activated receptor exchanges the GDP on the G protein for a GTP, and the cycle begins again.