Signaling systems consist of receptors that reside either in the cell membrane (surface receptors) or within the cells (intracellular receptors). Receptors are activated by a variety of extracellular signals or first messengers, including neurotransmitters, protein hormones and growth factors, steroids, and other chemical messengers. Some lipid-soluble chemical messengers move through the membrane and bind to cytoplasmic or nuclear receptors to exert their physiologic effects. Signaling systems also include transducers and effectors that are involved in conversion of the signal into a physiologic response. The pathway may include additional intracellular mechanisms, called second messengers. Many molecules involved in signal transduction are proteins. A unique property of proteins that allows them to function in this way is their ability to change their shape or conformation, thereby changing their function and consequently the functions of the cell. Proteins often accomplish these conformational changes through enzymes called protein kinases that catalyze the phosphorylation of amino acids in the protein structure.
Cell Surface Receptors
Each cell type in the body contains a distinctive set of surface receptors that enable it to respond to a complementary set of signaling molecules in a specific, preprogrammed way. These proteins are not static components of the cell membrane; they increase or decrease in number according to the needs of the cell. When excess chemical messengers are present, the number of active receptors decreases in a process called down-regulation; when there is a deficiency of the messenger, the number of active receptors increases through up-regulation. Three known classes of cell surface receptor proteins exist: G-protein–linked, ion-channel–linked, and enzyme-linked.
G-Protein–Linked Receptors. With more than a 1000 members, G-protein–linked receptors are the largest family of cell surface receptors. Although many intercellular messengers exist, they rely on the intermediary activity of a separate class of membrane-bound regulatory proteins to convert external signals (first messengers) into internal signals (second messengers). Because these regulatory proteins bind to guanine nucleotides such as guanine diphosphate (GDP) and guanine triphosphate (GTP), they are called G proteins. G-protein–linked receptors mediate cellular responses for numerous types of first messengers, including proteins, small peptides, amino acids, and fatty acid derivatives such as the prostaglandins.
Although there are differences among the G-protein–linked receptors, all share a number of features. They all have a ligand-binding extracellular receptor component, which functions as a signal discriminator by recognizing a specific first messenger, and they all undergo conformational changes with receptor binding that activates the G protein (Fig. 4.10). All G proteins are found on the cytoplasmic side of the cell membrane, and all incorporate the GTPase cycle, which functions as a molecular switch that exists in two states. In its activated (on) state, the G protein has a high affinity for GTP, and in its inactivated (off) state, it binds GDP.
At the molecular level, G proteins are heterotrimeric (i.e., they have three subunits) proteins (see Fig. 4.10). The three subunits are designated alpha (α), beta (β), and gamma (γ). The α subunit can bind either GDP or GTP and contains the GTPase activity. GTPase is an enzyme that converts GTP with its three phosphate groups to GDP with its two phosphate groups.
When GDP is bound to the α subunit, the G protein is inactive; when GTP is bound, it is active. The activated G protein has GTPase activity, so eventually the bound GTP is hydrolyzed to GDP, and the G protein reverts to its inactive state. Receptor activation causes the α subunit to dissociate from the receptor and the β and γ subunits and transmit the signal from the first messenger to its effector protein. Often, the effector is an enzyme that converts an inactive precursor molecule into a second messenger, which diffuses into the cytoplasm and carries the signal beyond the cell membrane. A common second messenger is cyclic adenosine monophosphate (cAMP). It is activated by the enzyme adenylyl cyclase, which generates cAMP by transferring phosphate groups from ATP to other proteins. This transfer changes the conformation and function of these proteins. Such changes eventually produce the cell response to the first messenger, whether it is a secretion, muscle contraction or relaxation, or a change in metabolism. Sometimes, it is the opening of membrane channels involved in calcium or potassium influx.
Enzyme-Linked Receptors. Like G-protein–linked receptors, enzyme-linked receptors are transmembrane proteins with their ligand-binding site on the outer surface of the cell membrane. Instead of having a cytosolic domain that associates with a G protein, their cytosolic domain either has intrinsic enzyme activity or associates directly with an enzyme. There are several classes of enzyme-linked receptors, including those that activate or have tyrosine kinase activity. Enzyme-linked receptors mediate cellular responses such as calcium influx, increased sodium–potassium exchange, and stimulation of glucose and amino acid uptake. Insulin, for example, acts by binding to a surface receptor with tyrosine kinase activity.
The signaling cascades generated by the activation of tyrosine kinase receptors are also involved in the function of growth factors. As their name implies, many growth factors are important messengers in signaling cell replacement and cell growth. Most of the growth factors belong to one of three groups: factors that foster the multiplication and development of various cell types (e.g., epidermal growth factor and vascular endothelial growth factor); cytokines, which are important in the regulation of the immune system; and colony-stimulating factors, which regulate the proliferation and maturation of white and red blood cells. All growth factors function by binding to specific receptors that deliver signals to target cells. These signals have two general effects: they stimulate the transcription of many genes that were silent in resting cells, and they regulate the entry of cells into the cell cycle and their passage through the cell cycle.
Ion-Channel–Linked Receptors. Ion-channel–linked receptors are involved in the rapid synaptic signaling between electrically excitable cells. Many neurotransmitters mediate this type of signaling by transiently opening or closing ion channels formed by integral proteins in the cell membrane. This type of signaling is involved in the transmission of impulses in nerve and muscle cells.
Some messengers, such as thyroid hormone and steroid hormones, do not bind to membrane receptors but move directly across the lipid layer of the cell membrane and are carried to the cell nucleus, where they influence DNA activity. Many of these hormones bind to a cytoplasmic receptor, and the receptor–hormone complex is carried to the nucleus. In the nucleus, the receptor–hormone complex binds to DNA, thereby increasing transcription of mRNA. The mRNAs are translated in the ribosomes, with the production of increased amounts of proteins that alter cell function.