Cell Signaling

• Cell communicate with each other by sending signals
• In cell signaling:

  • Signaling cell
  • Signaling molecule (ligand)
  • Responding cell
  • Receptor protein with ligand binding site
• For cell signaling to work, the responding cell must have the right receptor to receive (bind to) the signal
• specificity of ligand-receptor binding is brilliant way to have cells pay attention to the right signal its corresponding receptor will “hear” it and ignore the other signaling molecules
• The different types of cell signaling

  • Endocrine - signaling from distant cell.
  • Paracrine - involves two cells that are close to each other.
  • Autocrine - when a cell signals to itself
  • Contact-dependent signaling - occurs between adjacent cells.
• Signaling molecule (ligand) binds the receptor at the ligand binding site (via “lock and key” mechanism), which causes a conformational change that “activates” the receptor
• Upon activation the receptor triggers a chain of signaling inside the cell. This is called a signal transduction
• Wherever it does go, it will do something like activate an enzyme or turn on the transcription of a gene (the response)

  • this transmitted message can either stay in the cytosol or go to the nucleus
• The response is terminated so that new signals can be received
• Receptors aren’t always on the cell surface – it depends on the polarity of its ligand (signaling molecule)
• Polar signaling molecules can’t pass through the hydrophobic core of the plasma membrane, thus need receptors on the exterior of the cell
• When a signaling molecule binds to the ligand-binding site, the entire receptor molecule undergoes a conformational change, activating the receptor, which triggers downstream response
• Nonpolar signaling molecules (example: steroids) CAN pass through the hydrophobic core of the plasma membrane.
• Nonpolar

  • Their receptor is INSIDE the cell (in cytosol or nucleus)
• Nonpolar:

  • Once the signaling molecule is bound, receptor is activated, and response is triggered
• We can categorize cell-surface receptors based on their mode of activation and the properties of their signaling transduction pathways
• 3 classes of cell surface receptors:

  1. G protein-coupled receptor
  2. Receptor Kinases
  3. Ligand-gated ion channels
• For all pathways: Do not memorize steps!Instead for each...

  1. Notice:

  • Conformational changes
  • Interactions between proteins
  • Enzyme activities
• For all pathways: Do not memorize steps!Instead for each...

  2. Predict

  • What would happen if a mutation occurred? What would happen if a drug inhibited an enzyme?
• Ligand-Gated Ion Channels

  • Ion channels allow for the flow of ions across the plasma membrane.
  • Ion channels can be closed and opened.
• Ligand-Gated Ion Channels

  • Some ion channels open when bound by their ligand and are called ligand-gated channels. Ligand-gated channels are referred to as receptors
• Receptor Kinases

  • Receptor kinases are both receptors (bind ligands) and kinases (add a phosphate group to target proteins: phosphorylate things)
• Receptor Kinases

  • Overall process: ligands bind to receptors outside cell, triggering kinase portion of receptors to phosphorylate each other, which then activates signal transduction
• Receptor Kinase Activation and Signaling 3 Processes to understand:

  1. Dimerization - When a signaling molecule binds to a receptor kinase, the receptor partners with another receptor kinase bound to another molecule of the same ligand.
• Receptor Kinase Activation and Signaling 3 Processes to understand:

  2. Kinase activity - Dimerization activates the cytoplasmic kinase domains (inside the cell), causing each half to phosphorylate its partner at multiple sites along each other’s cytoplasmic domains.
• Receptor Kinase Activation and Signaling 3 Processes to understand:

  3. Active receptor and intracellular proteins - The now phosphorylated regions of the receptor provide a place for intracellular signaling proteins to bind and thus become active (which kicks off signaling path).
• A Typical Receptor Kinase Pathway PDGF (platelet-derived growth factor): 1

  • PDGF binds to PDGF receptor kinases on the surface of the cell, and the receptors dimerize and become active.
• A Typical Receptor Kinase Pathway PDGF (platelet-derived growth factor): 2

  • Dimerization activates the cytoplasmic kinase domains, causing them to phosphorylate each other.
  • The phosphorylated receptor activates (GDP to GTP) the cytoplasmic signaling protein Ras
• A Typical Receptor Kinase Pathway PDGF (platelet-derived growth factor): 3

  • GTP-bound Ras triggers a series of kinases(amplification) that eventually enter the nucleus and phosphorylate target proteins.
• A Typical Receptor Kinase Pathway PDGF (platelet-derived growth factor): 3

  • Inactivation: ligand (PDGF) does not bind the receptor, kinases are inactivated by phosphatases and Ras is inactivated when GTP bound to Ras is converted to GDP.
• G Protein-Coupled Receptors Activate Gproteins

  • G protein-coupled receptors associate with G proteins in the cytoplasm.
  • G protein can either be bound to GTP (in which case it’s active), or GDP (in which case it’s inactive).
• G Protein-Coupled Receptors Activate Gproteins

  • Instead of becoming incorporated into a nucleic acid, free nucleotides (like ATP and GTP) can ALSO be used for energy storage and transfer (like batteries)
• GTP = guanosine triphosphate; stores – and can thus transfer – lots of energy in the P-bonds (especially the outermost one)
• GDP = guanosine diphosphate has much less energy w/ just the one bond between 2 P groups (so it’s more stable, and thus not very active)
• G Protein-Coupled Receptors Activate Gproteins

  • When a ligand binds to a G protein- coupled receptor, induces conformational change in receptor that causes G protein to attach and exchange a GDP molecule with a GTP
• G Protein-Coupled Receptors Activate Gproteins

  • With GTP bound, G protein now activated and, in turn, activates some target protein.
  • As long as GTP is bound, G protein is active, and the signal continues to be transmitted (target protein remains activated).
• Adrenaline Signaling

  1. Adrenaline binds to a G protein-coupled receptor on cardiac muscle cells, GDP in the G protein is replaced by GTP and activates the G protein
• Adrenaline Signaling

  2. The GTP-bound α subunit of the activated G protein then binds to and activates an enzyme in the cell membrane called adenylyl cyclase. Thisenzyme converts the nucleotide ATP into cyclic AMP (cAMP)
• Adrenaline Signaling

  3. The small signaling molecule cAMP is the second messenger in this system (b/c it spreads message inside cell). It binds to and activates another enzyme, protein kinase A
• Adrenaline Signaling

  4. The protein kinase A phosphorylates proteins that controls the rate of heart contraction, causing heart rate to increase