Cell Signaling


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Cell Signaling

  1. 1. Cell Signaling at the Cell Surface
  2. 2. Hydrophilic Signals <ul><li>Chemicals signals that bind to cell-surface receptors activate signal-transduction pathways . </li></ul><ul><li>Binding to the receptor </li></ul><ul><li>Transduction via 2 nd messengers </li></ul><ul><li>[2 nd messenger activated by effector] </li></ul><ul><li>Response </li></ul>
  3. 3. Types of Signals <ul><li>Act outside the organism </li></ul><ul><li>Pheromones </li></ul><ul><li>Act within the organism </li></ul><ul><li>Local Regulators </li></ul><ul><li> Autocrine </li></ul><ul><li> Paracrine (e.g.,neurotransmitters, growth factors) </li></ul><ul><li>Long Distance (endocrine signaling) </li></ul><ul><li>Hormones </li></ul><ul><li>Some molecules can serve as both paracrine and endocrine signals. </li></ul>
  4. 4. How do signaling molecules work? <ul><li>1. Change the activity or function of a pre-existing protein. </li></ul><ul><li>2. Change the amount of protein in a cell by modifying transcription factors, leading to activation or suppression of gene transcription. </li></ul><ul><li>Response 1 generally occurs more rapidly. Why? </li></ul>
  5. 5. Classes of Receptors <ul><li>Generally activate pre-existing proteins: </li></ul><ul><li>G-protein coupled </li></ul><ul><li>Generally alter protein amounts found in cells: </li></ul><ul><li>Cytokine </li></ul><ul><li>Tyrosine kinase </li></ul><ul><li>TGF β </li></ul><ul><li>Hedgehog </li></ul><ul><li>Wnt </li></ul><ul><li>Notch </li></ul>
  6. 6. Common Properties of Cell-Surface Receptors - I <ul><li>All receptors are proteins </li></ul><ul><li>High ligand binding specificity </li></ul><ul><li>Ligands, on the other hand, exhibit binding versatility – one type of ligand may bind to different types of receptors to activate different pathways </li></ul><ul><li>Receptor-ligand complex exhibits effector specificity (a specific cellular response) </li></ul>
  7. 7. Common Properties of Cell-Surface Receptors - II <ul><li>Binding of ligand to receptor is by weak, non-covalent interactions and molecular complementarity </li></ul><ul><li>K D (Dissociation constant) = </li></ul><ul><li>[R][L]/[RL] </li></ul><ul><li>Maximal response need not require activation of all receptors present. </li></ul>
  8. 8. Common Properties of Cell-Surface Receptors - III <ul><li>Sensitivity of a cell to a ligand depends on the number of surface receptors </li></ul>
  9. 9. Second Messengers <ul><li>Binding of ligands to cell-surface receptors leads to the activation of intracellular molecules called second messengers. </li></ul><ul><li>Include: cAMP, cGMP, DAG, IP 3 , Ca +2 </li></ul><ul><li>cAMP activates protein kinase A </li></ul><ul><li>cGMP activates protein kinase G </li></ul><ul><li>DAG activates protein kinase C </li></ul><ul><li>IP 3 causes the release of Ca +2 </li></ul>
  10. 10. Role of Ca +2 <ul><li>Activate a variety of proteins that cause cellular responses, such as: </li></ul><ul><li>Muscle contraction in muscle cells </li></ul><ul><li>Release of neurotransmitters (exocytosis of vesicles in nerve cells) </li></ul><ul><li> Release of hormones (exocytosis in endocrine cells) </li></ul>
  11. 11. Other Proteins Involved in Signal-Transduction - I <ul><li>A. GTPase Switch Proteins </li></ul><ul><li>Belong to the GTPase superfamily </li></ul><ul><li>Are “on” when have bound GTP </li></ul><ul><li>Are “off” when have bound GDP </li></ul><ul><li>After activation, switches 1 and 2 (two segments of the protein) remove the P from GTP, causing inactivation. </li></ul>
  12. 12. Classes of GTPase Switch Proteins <ul><li>Trimeric that directly bind receptors </li></ul><ul><li>Monomeric that are indirectly linked to receptors (eg., Ras) </li></ul>
  13. 13. Other Proteins Involved in Signal-Transduction - II <ul><li>Protein Kinases </li></ul><ul><li>Enzymes tha phosphorylate other proteins. Animals cells contain two types – one phosphorylates the -OH goup of tyrosine, and one that phosphorylates the -OH group of serine or threonine or both. </li></ul><ul><li>Protein Phosphatases </li></ul><ul><li>Enzymes that remove phosphate groups from other proteins. </li></ul>
  14. 14. Receptors and Associated Signal-Transduction Proteins may be Localized. <ul><li>Some receptors may be uniformly distributed on the cell surface; however, others are localized to particular regions. </li></ul><ul><li>Clustering may be mediated by adapter domains of particular cytosolic proteins. </li></ul><ul><li>e.g., PDZ domains of proteins that localize receptors on the post- synaptic membrane </li></ul>
  15. 15. Protein clustering in lipid rafts. Recall that lipid rafts are non-random association of lipids (typically cholesterol and sphingolipids) in the plasma membrane. Many signaling receptors and associated proteins are found in lipid rafts associated with caveolin protein. These rafts are called caveolae.
  16. 16. G-Protein Coupled Receptors that Activate/Inhibit Adenylyl Cyclase <ul><li>Contain seven membrane-spanning (H1-H7) regions with their N-terminus in the exoplasmic face (facing the exterior of the cell) and their C-terminal segment on the cytosolic face. Four domain are in th eexterior (E1-E4) and four face the interior of the cell (C1-C4). C3 and C4 domains interact with trimeric G-proteins. </li></ul>
  17. 17. Structure of Trimeric G Protein <ul><li>Three subunits – α , β and </li></ul><ul><li>The beta and gamma sub-units remain together. </li></ul><ul><li>The alpha sub-unit is the GTPase. </li></ul>
  18. 18. Signal Amplification <ul><li>Amplification refers to the activation of increasing numbers of molecules downstream from the receptors </li></ul>
  19. 19. Activation of Adenylyl Cyclase <ul><li>Signal binds to receptor. </li></ul><ul><li>Receptor undergoes conformational change, becoming active. </li></ul><ul><li>Activated receptor binds to α subunit of G protein. </li></ul><ul><li>G α subunit undergoes a shape change, GDP dissociates and GTP binds. G α dissociates from G βγ subunit. </li></ul><ul><li>Hormone dissociates from the receptor. G α binds to effector protein (adenylyl cyclase), thereby activating it. </li></ul><ul><li>Hydrolysis of GTP to GDP within a few seconds inactivates G α , it re-associates with G βγ . </li></ul>
  20. 20. What does adenylyl cyclase do? <ul><li>Adenylyl cyclase synthesizes cAMP from ATP. </li></ul><ul><li>cAMP activates Protein Kinase A (PKA). </li></ul><ul><li>Protein kinase A activates additional proteins, eventually leading to a cellular response. </li></ul>
  21. 21. Two general types of G-protein coupled receptors <ul><li>β -andrenergic receptors stimulate adenylyl cyclase – increase [cAMP] </li></ul><ul><li>These are coupled to stimulatory G s protein. </li></ul><ul><li>α -andrenergic receptors inhibit adenylyl cyclase – decrease [cAMP] </li></ul><ul><li>These are coupled to an inhibitory G i protein. </li></ul>
  22. 22. Glycogen Metabolism <ul><li>Binding of epinephrine to G-protein associated β -andrenergic receptors in muscle and liver cells leads to increased cAMP production. </li></ul><ul><li>In both muscle and liver cells, glycogen is broken down to Glucose-1 P. </li></ul><ul><li>In muscle cells, the Glucose-1P is converted to Glucose-6 P which enters glycolysis. </li></ul><ul><li>In liver cells, the Glucose-6 P is hydrolyzed to glucose which is exported by GLUT2. </li></ul>
  23. 24. The Role of PKA in Glycogen Metabolism <ul><li>PKA both directly inhibits glycogen synthase and indirectly stimulates glycogen phosphorylase. </li></ul>
  24. 25. Muscarinic Acetylcholine Receptors in Heart Muscle <ul><li>Binding of acetylcholine causes receptor to bind to G i α subunit. GDP is replaced by GTP. </li></ul><ul><li>Activated G i α subunit dissociates from G βγ subunit. </li></ul><ul><li>G βγ subunit binds to K + channel, which opens. </li></ul><ul><li>K + flow out of the cell, causing a hyper-polarization. </li></ul><ul><li>Frequency of heart muscle contraction decreases. </li></ul>
  25. 26. G-Protein Associated Receptors that Activate Phospholipase C <ul><li>Binding of signal causes activation of phospholipase C. </li></ul><ul><li>Phospholipase C cleaves the membrane-bound PIP 2 to the membrane-bound DAG and cytosolic IP 3 . </li></ul><ul><li>IP 3 diffuses through the cytosol and binds to a chemical-gated Ca +2 channel on the smooth ER, causing Ca +2 to be released. </li></ul><ul><li>Ca +2 causes recruitment of PKC to the plasma membrane, where it interacts and is activated by DAG. </li></ul><ul><li>PKC activates other proteins, leading to cellular response. </li></ul>
  26. 27. Ca +2 /Calmodulin Complex <ul><li>Release of calcium ions into the cytosol from IP 3 -mediated processes can lead to a variety of cellular responses. </li></ul><ul><li>Calmodulin (the major calcium binding protein of cells) binds to 4 calcium ions to form a complex that interacts with and modulates the activity of many other proteins, including enzymes. </li></ul>