Cell Signaling Notes PDF

Cell Signaling Cell signaling - definition and context Cells in a multicellular organism usually communicate via signaling molecules ​ They may communicate via local or long-distance signaling Local signaling ​ Paracrine signaling ○​ Para → nearby ○​ A signaling cell act...

Cell Signaling Cell signaling - definition and context Cells in a multicellular organism usually communicate via signaling molecules ​ They may communicate via local or long-distance signaling Local signaling ​ Paracrine signaling ○​ Para → nearby ○​ A signaling cell acts on nearby target cells by secreting local regulators ○​ Animal cells: ​ E.g. Synaptic signaling in animal cells - Signalling between neurons ​ First, nerve cells release neurotransmitters that travel across the synapse into the target cell (neuron, muscle, another nerve cell) ​ This electrical impulse travels along a long conducting process of neurons called an axon. This signal eventually reaches the synapse where it triggers the release of chemical signal molecules (neurotransmitters) from the axon terminals ​ Then, the neurotransmitters travel across the synapse to affect the target cell, leading an increase of a decrease of a response (excitatory vs inhibitory) depending on what cells are involved in the process ​ Lastly, a response occurs from the chemical changes in the cell (i.e. opening of ion channels, muscle contraction, heart rate regulation, etc.) ○​ Plant cells: ​ Transcellular transport (without a plasmodesma linking the two cells) ​ Involves transport like carrier-based transport (i.e. active transport, facilitated diffusion), secretion, receptor-mediated exocytosis and endocytosis that lead to a response ​ Juxtacrine (cell-cell) signaling ○​ Juxta → next to  ○​ Direct contact between cells ○​ Cell junctions helps connect the cytoplasm of adjacent cells ​ Examples: ​ Gap junctions (animal cells) and plasmodesmata (plant cells) allow molecules to pass between adjacent cells without crossing plasma membranes ​ In the immune system, antigen presenting cells present antigens to helper T-cells for destruction ○​ Cell-cell recognition ​ Animal cells may communicate through proteins bound on the plasma membrane’s surface ​ Important for embryonic development and immune response Long distance signaling ​ Endocrine signaling (hormonal) ○​ Endocrine cells secrete hormones into body fluids (blood) ○​ This allows for the hormones to travel all across the body via the bloodstream, giving them easier access to target cells ○​ Slower than local signaling because distance is greater ○​ Note: hormones can actually reach all cells in our body, but are designed to only affect specific (target) cells ○​ Examples: ​ Insulin from the pancreas stimulates the cellular uptake of glucose ​ Hormones and pheromones Autocrine signaling ​ A cell can signal itself sometimes ​ It can secrete a molecule that binds to its own receptor and causes a response ​ E.g. cells releasing their own growth factor ​ Examples: ○​ In vertebrates, the presence of a foreign antibody causes T-cells to produce a growth factor to stimulate their own production. The increased number of T-cells helps to fight the infection. ○​ Quorum sensing is used by bacteria to determine the population density of their species in a local area. Steps in Cell Signaling 1.​ Reception (a ligand binds to a receptor protein) 2.​ Transduction (the binding of the ligand causes the receptor protein to change in some way, usually in a sequence of changes) 3.​ Response (the transduced signal then triggers a specific cellular response) Reception ​ Receptor protein: protein that receives a signal, located on or in the target cell ○​ Allows the cell to “hear” the signal and respond ○​ Most receptors are plasma membrane proteins, but some are located in the cell (intracellular vs intercellular cell signaling) ○​ Receptors bind to specific ligands → this specificity increases efficiency of cellular responses and saves energy, stopping them from reacting to every signal the cell encounters ​ Signaling molecule: acts as a ligand as it binds to the receptor protein ○​ Shape fits into a specific site on the receptor as it attaches there ○​ This ligand binding causes the receptor protein to undergo a change in shape ○​ This change of shape allows the receptor to receive a specific response instead of binding to all ligands in the organism, resulting in endless cellular responses Plasma membrane receptors Three major types G protein-coupled receptors ​ Cell surface transmembrane receptor that works with a G protein - a protein that binds with GTP ○​ GTP is kinda similar to ATP but with guanine instead of adenine hence the name ○​ The G protein is attached to the cytoplasm side of the plasma membrane but is able to move along it ○​ G protein functions as a switch that is either on or off depending if it’s attached to GTP or GDP → when GTP it’s active, when GDP it’s inactive ○​ Receptor and G protein work together with another protein, usually an enzyme ​ First, the ligand binds to the receptor protein ○​ This activates the receptor, changing its shape  ○​ G protein then comes to bind to it, and a GTP replaces the GDP previously on the G protein ○​ This activates the G protein ​ Next, the activated G protein goes over to the enzyme ○​ This alters the enzyme’s shape and activity ○​ Now, the enzyme can trigger the next steps leading to a cellular response ​ Next, the ligand dissociates from the receptor ○​ The frequency of binding and dissociation depends on the ligand concentration outside the cell ○​ When the ligand dissociates, the G protein hydrolyzes GTP into GDP and Pi ○​ Now the G protein is inactive again, so it leaves the enzyme and is ready to be reused again Receptor tyrosine kinases (RTK) ​ These kinase proteins are monomers when inactive ○​ They have a ligand binding site located extracellularly ○​ They also have an intracellular cell contains multiple tyrosines ​ First, signaling molecules bind to the receptor molecules ○​ This causes two of the receptor molecules (monomers) to come together to form a dimer ○​ Note that in some cases, larger clusters of more than 2 can form ​ Next, this dimerization activates the tyrosine regions ○​ Each tyrosine kinase uses an ATP to add a phosphate to itself ○​ ATP turns into ADP as the phosphate is used by the tyrosine kinases ○​ Kinase - think of phosphorylation!! ​ Next, relay proteins bind to the tyrosines ○​ Now that the receptor is fully activated, relay proteins come and bind to it ○​ Each relay protein binds to a phosphorylated tyrosine, activating the relay protein ○​ Each one of these activated relay proteins triggers a transduction pathway which leads to a cellular response Ion channel receptors (ligand-gated ion channels) ​ This is a protein channel that can let ions through the plasma membrane, but has a receptor as well ​ In its inactivated state, the channel is closed and ions can’t pass through ​ When the ligand binds to the receptor, the channel opens  ​ Now, specific ions will be able to pass through, rapidly changing the concentration of that specific ion inside the cell → this can trigger a cellular response ​ When the ligand dissociates, the ion channel becomes inactive again and the channel closes Intracellular receptors ​ Found in either the cytoplasm or nucleus ​ In this case, the signaling molecule must be able to pass through the cell’s plasma membrane ○​ Therefore they must be small enough and hydrophobic enough due to double phospholipid membrane ○​ E.g. steroid hormones, thyroid hormones, NO (gas) ​ After the signaling molecule passes through the plasma membrane, it binds to a receptor protein, activating it ​ This complex of receptor and ligand goes around and causes a cellular response ​ Ligand enters cytoplasm via diffusion Transduction ​ When the reception step occurs in the plasma membrane, the transduction step usually has multiple steps involving many molecules ​ This can help amplify the signal Signal transduction pathways ​ When a signaling molecule binds to a receptor in the plasma membrane, this triggers the first step in the signal transduction pathway ○​ This activated receptor activates another molecule, which activates another molecule, etc. until it reaches the place of the final cellular response ​ These molecules are often proteins (protein kinases) ​ They often act on other protein kinases in that pathway ​ Think of this step as a domino effect, or a cascade ○​ Remember that these molecules do not physically travel along the transduction pathway; rather, information is being relayed on from molecule to molecule ​ Usually, this information is via a shape change in the next protein ​ Most of the time, this shape change is because of phosphorylation Phosphorylation ​ Protein kinase: an enzyme that transfers phosphates from ATP to a protein ○​ We’ve seen this in receptor tyrosine kinases in reception ​ Phosphorylation cascade: where multiple proteins in a pathway are phosphorylated in turn ○​ After the receptor is activated by the signaling molecule, a relay molecule is activated ○​ This relay molecule activates a protein kinase, changing its shape ○​ This activated protein kinase can now activate another protein kinase, changing the new one’s shape as well ○​ This process continues until the last protein kinase activates a protein that triggers the cellular response ​ Protein phosphatases: enzymes that can rapidly remove phosphate groups from proteins ○​ This process is called dephosphorylation ○​ Dephosphorylating the protein kinases means rendering them inactive again (turning them off) ○​ This is important for a few reasons ​ They turn off the signal transduction pathway when the original signaling molecule is no longer there ​ They let the protein kinases be reused again when another signaling molecule comes by Second messengers ​ Second messengers: small, water soluble molecules/ions that are part of the signal transduction pathways ○​ The “first messenger” is considered to be the ligand that binds to the plasma membrane receptor protein ○​ Because of their size and solubility, they can easily spread throughout the cell via diffusion ​ Two widely used second messengers: cAMP (cyclic AMP) and Ca2+/IP3 Cyclic AMP (cAMP) ​ Produced from ATP via the enzyme adenylyl cyclase  ​ Epinephrine increases the production of cAMP by binding to a G protein coupled receptor on the plasma membrane ○​ This causes it to activate a G protein which goes and binds to adenylyl cyclase which produces cAMP ​ This newly produced cAMP activates another protein, protein kinase A, which triggers cellular responses Calcium ions and IP3 ​ Because of active transport, concentration of calcium is a lot lower in the cytosol compared to the endoplasmic reticulum ​ Therefore, a change in cytosolic calcium concentration is significant and can lead to cellular responses ​ A signaling molecule binding to a plasma membrane receptor causes an enzyme to form IP3 ​ IP3 diffuses through the cytosol and binds to an IP3 gated calcium channel in the ER membrane, causing it to open ​ Now Ca2+ ions can flow out into the cytosol via diffusion down their concentration gradient, and this will lead to a cellular response Response ​ In the end, the signal transduction pathways lead to the regulation of cellular activity ​ This cellular activity isn’t turning something on or off → it regulates the extent and specificity in multiple ways Signal amplification ​ Multiple steps in transduction help amplify the cell’s response to a signal ​ E.g. epinephrine triggering breakdown of glycogen ○​ Each epinephrine binding to a G protein coupled receptor produces 100 ish active adenylyl cyclase, each adenylyl cyclase forms 100 ish cAMP molecules etc. ○​ In the end, 1 epinephrine can trigger the response of 108 glycogens being broken down ​ This is because each protein is in its activated state long enough to activate multiple molecules of the next step Specificity ​ Different cells can respond differently to the same signaling molecule  ​ This is because the response of a cell to a signal depends on the receptor proteins, relay proteins, etc. Signaling efficiency ​ Scaffolding proteins: large relay proteins that have other relay proteins attached to it ​ Because they hold together proteins, these proteins can interact and pass on the signal without diffusing away → this increases efficiency Termination ​ A cell signaling pathway must have inactivation mechanisms ​ This is so that they can reset and be able to respond to more incoming signals ​ Each molecular change in the signaling pathways must only last for short periods of time → if they stay locked in to either active or inactive states, this could be really bad for the organism Apoptosis Apoptosis: when the organism tells the cell to kys ​ Programmed cell death, happens when cells are infected, damaged, or at the end of their functional life span ​ DNA is chopped up and cytoplasmic components are fragmented ​ Cell shrinks and forms blebs ​ Cell components are packaged in vesicles and digested by scavenger cells, leaving no trace ​ This is important because it protects neighboring cells from damage that could happen if the cells just leaked out all their contents  ​ Signals that trigger apoptosis can come from either inside or outside the cell ○​ Inside the cell, this can be caused by irreversible DNA damage ○​ Outside the cell, this can be caused by signaling molecules released by other cells that causes a signal transduction pathway Drugs’ effects on cell signaling ​