Enzyme-linked receptors can either function as enzymes or regulate enzymes. Most enzyme-linked receptors are protein kinases or associated with protein kinases. When ligands bind to these receptors, they cause the kinases to phosphorylate specific proteins on specific amino acids, resulting in the activation or inhibition of protein activity.

Nuclear receptors are small hydrophobic molecules, such as steroid hormones, thyroid hormones, retinoids, and vitamin D. These molecules have a long half-life and can diffuse across the plasma membrane. They bind to either nuclear receptors or cytoplasmic receptors. Once bound to their ligands, cytoplasmic receptors translocate to the nucleus. Some nuclear receptors, like those binding cortisol and aldosterone, are initially located in the cytosol and enter the nucleus upon hormone binding. On the other hand, receptors like the thyroid hormone receptor are already located in the nucleus. In both cases, inactive receptors are bound to inhibitory proteins, and the binding of hormones causes the dissociation of the inhibitory complex. Hormone binding also leads to the binding of coactivator proteins that activate gene transcription. The hormone-receptor complex regulates the transcription of specific genes. Gene activation usually occurs in two steps: an early primary response within approximately 30 minutes, which activates genes stimulating the production of a delayed secondary response that occurs over hours to days.

Each hormone elicits a specific response based on the cellular expression of the specific receptor and cell type-specific expression of gene regulatory proteins that interact with the activated receptor. These interactions regulate the transcription of a specific set of genes. Aside from gene-regulating steroid receptors, there is evidence suggesting the existence of membrane and juxtamembrane steroid receptors that mediate the rapid, non-genomic effects of steroid hormones.

Some membrane proteins do not meet the classical definition of receptors, but they serve a receptor-like function. These proteins recognize extracellular signals and transduce the signals into intracellular second messengers, which have biological effects. For example, upon activation by a ligand, some membrane proteins undergo regulated intramembrane proteolysis (RIP). This process produces a cytosolic peptide fragment that enters the nucleus and regulates gene expression. In this signaling pathway, ligand binding to a plasma membrane receptor leads to ectodomain shedding, facilitated by metalloproteinase-disintegrin family members. This shedding produces a carboxy-terminal fragment that serves as the substrate for γ-secretase. γ-Secretase induces RIP, causing the release of an intracellular domain of the protein. This released domain enters the nucleus and regulates transcription.
Enzyme-linked receptors either function as enzymes or are associated with and regulate enzymes (see
Fig. 3.4C ). Most enzyme-linked receptors are protein kinases or are associated with protein kinases, and ligand binding causes the kinases to phosphorylate a specific subset of proteins on specific amino acids, which in turn activates or inhibits protein activity.
Nuclear receptors are small hydrophobic molecules, including steroid hormones, thyroid hormones, retinoids, and vitamin D, that have a long biological half-life (hours to days), diffuse across the plasma membrane, and bind to nuclear receptors or to cytoplasmic receptors that, once bound to their ligand, translocate to the nucleus (see
Fig.
3.5 ). Some nuclear receptors, such as those that bind cortisol
Signal molecule as a dimer Signal molecule • Fig. 3.4 Three of the Four Classes of Plasma Membrane Receptors. See text for details. (Redrawn from Alberts B, et al: Molecular Biology of the Cell. 6th ed. New York: Garland Science; 2015.) and aldosterone, are located in the cytosol and enter the nucleus after binding to hormone, whereas other receptors, including the thyroid hormone receptor, are located in the nucleus. In both cases, inactive receptors are bound to inhibitory proteins, and binding of hormone results in dissociation of the inhibitory complex. Hormone binding causes the receptor to bind coactivator proteins that activate gene transcription. Once activated, the hormone-receptor complex regulates the transcription of specific genes. Activation of specific genes usually occurs in two steps: an early primary response (≈30 minutes), which activates genes that stimulate other genes to produce a delayed (hours to days) secondary response (see
Fig. 3.5).
Each hormone elicits a specific response that is based on cellular expression of the cognate receptor, as well as on cell type–specific expression of gene regulatory proteins that interact with the activated receptor to regulate the transcription of a specific set of genes (see for more details). In addition to steroid receptors that regulate gene expression, evidence also suggests the existence of membrane and juxtamembrane steroid receptors that mediate the rapid, nongenomic effects of steroid hormones.
Some membrane proteins do not fit the classic definition of receptors, but they subserve a receptor-like function in that they recognize extracellular signals and transduce the signals into an intracellular second messenger that has a biological effect. For example, on activation by a ligand, some membrane proteins undergo regulated intramembrane proteolysis (RIP), which elaborates a cytosolic peptide fragment that enters the nucleus and regulates gene expression (
Fig. 3.6 ). In this signaling pathway, binding of ligand to a plasma membrane receptor leads to ectodomain shedding, facilitated by members of the metalloproteinase-disintegrin family, and produces a carboxy-terminal fragment that is the substrate for γ-secretase. γ-Secretase induces RIP, thereby causing the release of an intracellular domain of
CHAPTER 3 Signal Transduction, Membrane Receptors, Second Messengers, and Regulation of Gene Expression 41 • Fig. 3.5 Steroid Hormones Stimulate the Transcription of Early-Response Genes and Late-Response Genes. See text for details. (Redrawn from Alberts B, et al: Molecular Biology of Cell. 6th ed. New York:
Garland Science; 2015.)
Translocation to the nucleus • Fig. 3.6 Regulated Intramembrane Proteolysis. See text for details. (Redrawn from Alberts B, et al: Molecular Biology of the Cell. 6th ed. New York: Garland Science; 2015.) the protein that enters the nucleus and regulates transcription (see