Cells in a multicellular organism need to communicate with one another to regulate their development into tissues, to control their growth and division, and to coordinate their functions. Many cells form communicating junctions that couple adjacent cells, allowing the exchange of ions and small molecules (see Chapter 4: Epithelial Tissue). Through these channels, also called gap junctions, signals pass directly from cell to cell without reaching the extracellular fluid. In other cases, cells display membrane-bound signaling molecules that influence other cells in direct physical contact.
Extracellular signaling molecules, or messengers, mediate three kinds of communication between cells. In endocrine signaling, hormones are carried in the blood to target cells (ie, cells with specific receptors to a hormone) throughout the body; in paracrine signaling, chemical mediators are rapidly metabolized so that they act on local cells only; and in synaptic signaling, neurotransmitters act only on adjacent nerve cells through special contact areas called synapses (see Chapter 9: Nerve Tissue & the Nervous System). In some cases, paracrine signals act on the same cell type that produced the messenger molecule, a phenomenon called autocrine signaling. Each cell type in the body contains a distinctive set of receptor proteins that enables it to respond to a complementary set of signaling molecules in a specific, programmed way (Figure 2–9).
Cells respond to chemical signals according to the library of receptors they have. In this schematic representation, three cells appear with different receptors, and the extracellular environment contains several ligands that will interact with the appropriate receptors. Considering that the extracellular environment contains a multitude of molecules, it is important that ligands and the respective receptors exhibit complementary morphology and great affinity.
Signaling molecules differ in their water solubility. Small hydrophobic signaling molecules, such as steroid and thyroid hormones, diffuse through the plasma membrane of the target cell and activate receptor proteins inside the cell. In contrast, hydrophilic signaling molecules, including neurotransmitters, most hormones, and local chemical mediators (paracrine signals), activate receptor proteins on the surface of target cells. These receptors, which span the cell membrane, relay information to a series of intracellular intermediaries that ultimately passes the signal to its final destination in either the cytoplasm or the nucleus. The numerous intercellular hydrophilic messengers rely on membrane proteins that direct the flow of information from the receptor to the rest of the cell. The best studied of these proteins are the G proteins, so named because they bind to guanine nucleotides. Once a first messenger (hormone, neurotransmitter, paracrine signal) binds to a receptor, conformational changes occur in the receptor; this, in turn, activates the G protein–guanosine diphosphate complex (Figure 2–10). A guanosine diphosphate–guanosine triphosphate exchange releases the subunit of the G protein, which acts on other membrane-bound intermediaries called effectors. Often, the effector is an enzyme that converts an inactive precursor molecule into an active second messenger, which can diffuse through the cytoplasm and carry the signal beyond the cell membrane. Second messengers trigger a cascade of molecular reactions that leads to changes in cell behavior. The examples listed in Table 2–2 illustrate the diversity of G proteins present in various tissues and their roles in regulating important cell functions.
Diagram illustrating how G proteins switch effectors on and off. (Modified and reprinted, with permission, from Linder M, Gilman AG: G proteins. Sci Am 1992;267:56.)
Reproduced, with permission, from Linder M, Gilman AG: G proteins. Sci Am 1992;267:56.
Several diseases have been shown to be due to defective receptors. For example, pseudohypoparathyroidism and a type of dwarfism are due to nonfunctioning parathyroid and growth hormone receptors. In these two conditions the glands produce the respective hormones, but the target cells do not respond, because they lack normal receptors.
Signaling Mediated by Intracellular Receptors
Steroid hormones are small hydrophobic (lipid-soluble) molecules; binding reversibly to carrier proteins in the plasma transports them in the blood. Once released from their carrier proteins, they diffuse through the plasma membrane lipids of the target cell and bind reversibly to specific steroid hormone–receptor proteins in the cytoplasm or the nucleus. The binding of hormone activates the receptor, enabling it to bind with high affinity to specific DNA sequences; this generally increases the level of transcription from specific genes. Each steroid hormone is recognized by a different member of a family of homologous receptor proteins. Thyroid hormones are modified lipophilic amino acids that also act on intracellular receptors.