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Cell Signalling (Signalling cascades (1)Transfer (The chemical messenger…

- - - - The signal pathway can be modulated by other factors along the way
- - - - Receptors are programmed to sense changes in ligand concentration, rather than specific concentrations
      - When receptors have been bound to ligands to long periods of time, the cell adapts so that the receptors no longer respond as strongly to the ligand.
        
        Receptor-mediated endocytosis removes receptors from the cell surface so that there are not as many available to interact with the ligand
        
        Desensitization changes the receptor so that it does not bind as strongly to ligands. Common method is through phosphorilation
- - - - Adrenaline/epinephrine binds to G-protein coupled receptor (GPCR). This causes adenylate cyclase activity (effector molecule), which causes the production of cAMP. cAMP creates cascades for different types of kinases which affect different targets in the cell. This promotes the glycogen synthesis. Is part of "fight or flight response"
    - - Part of an activated G protein binds to a specific target protein, changing its activity
      - Large heterotrimeric G-proteins
        
        Mediate signal transduction through G-protein linked receptors
        
        When ligand binds to GPCR, the conformational change causes a G-protein to associate with it, releasing its GDP
        
        The G alpha subunit then binds to a new GTP and detaches from the complex
        
        Depending on the G protein, either the G alpha subunit or the G beta-gamma subunit (which are still attached to each other) initiate signal transduction. Can be through either activation or inactivation of target molecule
        
        The G alpha subunit hydrolyzes its GTP molecule, changing it back into GDP. It then rebinds to the G beta gamma subunit, reforming an inactive G protein.
        
        Have G alpha, G beta and G gamma subunits
        
        eg. Novochok
        
        Inhibits acetylcholinesterase, so that acetylcholine (Ach) can't be removed from the synapse, and potassium ion channels are permanently opened
        
        This causes the cells to be flooded with potassium, and the cell is unable to function
        
        Is an example of interaction of the effector with the G beta subunit rather than interaction with the G alpha subunit
        
        GTP hydrolysis to cause the reassociation of G alpha subunits with G beta gamma subunits is enhanced by GTPase activating proteins (GAPs)
        
        Secondary Messengers
        
        cyclic AMP
        
        Is produced from adenylyl cyclase from cytosolic ATP when the adenylyl cyclase is activated by the binding of a G protein alpha subunit+GTP.
        
        Posphodiesterase degrades cAMP into AMP
        
        After the G protein is inactivated, adenylyl cyclase stops producing cAMP. The remaining cAMP needs to be degraded by phosphodiesterase. Eg. cAMP is activating targets that allow you to contract your muscles. When you no longer want to contract your muscle, phosphodiesterase degrades the cAMP.
        
        Activates PKA (protein kinase A) by binding to its regulatory subunits, which releases its pseudosubstrates.
        
        PKA phosphorylates serine and threonine residues on proteins using ATP as its phosphate source.
        
        Is a secondary messenger signal responsible for many functions in the body. eg. glycogen degradation
        
        Inositol-1,4,5-trisphosphate and diacylglycerol
        
        Inositol-1,4,5-trisphosphate (IP3) and diacylglycerol are both second messengers
        
        Are formed when the enzyme phospholipase C (specifically C beta) cleaves PIP2 into IP3 and diacylglycerol. C beta (the phosphlipase C) is activated by the binding of the alpha subunit + GTP from the G protein Gq (like the magazine)
        
        PIP2 is a lipid membrane
        
        IP3 moves through the cytosol and binds to the IP3 receptor channel, which is a ligand gated calcium channel.
        
        This releases calcium ions into the cytoplasm
        
        The concentration of calcium ions in the cell is regulated by calcium ATPases in the plasma membrane and ER, which transport calcium ions out of the cytoplasm
        
        Calcium Induced Calcium Release (CIRC): IP3 receptor channels and ryanodine receptor channels are both sensitive to calcium concentration in the cell. A rapid increase of calcium ions in the cell will activate them, causing them to release more calcium ions into the cytoplasm from the ER or SER. The ryanodine receptor channel is directly sensitive to calcium ions, whereas the IP3 receptor channel's sensitivity is mediated by the binding of IP3 to it
        
        Calmodulin mediates calcium ion activated processes in the cell. Binds four calcium ions, two in each hand.
        
        Both the calcium released by IP3 receptor channel and diacylglycerol activate various protein kinase As (PKAs), which phosphorylate serine and threonine residues on a variety of target proteins.
      - Small monomeric G-proteins
      - Activation depends on the binding of GTP or GDP (GTP usually = active, GDP usually = inactive)
      - GAPs, GEFs and GDIs all regulate G protein function
      - Usually only remain active for a short period of time so that they can respond to changing conditions
    - - GPCRs have 7 transmembrane alpha helices, connected by alternating extracellular or cytosolic loops
      - The extracellular portion of a GPCR has a specific conformation which allows for specific binding (unique messenger binding site)
      - the cytosolic portion of the GPCR has a part that interacts with the G-protein, as well as phosphorylation sites for protein kinase A and phosphorylation sites for G-protein coupled receptor kinases (GRKs). The phosphorylation sites are for regulation.
    - - GRKs (G protein linked receptor kinases) phosphorylate amino acids in the cytosolic domain of the GPCR (G-protein coupled receptor). Act on activated GPCRs.
        
        cAMP phosphodiesterase (PDE) is activated
        
        beta-arrestin binds to the phosphorylated active site of the GPCR, further desensitizing it to the ligand, and in some cases causing endocytosis.
      - Protein kinase A
        
        Is an example of negative feedback during signalling
        
        Is activated through the signalling cascade of adenylyl cyclase, which is mediated by g protein coupled receptors, but then phosphorylates amino acids on the GPCR, inhibiting it
- - - - Agonists bind tightly to a receptor and induce its signal-eg. Fentanyl (was originally used as a strong pain killer. Binds to the receptors for opiates.
      - Antagonists bind tightly to a receptor and do not set off a signal cascade. They prevent other signals from binding to the receptor. Eg. Naloxon has a Kd that is lower than fentanyl, so it binds to the opiate receptors and prevents fentanyl from binding
- - - - Takes the input of an ATP molecule, which is turned into ADP
  - - - Takes the input of one H2O molecule, and releases one inorganic phosphate (Pi)
- - - - Receptor sets of secondary signalling cascade within the cell.
        
        Are 1) G-protein coupled, 2) enzyme linked or 3) ion-channel linked