unitD 1

• Cell signaling


  Cells must respond to their environment and can communicate with one another
• Cell signaling


  • S. cerevisiae extend toward course cell in response to a mating factor produced by neighboring cells
• Signaling molecules


  Molecules synthesized and released by signaling cells that produce a specific response only in target cells that have receptors for the signaling molecules

  
• Signal transduction


  The process of converting an extracellular signal (signaling molecule A) into an intracellular signal (signaling molecule in a target cell)

  
• Intracellular signals can regulate

  • Protein synthesis
  • Cell death
  • Transcription
  • Metabolic pathways (glycolysis, TCA, etc..)

  
• Six steps in signaling

  1. Synthesis of the signaling molecule by the signaling cell

  2. Release of the signaling molecule by the signaling cell

  3. Transport of the signaling molecule to the target cell

  4. Detection of the signal by a specific receptor protein

  5. A change in cellular metabolism, function, or development triggered by the receptor-signaling molecule complex

  6. Removal of the signaling molecule, which terminates the cellular response

  
• Types of signaling


  • Endocrine
  • Paracrine
  • Neuronal
  • Contact-dependent

  
• Endocrine signaling

  Signaling molecules, called hormones, act on target cells distant from their site of synthesis by endocrine cells

  
• Paracrine signaling


  Signaling molecules released by a signaling cell into the extracellular medium act locally to affect target cells in close proximity to the signaling cell

  
• Neuronal signaling


  Nerve cells (neurons) send electrical signals along their axons, which are then converted to chemical form: neurotransmitters are released

  
• Contact-dependent signaling


  A membrane-anchored signal in the plasma membrane of the signaling cell binds to a receptor molecule embedded in the plasma membrane of the target cell, requiring cells to be in direct membrane-to-membrane contact

  
• Cell receptors


  Cell-surface receptors and intracellular receptors

  
• The extracellular signaling molecule alone is not the signal, the signal depends on how the target cell interprets the signaling molecule, which is dictated by intracellular signaling pathways

  
• Different combinations of signal molecules and how they bind to their respective cell-surface receptors produce different outcomes

  
• Some cells may require specific signal molecules to survive or additional signal molecules in order to grow or differentiate
• The presence of one signal molecule may modify the effects of another signal molecule downstream
• Intracellular signaling pathways


  Signaling pathways consist of a series of proteins and/or second messengers, where each protein in a pathway alters the conformation or activity of the next protein

  
• Intracellular signaling pathways can

  • Relay the signal onward and spread signal through cell
  • Amplify signal received by activating messenger molecules
  • Detect signals and integrate them within the cell
  • Distribute the signal to multiple effector proteins
  • Engage in feedback in order to modulate the cell's response to the signal

  
• Molecular switches in signaling pathways

  • Phosphorylation-dephosphorylation
  • GTP binding (e.g. G-protein-coupled receptor)
  • Assembly-disassembly of protein complexes
  • Proteolysis

  
• Protein phosphorylation


  Can activate or inactivate an enzyme, promote or interfere with protein-protein interactions, change the subcellular location of the protein, or trigger protein degradation
• Main classes of cell-surface receptors

  • Ion channel-coupled receptors
  • G-protein receptors
  • Enzyme-coupled receptors

  
• Ion-channel-coupled receptors


  Transduce a chemical signal (in the form of a pulse of a secreted neurotransmitter delivered to target cell) into an electrical signal by inducing conformational change that opens ion channels

  
• 1. protein-coupled receptors (GPCRs)


  Made of single polypeptide chain, compose the largest family of cell-surface receptors, mediate response to a vast number of extracellular signal molecules

  
• GPCR activation


  G protein and its receptor are inactive in unstimulated state, signal molecule binding induces conformational change in α-subunit of G protein to release GDP and bind GTP, causing dissociation of α-subunit to activate effector proteins downstream
• GPCR inactivation


  G protein switches "off" by hydrolyzing GTP to GDP, α-subunit has GTPase activity and controls timing of G protein activity
• G proteins that directly regulate ion channels


  Subset of G proteins that directly regulate ion channel activity, e.g. acetylcholine binding triggers G protein activation to open K+ channels and slow heart rate

  
• Cyclic AMP signaling pathway

  G proteins activate adenylyl cyclase to synthesize cAMP, cAMP activates protein kinase A (PKA) which phosphorylates downstream proteins, cAMP levels are mediated by different extracellular signal molecules
• In skeletal muscle cells, epinephrine binding to GPCR activates G proteins which activate adenylyl cyclase, increasing cAMP and activating PKA, resulting in decreased glycogen levels to make glucose readily available during exercise
• Inositol phospholipid pathway


  Activated phospholipase C cleaves inositol phospholipid to generate second messengers IP3 and DAG, IP3 triggers release of Ca2+ from ER and DAG recruits and activates protein kinase C

  
• The rush of Ca2+ ions into the cytosol causes indirect effects like activating Ca2+/calmodulin-dependent protein kinases (CaM Kinases) important for learning and memory
• GPCRs are the most common focus of drug development for neurodegenerative research, e.g. β-arrestin-biased ligands can suppress glia-derived inflammation and prevent neuron loss in Parkinson's disease models
• Cell signaling


  Cells must respond to their environment and can communicate with one another
• Cell signaling


  • S. cerevisiae extend toward course cell in response to a mating factor produced by neighboring cells
• Signaling molecules


  Molecules synthesized and released by signaling cells that produce a specific response only in target cells that have receptors for the signaling molecules

  
• Signal transduction


  The process of converting an extracellular signal (signaling molecule A) into an intracellular signal (signaling molecule in a target cell)

  
• Intracellular signals can regulate

  • Protein synthesis
  • Cell death
  • Transcription
  • Metabolic pathways (glycolysis, TCA, etc..)

  
• Six steps in signaling

  1. Synthesis of the signaling molecule by the signaling cell

  2. Release of the signaling molecule by the signaling cell

  3. Transport of the signaling molecule to the target cell

  4. Detection of the signal by a specific receptor protein

  5. A change in cellular metabolism, function, or development triggered by the receptor-signaling molecule complex

  6. Removal of the signaling molecule, which terminates the cellular response

  
• Types of signaling


  • Endocrine
  • Paracrine
  • Neuronal
  • Contact-dependent

  
• Endocrine signaling


  Signaling molecules, called hormones, act on target cells distant from their site of synthesis by endocrine cells

  
• Paracrine signaling


  Signaling molecules released by a signaling cell into the extracellular medium act locally to affect target cells in close proximity to the signaling cell