G-protein-coupled receptors regulate intracellular reactions by an indirect mechanism involving an intermediate transducing molecule, called the GTP-binding proteins or G-proteins. Because these receptors all share the structural feature of crossing the plasma membrane seven times, they are also referred to as 7-transmembrane receptors or metabotropic receptors; see Chapter 7.
Hundreds of different G-protein-linked receptors have been identified. Rhodopsin, a light-sensitive 7-transmembrane protein in retinal photoreceptors, is another form of G-protein-linked receptor see Chapter Intracellular receptors are activated by cell-permeant or lipophilic signaling molecules Figure 8. Many of these receptors lead to the activation of signaling cascades that produce new mRNA and protein within the target cell. Often such receptors comprise a receptor protein bound to an inhibitory protein complex.
When the signaling molecule binds to the receptor, the inhibitory complex dissociates to expose a DNA-binding domain on the receptor. This activated form of the receptor can then move into the nucleus and directly interact with nuclear DNA, resulting in altered transcription. Some intracellular receptors are located primarily in the cytoplasm, while others are in the nucleus.
In either case, once these receptors are activated they can affect gene expression by altering DNA transcription. By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.
Turn recording back on. Action of steroid hormones. The steroid hormones diffuse across the plasma membrane and bind to nuclear receptors, which directly stimulate transcription of their target genes.
The steroid hormone receptors bind DNA as dimers. Ligand binding has distinct effects on different receptors. Some members of the steroid receptor superfamily , such as the estrogen and glucocorticoid receptors, are unable to bind to DNA in the absence of hormone. The binding of hormone induces a conformational change in the receptor, allowing it to bind to regulatory DNA sequences and activate transcription of target genes.
In other cases, the receptor binds DNA in either the presence or absence of hormone, but hormone binding alters the activity of the receptor as a transcriptional regulatory molecule. For example, thyroid hormone receptor acts as a repressor in the absence of hormone, but hormone binding converts it to an activator that stimulates transcription of thyroid hormone-inducible genes Figure Gene regulation by the thyroid hormone receptor. Thyroid hormone receptor binds DNA in either the presence or absence of hormone.
However, hormone binding changes the function of the receptor from a repressor to an activator of target gene transcription. The simple gas nitric oxide NO is a major paracrine signaling molecule in the nervous, immune, and circulatory systems. Like the steroid hormones , NO is able to diffuse directly across the plasma membrane of its target cells.
The molecular basis of NO action, however, is distinct from that of steroid action; rather than binding to a receptor that regulates transcription , NO alters the activity of intracellular target enzymes. Nitric oxide is synthesized from the amino acid arginine by the enzyme nitric oxide synthase Figure Once synthesized, NO diffuses out of the cell and can act locally to affect nearby cells.
Its action is restricted to such local effects because NO is extremely unstable, with a half-life of only a few seconds. One well-characterized example of NO action is signaling the dilation of blood vessels. The first step in this process is the release of neurotransmitters, such as acetylcholine, from the terminus of nerve cells in the blood vessel wall.
These neurotransmitters act on endothelial cells to stimulate NO synthesis. NO then diffuses to neighboring smooth muscle cells where it reacts with iron bound to the active site of the enzyme guanylyl cyclase. This increases enzymatic activity, resulting in synthesis of the second messenger cyclic GMP discussed later in this chapter , which induces muscle cell relaxation and blood vessel dilation. For example, NO is responsible for signaling the dilation of blood vessels that leads to penile erection.
It is also interesting to note that the medical use of nitroglycerin in treatment of heart disease is based on its conversion to NO, which dilates coronary blood vessels and increases blood flow to the heart. Synthesis of nitric oxide. The enzyme nitric oxide synthase NOS catalyzes the formation of nitric oxide from arginine. Another simple gas, carbon monoxide CO , also functions as a signaling molecule in the nervous system. CO is closely related to NO and appears to act similarly as a neurotransmitter and mediator of blood vessel dilation.
The synthesis of CO in brain cells, like that of NO, is stimulated by neurotransmitters. In addition, CO can stimulate guanylate cyclase, which may also represent the major physiological target of CO signaling.
The neurotransmitters carry signals between neurons or from neurons to other types of target cells such as muscle cells. The release of neurotransmitters is signaled by the arrival of an action potential at the terminus of a neuron see Figure The neurotransmitters then diffuse across the synaptic cleft and bind to receptors on the target cell surface.
Note that some neurotransmitters can also act as hormones. For example, epinephrine functions both as a neurotransmitter and as a hormone produced by the adrenal gland to signal glycogen breakdown in muscle cells.
Structure of representative neurotransmitters. The neurotransmitters are hydrophilic molecules that bind to cell surface receptors. Because the neurotransmitters are hydrophilic molecules, they are unable to cross the plasma membrane of their target cells.
Therefore, in contrast to steroid hormones and NO or CO, the neurotransmitters act by binding to cell surface receptors. Many neurotransmitter receptors are ligand -gated ion channels, such as the acetylcholine receptor discussed in the preceding chapter see Figure Neurotransmitter binding to these receptors induces a conformational change that opens ion channels, directly resulting in changes in ion flux in the target cell. Other neurotransmitter receptors are coupled to G proteins —a major group of signaling molecules discussed later in this chapter that link cell surface receptors to a variety of intracellular responses.
In the case of neurotransmitter receptors, the associated G proteins frequently act to indirectly regulate ion channel activity. The widest variety of signaling molecules in animals are peptides, ranging in size from only a few to more than a hundred amino acids. This group of signaling molecules includes peptide hormones , neuropeptides, and a diverse array of polypeptide growth factors Table Well-known examples of peptide hormones include insulin, glucagon, and the hormones produced by the pituitary gland growth hormone, follicle-stimulating hormone, prolactin, and others.
Neuropeptides are secreted by some neurons instead of the small-molecule neurotransmitters discussed in the previous section. Some of these peptides, such as the enkephalins and endorphins , function not only as neurotransmitters at synapses but also as neurohormones that act on distant cells.
The enkephalins and endorphins have been widely studied because of their activity as natural analgesics that decrease pain responses in the central nervous system. Discovered during studies of drug addiction, they are naturally occurring compounds that bind to the same receptors on the surface of brain cells as morphine does.
The polypeptide growth factors include a wide variety of signaling molecules that control animal cell growth and differentiation. NGF is a member of a family of polypeptides called neurotrophins that regulate the development and survival of neurons. During the course of experiments on NGF, Stanley Cohen serendipitously discovered an unrelated factor called epidermal growth factor , or EGF that stimulates cell proliferation.
EGF, a amino-acid polypeptide Figure Structure of epidermal growth factor EGF. They are located in the cytoplasm or even inside the nucleus and only bind ligands the intracellular receptors for ligands that can cross the cell membrane.
Ligand binding causes the release of the chaperone molecule that in non-activated state covers the DNA binding domain. The exposure of the DNA binding domain in the receptor protein leads to binding of the receptor to DNA and direct activation of transcription.
A much bigger family of cell surface receptors can be classified into several groups based on the similarity of signaling strategies they use to pass the message from the ligand to the cell metabolism or behavior.
G protein-coupled receptors activate the production of second messengers. Second messengers elicit a cellular response by binding to the intracellular targets and turning them on or off. Another important group of cell surface receptors, receptor tyrosine kinases RTK , have a built-in enzyme, a tyrosine kinase, as a part of their intracellular domain. Ligand binding activates the kinase turns on the enzyme , which phosphorylates the receptor itself.
Phosphorylated receptor attracts adapter proteins that pass the signal downstream to cellular effector proteins. Cytokine receptors function very similarly to RTKs but they recruit the kinases from the cytosol instead of having them as a part of the protein.
Ion channel receptors are already known to you from the previous chapter. They are simply ligand-gated ion channels. In response to ligand binding, they open and let ions flow through the membrane. Inflow or outflow of ions changes cell behavior. All Rights Reserved. Skip to content No cell is an island. Steps of cellular response to receptor activation Communication between cells progresses in several steps, which have common general features with one goal.
Steps during the process of cell to cell signaling. Signal recognition by receptor 2. Cellular effects 4. Receptor adaptation 5. Signal recognition Receptors are the molecules dedicated to signal recognition. The four most common signal transduction strategies are: Production of second messengers Direct activation of transcription Molecular recognition by adapter proteins Phosphorylation of cellular substrates Opening of ion channels The effects of activation of the receptor are more than a linear event.
Signal transduction strategies Cells use multiple strategies to pass the signal they receive into metabolic changes, cell movement, gene expression, and many other cellular effects. Intracellular receptors Signaling by steroid receptors Intracellular receptors aka steroid receptors are a family of ligand-activated transcription factors.
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