Cell Signalling Overview

  • Signalling Pathways Overview

    • Shift from ion channel signalling to receptor pathway signalling.
    • Receptor proteins (green) on the cell surface bind to extracellular signalling molecules initiating a cascade of events leading to cellular response.
    • Some receptors are located inside the cell, requiring signalling molecules that can cross the membrane (e.g., hydrophobic molecules, gases).

  • Molecular Switches

    • Key concept in signalling involving molecular switches:
    • Two types of switches:
      • Phosphorylation Switch:
      • Protein in inactive state can be activated by the addition of a phosphate from ATP.
      • The inactive state reverts once the phosphate is removed.
      • GTP Binding Protein Switch:
      • Similar concept as phosphorylation but involves GTP. Activation occurs when GTP binds to the protein, resulting in GDP release.

  • Second Messengers

    • Important in signal amplification and relay.
    • Types of second messengers discussed in the lecture:
    • Cyclic AMP (cAMP):
      • First second messenger discovered by Earl Sutherland.
      • Generated from ATP by adenylate cyclase, activated by Gs protein.
      • Targeted by phosphodiesterase, which degrades cAMP to AMP turning off the signal.
      • cAMP activates Protein Kinase A (PKA), leading to phosphorylation of target proteins.
    • Diacylglycerol (DAG) and Inositol trisphosphate (IP3):
      • Both produced by phospholipase C (PLC) when it acts on phosphatidylinositol 4,5-bisphosphate (PIP2).
      • DAG stays in the membrane and activates PKC in the presence of calcium released by IP3.
      • IP3 releases calcium from the endoplasmic reticulum (ER) through IP3 receptors.
      • Calcium binds to calmodulin (CaM), activating CaM-dependent protein kinase (CaMK).

  • G-Protein Coupled Receptors (GPCRs)

    • Large family of receptors (~800) involved in various signalling pathways.
    • Common structure: Seven transmembrane domains.
    • GPCRs activated by various stimuli including hormones (e.g., adrenaline, glutamate).
    • Activation of GPCRs involves the exchange of GDP for GTP on G-proteins, activating downstream signalling pathways.

  • Receptor Tyrosine Kinases (RTKs)

    • Different structure from GPCRs; typically one or two transmembrane regions.
    • Activated by growth factors (e.g., insulin, epidermal growth factor).
    • Fossure two monomers to form dimers upon ligand binding, leading to auto-phosphorylation.
    • Recruits adaptor proteins (e.g., GRB2) and activates downstream proteins (e.g., Ras, a monomeric G protein) to transmit signals.

  • Mitogen Activated Protein Kinase (MAPK) Pathway

    • Initiates following activation of RTKs.
    • Involves a cascade of phosphorylation events starting with MAPK kinase kinase (MAP3K), then MAPK kinase (MAP2K), and finally MAPK itself.
    • Physiological relevance includes mesoderm induction during early development.

  • Conclusion

    • Understanding these signalling pathways is crucial for insights into cellular responses to external signals, impacting drug development and therapeutic strategies.