Week 13

• Welcome to MCB 181R
• Dr. Corin Gray
• Week 13 - Cell Signaling
• Where do I access the exam practice? - On Achieve.
• Can you please post the study guide earlier? - Yes, working on it!
• How much of the exam is cumulative? - About 20% which means there are usually 3-4 cumulative true/false and 4-5 cumulative multiple-choice questions. The free response questions assess your learning of multiple learning objectives and can also be considered cumulative because our content builds.
• Extra Credit Please! - There will be several more survey related opportunities that add 0.1 - 0.2 to your final grade. Also, if you attend 6 SI sessions you will receive an additional 2% added to your final grade. Deadline: April 26th.
• Guest speakers are great but please not right before exams. - Heard!
• Reminder: My email response time is 48 hours.
• Essential elements for cell signaling/communication


  • Signaling cell
  • Signaling molecule (ligand)
  • Receptor protein with ligand binding site
  • Responding cell

  
• Remember: For signal transduction to occur the responding cell must have the receptor for the signaling molecule.

  
• Steps in Cell Signaling


  1. The signaling molecule (ligand) binds to a region on the receptor called the ligand binding site

  2. When the ligand binds, a conformational change in the receptor takes place that triggers transduction

  3. This message can remain in the cytosol or go to the nucleus

  
• Nonpolar signaling molecules


  Can pass through the hydrophobic core of the plasma membrane, their receptor (cytosol or nucleus) is inside the cell, when bound they form activated receptor complexes that regulate gene expression

  
• Polar signaling molecules


  Cannot pass through the hydrophobic interior of the plasma membrane, generally need receptors on the exterior of the cell, when bound the entire receptor molecule undergoes a conformational change, activating the receptor

  
• Ligand-Gated Ion Channels


  Ion channels that open when bound by their ligand, referred to as receptors

  
• Facilitated diffusion


  Molecules that cannot move across the lipid bilayer directly can move passively toward a region of lower concentration through a membrane protein channel or carrier protein down or with the concentration gradient
• Receptor kinases


  1. Are both receptors (bind ligands) and kinases (catalyze the addition a phosphate group)

  2. When a signaling molecule (ligand) binds (noncovalent) to a receptor kinase, the receptor partners (forms a dimer) with another receptor kinase bound to another molecule of the same ligand

  3. Dimerization activates the cytoplasmic kinase domains, causing them to phosphorylate each other at multiple sites on their cytoplasmic tails

  4. These phosphorylated areas provide a place for other proteins to bind and become active
• An Example Receptor Kinase Pathway

  1. Activation: PDGF (platelet-derived growth factor) binds to receptor kinases on the surface of the cell, and the receptors dimerize and become active

  2. Dimerization activates the cytoplasmic kinase domains, causing them to phosphorylate each other

  3. The phosphorylated receptor activates (GDP to GTP) the cytoplasmic signaling protein Ras (G protein)

  4. Amplification: GTP-bound Ras triggers a series of kinases that eventually enter the nucleus and phosphorylate target proteins. Example: transcription factors that switch on genes needed for cell division so that the cut can heal

  5. 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 G proteins


  1. When a ligand binds to a G protein-coupled receptor, the receptor binds to and activates the G protein by replacing GDP with GTP

  2. G protein-coupled receptors associate with G proteins bound to GTP and GDP in the cytoplasm

  3. Activation: When a G protein is bound to GTP, it is active; when it is bound to GDP, it is inactive

  4. Transduction: If bound to GTP, the G protein is on, and the signal continues to be transmitted
• An Example GPCR Pathway

  Activation: Adrenaline (ligand) binds to a G protein
• G Protein-Coupled Receptors


  When a ligand binds to a G protein-coupled receptor, the receptor binds to and activates the G protein by replacing GDP with GTP
• G protein-coupled receptor activation


  1. Ligand binds to receptor

  2. Receptor binds and activates G protein by replacing GDP with GTP
• G protein activation


  When bound to GTP, the G protein is active; when bound to GDP, it is inactive
• G protein signal transduction

  If bound to GTP, the G protein is on, and the signal continues to be transmitted
• GPCR pathway example


  • Adrenaline (ligand) binds to GPCR on cardiac muscle cells
  • GDP in G protein replaced by GTP, activating G protein
  • GTP-bound α subunit binds to and activates adenylyl cyclase
  • Adenylyl cyclase converts ATP to cAMP (second messenger)
  • cAMP binds to and activates protein kinase A
  • Phosphorylation of proteins by protein kinase A increases rate of contraction
• GPCR signal amplification


  • Each adrenaline-bound receptor activates multiple G proteins
  • Each adenylyl cyclase produces large amounts of cAMP
  • Each active protein kinase A activates multiple protein targets
• GPCR signal termination


  1. Adrenaline leaves receptor, receptor reverts to inactive conformation

  2. G proteins convert GTP to GDP, becoming inactive, inactivating adenylyl cyclase

  3. Enzymes degrade cAMP, stopping activation of more protein kinase A

  4. Phosphatases remove phosphate groups from activated proteins, making them inactive
• Steroid hormones


  Small, hydrophobic chemical signaling molecules that can easily pass through cell's plasma membrane
• Steroid hormone signaling pathway

  1. Cortisol (steroid hormone) passes through plasma membrane

  2. Cortisol-receptor complex forms in cytoplasm, receptor undergoes conformation change

  3. Cortisol-receptor complex enters nucleus and binds to DNA

  4. Cortisol-receptor complex acts as transcription factor, causing transcription of target genes

  5. Transcribed mRNA is translated into proteins that help body respond to stress