Each cell in a multicellular animal is programmed to respond to a specific set of extracellular signal molecules produced by other cells. The signal molecules act by binding to a complementary set of receptor proteins expressed by the target cells. Most extracellular signal molecules activate cell-surface receptor proteins, which act as signal transducers, converting the extracellular signal into intracellular ones that alter the behavior of the target cell. Activated receptors relay the signal into the cell interior by activating intracellular signaling proteins. Some of these signaling proteins transduce, amplify, or spread the signal as they relay it, while others integrate signals from different signaling pathways. Some function as switches that are transiently activated by phosphorylation or GTP binding. Large signaling complexes form by means of modular interaction domains in the signaling proteins, which allow the proteins to form functional signaling networks.
Target cells use various mechanisms, including feedback loops, to adjust the ways in which they respond to extracellular signals. Positive feedback loops can help cells to respond in an all-or-none fashion to a gradually increasing concentration of an extracellular signal and to convert a short-lasting signal into a long-lasting, or even irreversible, response. Negative feedback allows cells to adapt to a signal molecule, which enables them to respond to small changes in the concentration of the signal molecule over a large concentration range.
G-protein-coupled receptors (GPCRs) form the largest family of cell-surface receptors, and they mediate most responses to signals from the external world, as well as signals from other cells, including hormones, neurotransmitters, and local mediators. Our senses of sight, smell, and taste depend on them. There are more than 800 GPCRs in humans, and in mice there are about 1000 concerned with the sense of smell alone. The signal molecules that act on GPCRs are as varied in structure as they are in function and include proteins and small peptides, as well as derivatives of amino acids and fatty acids, not to mention photons of light and all the molecules that we can smell or taste. The same signal molecule can activate many different GPCR family members; for example, adrenaline activates at least 9 distinct GPCRs, acetylcholine another 5, and the neurotransmitter serotonin at least 14. The different receptors for the same signal are usually expressed in different cell types and elicit different responses.
Despite the chemical and functional diversity of the signal molecules that activate them, all GPCRs have a similar structure. They consist of a single polypeptide chain that threads back and forth across the lipid bilayer seven times, forming a cylindrical structure, often with a deep ligand-binding site at its center (Figure 15–21). In addition to their characteristic orientation in the plasma membrane, they all use G proteins to relay the signal into the cell interior.
The GPCR superfamily includes rhodopsin, the light-activated protein in the vertebrate eye, as well as the large number of olfactory receptors in the vertebrate nose. Other family members are found in unicellular organisms: the receptors in yeasts that recognize secreted mating factors are an example. It is likely that the GPCRs that mediate cell–cell signaling in multicellular organisms evolved from the sensory receptors in their unicellular eukaryotic ancestors.
It is remarkable that almost half of all known drugs work through GPCRs or the signaling pathways GPCRs activate. Of the many hundreds of genes in the human genome that encode GPCRs, about 150 encode orphan receptors, for which the ligand is unknown. Many of them are likely targets for new drugs that remain to be discovered.