Propagation of the Cellular Signal

Binding Initiates a Signaling Pathway

Ligand binding to cell-surface receptors activates the receptor’s intracellular components setting off a signaling pathway or cascade.

Learning Objectives

Recognize the relationship between a ligand’s structure and its mechanism of action.

Key Takeaways

Key Points

  • Signaling pathways can be complicated since most cellular proteins can affect different downstream events.
  • Cell -surface receptors are integral in signaling pathways.
  • Ion channel -linked receptors open a channel once a ligand binds allowing specific ions to pass through the membrane.
  • G-protein-linked receptors activate a membrane protein called a G-protein once a ligand binds.
  • Enzyme -linked receptors are cell-surface receptors with intracellular domains.

Key Terms

  • ligand: an ion, molecule, or functional group that binds to another chemical entity to form a larger complex
  • receptor: a protein on a cell wall that binds with specific molecules so that they can be absorbed into the cell in order to control certain functions

Cell-surface receptors, also known as transmembrane receptors, are membrane-anchored (integral) proteins that bind to external ligand molecules. This type of receptor spans the plasma membrane and performs signal transduction in which an extracellular signal is converted into an intracellular signal. Ligands that interact with cell-surface receptors do not have to enter the cell that they affect. Cell-surface receptors are also called cell-specific proteins or markers because they are specific to individual cell types. Each cell-surface receptor has three main components: an external ligand-binding domain, a hydrophobic membrane-spanning region, and an intracellular domain inside the cell. The ligand-binding domain is also called the extracellular domain. The size and extent of each of these domains vary widely, depending on the type of receptor. Cell-surface receptors are involved in most of the signaling in multicellular organisms.

There are three general categories of cell-surface receptors: ion channel-linked receptors, G-protein-linked receptors, and enzyme-linked receptors.

  1. Ion channel-linked receptors bind a ligand and open a channel through the membrane that allows specific ions to pass through. To form a channel, this type of cell-surface receptor has an extensive membrane-spanning region. When a ligand binds to the extracellular region of the channel, there is a conformational change in the protein’s structure that allows ions such as sodium, calcium, magnesium, and hydrogen to pass through.
  2. G-protein-linked receptors bind a ligand and activate a membrane protein called a G-protein. The activated G-protein then interacts with either an ion channel or an enzyme in the membrane. All G-protein-linked receptors have seven transmembrane domains, but each receptor has its own specific extracellular domain and G-protein-binding site.
  3. Enzyme-linked receptors are cell-surface receptors with intracellular domains that are associated with an enzyme. In some cases, the intracellular domain of the receptor itself is an enzyme. Other enzyme-linked receptors have a small intracellular domain that interacts directly with an enzyme. When a ligand binds to the extracellular domain, a signal is transferred through the membrane, activating the enzyme. Activation of the enzyme sets off a chain of events within the cell that eventually leads to a response.

After the ligand binds to the cell-surface receptor, the activation of the receptor’s intracellular components sets off a chain of events that is called a signaling pathway or a signaling cascade. In a signaling pathway, second messengers, enzymes, and activated proteins interact with specific proteins, which are in turn activated in a chain reaction that eventually leads to a change in the cell’s environment. The events in the cascade occur in a series, much like a current flows in a river. Interactions that occur before a certain point are defined as upstream events; events after that point are called downstream events.

image

Ligand Initiated Signaling Pathway: An example of ligand initiated signaling pathways is when epidermal growth factor (EGF) binds to its receptor. A complex cascade of downstream events causes the cell to grow and divide.

Signaling pathways can get very complicated very quickly because most cellular proteins can affect different downstream events, depending on the conditions within the cell. A single pathway can branch off toward different endpoints based on the interplay between two or more signaling pathways. The same ligands are often used to initiate different signals in different cell types. This variation in response is due to differences in protein expression in different cell types. Another complicating element is signal integration of the pathways in which signals from two or more different cell-surface receptors merge to activate the same response in the cell. This process can ensure that multiple external requirements are met before a cell commits to a specific response.

The effects of extracellular signals can also be amplified by enzymatic cascades. At the initiation of the signal, a single ligand binds to a single receptor. However, activation of a receptor-linked enzyme can activate many copies of a component of the signaling cascade, which amplifies the signal.

Methods of Intracellular Signaling

Signaling pathway induction activates a sequence of enzymatic modifications that are recognized in turn by the next component downstream.

Learning Objectives

Explain how the binding of a ligand initiates signal transduction throughout a cell

Key Takeaways

Key Points

  • Phosphorylation, the addition of a phosphate group to a molecule such as a protein, is one of the most common chemical modifications that occurs in signaling pathways.
  • The activation of second messengers, small molecules that propagate a signal, is a common event after the induction of a signaling pathway.
  • Calcium ion, cyclic AMP, and inositol phospholipids are examples of widely-used second messengers.

Key Terms

  • second messenger: any substance used to transmit a signal within a cell, especially one which triggers a cascade of events by activating cellular components
  • phosphorylation: the addition of a phosphate group to a compound; often catalyzed by enzymes

The induction of a signaling pathway depends on the modification of a cellular component by an enzyme. There are numerous enzymatic modifications that can occur which are recognized in turn by the next component downstream.

One of the most common chemical modifications that occurs in signaling pathways is the addition of a phosphate group (PO4–3) to a molecule such as a protein in a process called phosphorylation. The phosphate can be added to a nucleotide such as GMP to form GDP or GTP. Phosphates are also often added to serine, threonine, and tyrosine residues of proteins where they replace the hydroxyl group of the amino acid. The transfer of the phosphate is catalyzed by an enzyme called a kinase. Various kinases are named for the substrate they phosphorylate. Phosphorylation of serine and threonine residues often activates enzymes. Phosphorylation of tyrosine residues can either affect the activity of an enzyme or create a binding site that interacts with downstream components in the signaling cascade. Phosphorylation may activate or inactivate enzymes; the reversal of phosphorylation, dephosphorylation by a phosphatase, will reverse the effect.

image

Example of phosphorylation: In protein phosphorylation, a phosphate group (PO4-3 ) is added to residues of the amino acids serine, threonine, and tyrosine.

The activation of second messengers is also a common event after the induction of a signaling pathway. They are small molecules that propagate a signal after it has been initiated by the binding of the signaling molecule to the receptor. These molecules help to spread a signal through the cytoplasm by altering the behavior of certain cellular proteins.

Calcium ion is a widely-used second messenger. The free concentration of calcium ions (Ca2+) within a cell is very low because ion pumps in the plasma membrane continuously use adenosine-5′-triphosphate ( ATP ) to remove it. For signaling purposes, Ca2+ is stored in cytoplasmic vesicles, such as the endoplasmic reticulum, or accessed from outside the cell. When signaling occurs, ligand-gated calcium ion channels allow the higher levels of Ca2+ that are present outside the cell (or in intracellular storage compartments) to flow into the cytoplasm, which raises the concentration of cytoplasmic Ca2+. The response to the increase in Ca2+ varies, depending on the cell type involved. For example, in the β-cells of the pancreas, Ca2+ signaling leads to the release of insulin, whereas in muscle cells, an increase in Ca2+ leads to muscle contractions.

Another second messenger utilized in many different cell types is cyclic AMP (cAMP). Cyclic AMP is synthesized by the enzyme adenylyl cyclase from ATP. The main role of cAMP in cells is to bind to and activate an enzyme called cAMP-dependent kinase (A-kinase). A-kinase regulates many vital metabolic pathways. It phosphorylates serine and threonine residues of its target proteins, activating them in the process. A-kinase is found in many different types of cells; the target proteins in each kind of cell are different. Differences give rise to the variation of the responses to cAMP in different cells.

image

Example of cAMP as a second messenger: This diagram shows the mechanism for the formation of cyclic AMP (cAMP). cAMP serves as a second messenger to activate or inactivate proteins within the cell. Termination of the signal occurs when an enzyme called phosphodiesterase converts cAMP into AMP.

Present in small concentrations in the plasma membrane, inositol phospholipids are lipids that can also be converted into second messengers. Because these molecules are membrane components, they are located near membrane-bound receptors and can easily interact with them. Phosphatidylinositol (PI) is the main phospholipid that plays a role in cellular signaling. Enzymes known as kinases phosphorylate PI to form PI-phosphate (PIP) and PI-bisphosphate (PIP2).