Cell Communication and Signal Transduction Pathways
During a scary moment, like a car braking hard in front of your school bus, your adrenal glands release epinephrine. Within seconds your heart pounds, your breathing speeds up, and your liver releases glucose. A tiny amount of one molecule changes thousands of cells at once. How can a molecule that never even enters the cell make it do something so big?
Signals, ligands, and receptors
Cells constantly "talk" to each other with chemical messages. The message is a signal molecule, called a ligand. The cell that gets the message has a receptor, a protein that binds the ligand at a specific site.
Think of a key and a lock. Only the right key (ligand) fits the lock (receptor). That is why a hormone can travel through the whole bloodstream but only change the cells that have the matching receptor. Binding changes the receptor's shape (a conformational change), and that change is what passes the message on.
Where is the receptor? Large or polar ligands, like insulin or epinephrine, cannot cross the nonpolar phospholipid bilayer, so they bind cell-surface receptors. Small nonpolar ligands, like steroid hormones (estrogen, testosterone), pass through the membrane and bind intracellular receptors in the cytoplasm or nucleus.
How far does the signal travel?
| Type | Who receives the signal? | Example |
|---|---|---|
| Autocrine | The same cell that sent it | A cell makes a growth factor for its own receptors |
| Paracrine | Nearby cells (short distance) | A neurotransmitter crossing a synapse |
| Endocrine | Distant cells, carried by the blood | Insulin from the pancreas to liver cells |
| Direct (juxtacrine) | A touching cell | A surface molecule binding a receptor on a neighbor |
Define the terms ligand* and receptor*. Then describe in one or two sentences what usually happens to a receptor protein when the correct ligand binds to it.
Define the terms ligand and receptor. Then describe in one or two sentences what usually happens to a receptor protein when the correct ligand binds to it.
Classify each example as autocrine, paracrine, endocrine, or direct (juxtacrine) signaling: (a) insulin released by the pancreas travels in the blood to liver cells; (b)…
Classify each example as autocrine, paracrine, endocrine, or direct (juxtacrine) signaling:
(a) insulin released by the pancreas travels in the blood to liver cells;
(b) a cell secretes a growth factor that binds to receptors on that same cell;
(c) a neuron releases a neurotransmitter that diffuses across a synapse to the neighboring cell;
(d) a signal molecule on the surface of one cell binds a receptor on a touching cell.
Reception, transduction, response
Signaling always follows three stages.
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Reception: the ligand binds the receptor.
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Transduction: the signal is relayed and often amplified inside the cell, through a series of molecules called a signal transduction pathway.
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Response: the cell does something: turns a gene on or off, changes an enzyme's activity, moves, divides, or dies.
Why use a relay instead of one step? Because a relay can amplify the signal (one receptor activates many molecules) and gives the cell many places to regulate the message.
The three stages of cell signaling are reception, transduction, and response. For each event below, name the stage it belongs to: (a) epinephrine binds to a G…
The three stages of cell signaling are reception, transduction, and response. For each event below, name the stage it belongs to:
(a) epinephrine binds to a G protein-coupled receptor on a liver cell;
(b) a series of protein kinases phosphorylate one another in turn;
(c) glycogen is broken down into glucose.
Three types of cultured cells are exposed to hormone X, and researchers measure whether the cells make protein Y. | Cell type | Has receptor for hormone X? | Downstream…
Three types of cultured cells are exposed to hormone X, and researchers measure whether the cells make protein Y.
| Cell type | Has receptor for hormone X? | Downstream kinase | Protein Y made? |
|---|---|---|---|
| A | Yes | Functional | Yes |
| B | No | Functional | No |
| C | Yes | Nonfunctional | No |
Explain why cells B and C both fail to respond, even though they fail for different reasons. Then propose one experiment that would show whether the defect in cell C is upstream or downstream of the kinase.
G protein-coupled receptors and second messengers
A very common receptor is the G protein-coupled receptor (GPCR). It works like this:
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The ligand binds the GPCR, which changes shape.
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The receptor activates a nearby G protein by making it swap GDP for GTP.
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The active G protein activates an enzyme, such as adenylyl cyclase.
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Adenylyl cyclase converts ATP into cAMP.
cAMP is a second messenger: a small, nonprotein molecule that spreads quickly through the cell and relays the message. (The first messenger is the ligand.) Because it is small, it diffuses fast, and a single receptor can make hundreds of cAMP molecules, which is amplification.
The G protein turns itself off: it slowly breaks GTP down to GDP. Also, the enzyme phosphodiesterase breaks cAMP into AMP, which ends the signal. Ending a signal matters as much as starting it.
In a heart muscle cell, epinephrine binds a G protein-coupled receptor, which activates a G protein, then adenylyl cyclase, which makes the second messenger cAMP. cAMP…
In a heart muscle cell, epinephrine binds a G protein-coupled receptor, which activates a G protein, then adenylyl cyclase, which makes the second messenger cAMP. cAMP activates protein kinase A, and the heart beats faster. The enzyme phosphodiesterase breaks down cAMP into AMP. A drug blocks phosphodiesterase. Predict how the drug changes the cell's response to a given amount of epinephrine, and explain your reasoning.
Cholera toxin, produced by Vibrio cholerae*, chemically modifies the G protein in intestinal cells so that it cannot turn itself off and stays active. This keeps…
Cholera toxin, produced by Vibrio cholerae, chemically modifies the G protein in intestinal cells so that it cannot turn itself off and stays active. This keeps adenylyl cyclase active and raises cAMP, which causes the cells to secrete large amounts of chloride ions and water into the intestine, producing severe diarrhea. (a) Trace the pathway from the G protein to the symptom. (b) Explain why the toxin has a much larger effect than a single signal molecule binding a receptor once. (c) A researcher proposes a drug that blocks the cell-surface receptor. Evaluate whether it would reverse the toxin's effect, and justify your answer.
Phosphorylation cascades and when things go wrong
Many pathways use protein kinases, enzymes that add a phosphate group from ATP to another protein (phosphorylation). Phosphorylation changes a protein's shape and usually turns it on (sometimes off). In a phosphorylation cascade, kinase 1 activates kinase 2, which activates kinase 3, and so on. Each active kinase can activate many copies of the next, so the signal is amplified.
Enzymes called phosphatases do the opposite: they remove phosphate groups and switch the proteins off. Kinases and phosphatases together control how strong a signal is and how long it lasts.
Another receptor type is the receptor tyrosine kinase (RTK). When a growth factor binds, two receptors pair up and phosphorylate each other, which launches a cascade that often tells the cell to divide.
When signaling goes wrong
A mutation in a receptor or kinase can make it always active, even with no ligand. A receptor for growth factors that is always on tells the cell to divide nonstop, which is a step toward cancer. Other problems: a missing receptor (cell can't respond), a nonfunctional kinase (message stops midway), or a toxin or drug that blocks or locks a step.
A growth factor normally binds a receptor tyrosine kinase, which starts a phosphorylation cascade that tells the cell to divide. A mutation in the receptor gene makes…
A growth factor normally binds a receptor tyrosine kinase, which starts a phosphorylation cascade that tells the cell to divide. A mutation in the receptor gene makes the receptor active even when no growth factor is present. Predict what happens to the rate of cell division in cells with this mutation, and explain why this kind of mutation is linked to cancer.
Researchers add a ligand to normal cells and to mutant cells that lack a phosphatase enzyme. They then measure the amount of phosphorylated signaling protein (arbitrary…
Researchers add a ligand to normal cells and to mutant cells that lack a phosphatase enzyme. They then measure the amount of phosphorylated signaling protein (arbitrary units) over time.
| Time (min) | Normal cells | Mutant cells |
|---|---|---|
| 0 | 1 | 1 |
| 5 | 9 | 9 |
| 15 | 6 | 9 |
| 30 | 2 | 9 |
(a) Describe the pattern in each cell type. (b) Explain what role the phosphatase plays in the pathway. (c) Predict how the cellular response of the mutant cells differs from that of normal cells over 30 minutes, and justify your prediction. (d) Describe one control you would include in this experiment.
Back to the start: epinephrine never enters the cell, but it binds a surface receptor. A relay of G protein, cAMP, and kinases amplifies the message, so one molecule can change thousands of proteins.
Summary
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A ligand binds a specific receptor, changing its shape. Only cells with the matching receptor respond.
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Signals can be autocrine, paracrine, endocrine, or by direct contact.
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Signaling has three stages: reception, transduction, response.
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GPCRs activate G proteins and enzymes such as adenylyl cyclase, producing the second messenger cAMP. Phosphodiesterase breaks cAMP down.
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Kinases add phosphates and phosphatases remove them; cascades amplify the signal.
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Mutations, toxins, and drugs can lock a pathway on or off, which can cause disease such as cancer or cholera symptoms.