7 - Unit One Revision

Receptor signaling: core ideas

• Cells react to signals (ligands) that attach to special proteins called receptors. This binding starts a chain reaction with relay molecules, leading to a cell's response.

• Receptors can bind to different ligands. Ligands can either fully activate, partly activate, or not activate signaling, depending on how effective they are.

• Signaling can be adjusted by how ligands compete for binding, how much the receptor is activated, and built-in feedback to lower the signal.

• Drugs are usually small molecules that interact with biological targets to change how signals bind and transmit, thus altering cell behavior. For example, penicillin binds to bacterial enzymes that build cell walls, stopping them from working and killing the bacteria.

• Signals are passed along by relay molecules and often get stronger at each step, so even a small initial signal can cause a big cell response.

• Turning off or reducing signals is crucial to prevent over-activation. This happens through methods like negative feedback loops and making receptors less sensitive (desensitization).

• The basic process of life (DNA -> RNA -> protein) shows how signaling pathways can control which genes are active and how cells behave.

• Cells aren't all alike; cell differentiation changes which genes are used and which signaling pathways are active, creating different cell types with specific jobs.

• Scientists use methods like fluorescence microscopy and electron microscopy to study signaling and where proteins are located. Using antibodies and fluorescent tags helps visualize protein movement and how signaling unfolds.

• The exam will test both your understanding of these processes and your ability to use these ideas in real-world situations (e.g., signaling in diseases, cell differentiation, or designing experiments).

Insulin receptor signaling: two ligands and outcomes

• Let's consider two hypothetical ligands: insulin (a full activator) and compound A (a partial activator that binds less strongly).

  • If someone has type 1 diabetes (very little or no insulin), compound A could attach to the insulin receptor and slightly boost signaling, which might help the cells absorb more glucose.

  • In a person with normal insulin levels, insulin causes a strong signal and glucose uptake. If compound A also binds, it would compete with insulin, leading to a weaker overall activation than insulin alone would provide.

• Main idea: A receptor can be activated by more than one ligand. The final signal depends on what each ligand does to the receptor and how they compete for a spot.

Receptors, ligands, and competition

• Antagonist-like ligands can bind to receptors but don't cause the same strong signal as the main activator (agonist). When present, they compete for the receptor, reducing the maximum activation the agonist can achieve.

• If two ligands fight for the same receptor, the overall activation is less because when one ligand is bound, the other can't attach.

• The final signal inside the cell depends on the shape change the bound ligand causes and how well the receptor can phosphorylate itself and attract other signaling proteins.

Receptor activation: conformational change and autophosphorylation

• When insulin binds to its receptor, it changes the receptor's shape. This change allows the receptor's internal parts (kinase domains) to phosphorylate themselves (autophosphorylation).

• This autophosphorylation creates spots where other signaling proteins (like IRS-1) can attach, spreading the signal through a cascade of phosphorylation events.

• Key concept: A receptor tyrosine kinase (RTK), like the insulin receptor, turns an outside signal (ligand binding) into an inside signal (phosphorylation) within the cell.

Drug concepts and a clinical anchor

• Drugs are typically small organic molecules that interact with specific biological targets to change how they bind and signal, which then produces a therapeutic effect.

• An example is penicillin, which stops bacteria from building their cell walls by binding to the enzymes involved in this process. This leads to the bacteria dying.

• Takeaway: Small molecules can control signaling by either stopping or boosting binding, thereby changing how cells respond.

Signal attenuation and negative feedback in insulin signaling

• After eating, blood glucose goes up. This causes insulin to be released, which helps cells take up glucose, bringing blood glucose back to normal levels.

• Once glucose levels are normal, insulin signaling decreases. This shows how negative feedback works in the system.

• Desensitization: Insulin signaling can reduce the number of insulin receptors on the cell surface. This happens through changes in gene expression (e.g., an increase in FOXO-mediated transcription of genes that reduce insulin receptor expression), making cells less sensitive to insulin over time.

• PTEN acts like a brake in the PI3K pathway by changing $\text{PIP}<em>3$ back to $\text{PIP}</em>2$, which lowers the signal.

• The signaling pathway is constantly changing: Kinases boost signals, while phosphatases (like PTEN) reduce them, keeping everything in balance.

FOXO and desensitization: central dogma in signaling

• FOXO is a transcription factor that is affected by insulin signaling.

• When insulin signaling is active, a protein called AKT can stop FOXO from working (by phosphorylating it and keeping it in the cytoplasm). This reduces the transcription of certain genes, including the gene for the insulin receptor itself.

• The outcome: fewer insulin receptor mRNA molecules and, therefore, fewer insulin receptors on the cell surface. This contributes to desensitization and makes cells less responsive to insulin.

• This creates a feedback loop: Signaling starts, then feedback reduces the number of available receptors to prevent too much activation.

PI3K–AKT pathway: metabolic effects and membrane trafficking

• When the insulin receptor phosphorylates itself, it recruits IRS-1, which then activates PI3K.

• PI3K converts $\text{PIP}<em>2$ to $\text{PIP}</em>3$, which is essential for activating AKT.

• AKT then phosphorylates various targets that lead to metabolic effects:

  • It activates glycogen synthase, which increases the production of glycogen (stored glucose).

  • It causes GLUT4 transporters to move to the cell's outer membrane, increasing glucose uptake into the cell.

• Key reactions:
  $\text{PIP}<em>2 \xrightarrow{\text{PI3K}} \text{PIP}</em>3$
  $\text{PIP}<em>3 \xrightarrow{\text{PTEN}} \text{PIP}</em>2$

• AKT activation also plays a role in controlling gene expression and cell survival pathways. The balance between kinases and phosphatases determines the overall cellular response.