Cell Signaling Notes

Secondary Messengers and Signal Transduction

• Secondary messengers are key for coursework.
• Signal transduction involves secondary messengers and their effects within the cell.
• Comparison and contrast of messenger systems and their effects.
• Discussion of second messengers in the context of a receptor.

Receptor Types

• Receptors are proteins embedded in the membrane that bind to signals.
• They pass the message along, similar to playing tag.
• Receptors undergo a shape change upon binding.
• Describe and explain the structure of receptors and their functions.
• Compare and contrast the response times between receptor types.

Level 4 Knowledge

• Exocytosis: releasing a signal from a cell.
• Binding to antigens on microorganisms.
• Carbohydrates on the outside of cells and their information.

Filling in the Details

• Biochemistry: receptors, structure and message propagation.
• Physiology: message that comes in and the effects.
• Neuroscience: different receptors present on neurons in the brain.
• Pharmacology: receptors as drug targets.
• Immunology: immune cells use cell signaling to turn on and off.
• Pathology and medicine: what happens when it all goes wrong.

Advanced Studies

• Advanced pharmacology and biochemistry, circadian rhythms, toxicology and immunology are all applied based on this content.

Signaling Explained

• Signaling involves transferring information from outside the cell.
• Extracellular signaling molecule: coming from outside of the cell.
• The signal can originate from a neighboring cell or a distant location in the body, such as hormones transported via the blood.
• Receptor acts as a detector of the signal.
• Shape change occurs upon binding, enabling a new action.
• Intracellular signaling proteins are activated.
• Steps occur in a particular order.
• Effector proteins: enzymes (metabolic), transcription regulators, or cytoskeletal proteins.

Signal Reception Process

• Signal: protein, short peptide, ion, or small molecule (e.g., ATP).
• Means of signal transportation to the desired location.
• Receptor: like a detector, e.g., tyrosine kinase receptor (insulin receptor).
• Interpretation: secondary messengers like kinases.
• Response: the final needed outcome.
• Issues in the middle lead to uncontrolled growth or loss of expression.

Signal, Receptor, and Outcome

• Neurotransmitter: noradrenaline, glutamate, acetylcholine released from presynaptic neuron to a receptor on the other side.
• Outcome: change in ion concentration leading to depolarization.
• Insulin: released into blood, binds to insulin receptor, changes glucose uptake.
• Proteins/peptides activate adenyl cyclase, which changes levels of cyclic AMP (converts ATP to cyclic AMP).
• Cyclic AMP binds to an enzyme, activating it to phosphorylate the next protein in a kinase cascade.

Interpreting Signals

• Proteins and enzymes are often modified.
• Modifications: phosphorylation, acetylation, methylation, cleavage.
• Modifications cause a change in shape.
• Cleavage: trimming a couple of amino acids to cause activation and change in shape.
• Catalytic site: Enzymes are only active if they're in the right shape and folded properly.

Phosphorylation

• Adding a highly negatively charged phosphate group changes the protein shape.
• Kinase adds a phosphate group to the OH group of serines and threonines.
• The negative charges may repel chains or interact with other proteins.
• The shape change enables it to become active.
• Turning off: protein phosphatase removes the phosphate group.
• More kinases than phosphatases lead to accumulation of phosphorylated protein.
• ${GTP}$ can be used like ${ADP}$ as a donor of a phosphate group; alternatively, ${GDP}$ can bind to the protein.
• ${GTPases}$: ${GTP}$ binding proteins act as a switch.
• ${GDP}$ is removed by ${Gef}$ (guanidine exchange factor), enabling ${GTP}$ to bind.
• When associated with ${GTP}$, it changes shape and becomes active.
• ${GAP}$ proteins aid the removal of a phosphate group from ${GTP}$, becoming ${GDP}$.
• Two different ways in turning proteins on, depending on whether they can bind to ${GDP}$ or ${GTP}$ or not.

Signal Transduction Cascade

• Receptor binding to signal is the first step.
• Ligands bind to ligand binding domains on the protein.
• Transmembrane domain goes through the membrane.
• Inactive kinase becomes active upon ligand binding, leading to a chain reaction of events.
• Kinase adds phosphate groups to proteins.
• Activated proteins expose nuclear localization signal and move into the nucleus.
• Binds to ${DNA}$ and activates transcription.
• Phosphatases remove phosphate groups, turning them off.
• The ATM analogy: as long as the ligand is in the domain, it allows phosphorylation of the next protein.

Efficient Signal Transmission

• Enzymes need to be active.
• Good supply of signal/ligand.
• Receptor and enzymes needed.
• Need something on the cell surface to hold everything closer together.
• Lipid rafts allow things to be close together.
• Lipid rafts can also separate them if a receptor shouldn't be activated.
• The receptor helps chelate everything together.

Scaffold Proteins

• Scaffolding effect: Scaffolding protein recognizes the activated receptor.
• Positions in scaffolding protein have different shapes with binding motifs and structural motifs.
• Particular order: when the ligand binds to the receptor, shape change passes a signal to protein one, which activates protein two, etc.
• Arranged next to each other to easily tap the next person on the shoulder, pass this on.
• Being close enough to the previous protein is enough to turn the next protein on.
• Proximity induction is when you're turning a protein on just by being close together.

Complex Formation

• Complex formation: inactive receptor with inactive intracellular binding proteins, then binding of the signal or ligand to the receptor.
• Phosphorylation events (little p's) happening that are recognized by intracellular signaling proteins which then come there.
• These phosphorylation events are very similar, very specific shapes to recognize to a very small number of specific proteins.

Phosphoinositides

• Inactive receptor needs some phospholipids in the membrane, phosphoinositides.
• These are phosphorylated.
• Activate the receptor and they become phosphorylated even more.
• These have 2 phosphate groups, add a third phosphate group.
• Signal that will then recruit these intracellular signaling proteins to them.
• Close by to the receptor, they're then going to get acted on by the receptor to pass along the signal.
• Need to be next to the membrane.
• Big flag waiting, ready, when you're active, activate me.

Secondary Messengers

• Things that go away and cause something to happen.
• Cyclic AMP activates protein kinase A.
• Cyclic GMP activates some enzymes.
• Diacylglycerol and IP3 are generated from the action from breakdown of lipids.
• IP3 can activate the release of calcium from the endoplasmic reticulum, and the same with diacylglycerol.
• Cyclic AMP: may either bind directly to something and cause displacement of regulatory subunit.
• Like ${GDP}$ or ${GTP}$, causing a conformational change.
• Protein kinase A is activated by cyclic AMP.
• Cyclic GMP activates protein kinase G and opens cation channels.
• Diacylglycerol activates protein kinase C.
• IP3 is acting on calcium channels.

Amplification

• Adrenaline binds to multiple receptors, each receptor changes multiple proteins.
• A chain of events that activates multiple proteins to the next step.
• ${10}$ receptors on cell surface, each of them binds to ${10}$, so the next step is ${100}$ activated proteins, etc.
• Generating large volumes of cyclic AMP, which then causes the activation, each of those activating protein kinase A.
• May activate similar pathways that might have the same outcome.
• Or activating those pathways then converges onto the same pathway.
• May have a single point that it's activating.
• Coordinated effect is like ganging up.

Receptor Types

• Channel linked receptors: a hole in the membrane that's controlled by the protein. (Ions move through).
• Enzymatic receptors: ligand combines to the receptor, which then becomes active.
• G protein coupled receptors: transmembrane receptor binds to a ligand, and there are three proteins down here that are the G proteins, and they convey the message.

Channel Linked Receptors

• Forms a pore in the membrane only open when the signal is there
• Restricts the movements of ions from one side to the other
• Observed in neurons

G Proteins

• Seven transmembrane domain containing proteins
• Embedded in the membrane
• Associated with some sort of inner surface protein to pass on the message
• Four flavors

Enzyme Coupled Receptors

• Single transmembrane receptor that has to dimerize
• Has to bring those together to activate and recruit the intracellular proteins