1 / 50

Topic 3 Cell Signalling

Topic 3 Cell Signalling. Messengers. Chemical Endocrine Paracrine Autocrine Electrical. Endocrine Signals. Act over long distances Distributed via the bloodstream Examples include Insulin Peptide hormone—Islets of Langerhans —pancreas

Download Presentation

Topic 3 Cell Signalling

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  1. Topic 3Cell Signalling

  2. Messengers • Chemical • Endocrine • Paracrine • Autocrine • Electrical

  3. Endocrine Signals • Act over long distances • Distributed via the bloodstream • Examples include • Insulin • Peptide hormone—Islets of Langerhans—pancreas • Signals muscle and adipose to uptake glucose in response to high blood glucose • Nobel Prize—1923—Banting and Macleod—discovery of insulin

  4. Paracrine & AutocrineSignals • Paracrine: • Act over short distances • Released locally • Example • Epidermal growth factor • Stimulates growth and development • Autocrine • Act on the cell that secretes them

  5. Flow of Information • Chemical messenger=ligand • Ligand acts as primary messenger • Activation of other molecules • Secondary messenger system

  6. Receptors • Usually transmembrane proteins • Exception is steroid hormone receptors • Ligand binding domain • Specific to signal that they receive • Specificity is via ligand binding domain • Can have different affinities for different ligands • Ligand binding affects intracellular activities by • Changing conformation of the receptor • Clustering of receptors

  7. Two types of receptors G-protein coupled receptors Protein kinase linked receptors

  8. GPCR structure • Single polypeptide • Main function—activation of G protein • 7 transmembrane domains • Ligands bind near extracellular domain • Several cytoplasmic domains near TM5, TM6, TM7 and maybe TM4 mediate G protein binding • Large protein superfamily

  9. Structure of GPCR

  10. G proteins • Bound to the inner side of the plasma membrane • 3 subunits • α, βand γ • Inactive form • 3 subunits associated with each other; α is also bound to GDP • Activated • GDP replaced by GTP; α subunit + GTP dissociate from β and γ subunits

  11. Activation of GPCR http://www.nature.com/scitable/content/ne0000/ne0000/ne0000/ne0000/14673543/U4.cp2.1_nature01307-f1.2.jpg

  12. Activated G Protein • Can activate ion channels • Activate 2nd messenger cascades • Cyclic AMP • Cyclic GMP • Phospholipase C pathway

  13. Inactivation of G protein α subunit of G protein contains a GTPase GTP degraded to GDP α subunit reassociates with β and γ subunits

  14. Cyclic AMP cascade http://t3.gstatic.com/images?q=tbn:ANd9GcQev_GY0IC6y5BsuY4GoQ-8UaWogpktHlZpStl29YimNMDMXGP7 • G protein activates adenylylcyclase • Catalyzes conversion of ATP to cyclic AMP • Cyclic AMP activates protein kinases • Protein kinasesphosphorylate other proteins • Activation of ion channels • Metabolic changes • Changes in transcription factors

  15. Cyclic AMP http://psychology.jrank.org/article_images/psychology.jrank.org/neurotransmitters-and-neuromodulators.9.jpg

  16. Termination of cAMP activity • Cyclic AMP activity terminated by a phosphodiesterase • Converts cyclic AMP to 5’AMP

  17. cAMP activation of protein kinases

  18. Cyclic GMP cascade http://t2.gstatic.com/images?q=tbn:ANd9GcQBJuFA6x0bdMfdJ27IcwR_oWPfDzTSaawOQ8mzeR13LVmColSLXQ Very similar to cyclic AMP Utilized guanidine instead of adenosine GPCRs activate guanylylcyclase Activation of cGMP-dependent protein kinases

  19. Phospholipase C pathways • Common membrane protein: • Phosphotidylinositol 4,5-biphosphate (PIP2) • ligands bind GPCR • G proteins activated • α subunit activates a membrane-bound enzyme • Phospholipase C (PLC) • PLC catalyzes hydrolysis of PIP2 into inositoltriphosphate (IP3) and diacylglycerol (DAG)

  20. Phospholipase C cleavage of PIP2 http://www.ncbi.nlm.nih.gov/bookshelf/picrender.fcgi?book=dbio&part=A1401&blobname=ch7f28.jpg

  21. IP3 pathway IP3 was the polar head of the phospholipid Freely diffuses into cytoplasm Releases Ca2+ from intracellular stores

  22. Phospholipase C http://psychology.jrank.org/article_images/psychology.jrank.org/neurotransmitters-and-neuromodulators.11.jpg

  23. DAG pathway Nonpolar component of phospholipid Diffuses through the membrane bilayer Activates protein kinase C (PKC) Results in protein phosphorylaton

  24. Ca2+ and PKC • Ca2+ released by IP3 can enhance activation of PKC • Activating calmodulin • Calmodulin + Ca2+ • Activation of calcium/calmodulin-dependent protein kinases

  25. Disruption of GPCR Signalling Cascades • Vibriocholerae • Intestinal tract • Bordetellapertussis • lungs

  26. Calcium’s Role • Major role in regulation of cell functions • Maintained at low concentration in cytosol • Calcium ATPases • In neurons • Influx of extracellular calcium • Release of neurotransmitters • In cardiac and skeletal muscle • Released from sacroplasmic reticulum • Involved in contraction

  27. Calcium Regulation in the Cell

  28. Other roles • Fertilization • Ca release from spermsperm activation binding to mature eggfertilization • Release of internal stores of Ca in egg • stimulation of cortical vesicles to prevent polyspermy • Resumption of metabolic processes • Initiation of embryogenesis

  29. Ca binding to effector proteins • Calcium can bind directly to some proteins altering their activity • Example is Calmodulin • Conformational change when Ca binds • Ca-Calmodulin can bind to protein kinases or phosphatases

  30. βγ subunits of G protein Can activate protein receptors i.e.—muscarinic acetylcholine receptor

  31. Protein Kinase-Associated Receptors • Binding of ligand to PK-associated receptor stimulates kinase activity • Transmission of signal via phosphorylation cascades • 2 major classes • Tyrosine kinase receptors • Serine-threonine receptors

  32. Growth factors • Cell culture studies • Plasma—no cell growth • Whole blood with unactivated platelets but no red or white blood cells • Serum---cells grow • Clear fluid remaining after blood clots • During clotting, platelets release platelet-derived growth factor • Stimulates fibroblast growthscar

  33. Growth factors • Receptor is tyrosine kinase • Other GFs include • Insulin • Insulin-like growth factor • Fibroblast growth factor • Epidermal growth factor • Nerve growth factor

  34. Receptor Tyrosine Kinases • Single peptide chain • 1 transmembrane domain • Extracellular domain=ligand receptor • Cytosolic domain=protein kinase • Contains tyrosines that are targets for their own kinase activity • 1st discovered = Src • Encoded by src gene of avian sarcoma virus

  35. Activation of RTKs • Ligand binds • RTKs aggregate • Tyrosine kinasephosphorylatestyrosines of neighbouring RTKs =autophosphorylation

  36. Ras pathway • Involves a number of proteins including: • Ras – small monomeric G protein • GEF – guanine-nucleotide exchange factor • Sos—GEF that activates Ras • GRB2 – contains SH2 domain which binds to RTK

  37. Ras • RTK phosphorylated • GRB2 and Sos form a complex • Bind to RTK activating Sos • Sos activates Ras to release GDP and bind GTP • Activated Rasphosphorylatesthreonine and serines of MEK (also known as MAPK) • MAPK phosphorylate transcription factors • GTPase activation protein—hydrolyzes GTP on Ras Ras inactivation

  38. RTKs activate other pathways • Phospholipase C pathway • RTK activates PLC-gamma • PLC-gamma has a SH2 domain • GPCR activates PLC-beta

  39. Scaffolding • Formation of multiprotein complexes • Cascading is more efficient • Cellular responses restricted to a smaller area

  40. Serine-ThreonineKinases • Receptor for transforming growth factor β • TGFβ binds to ser/thrkinase receptor • 2 types—type I and type II • Type II phosphorylates type I • Type I phosphorylates R-Smad • R-Smad complexes with Smad 4 • Moves to nucleus • Regulates gene expression

  41. You should be able to: Compare and contrast GPCR and protein kinase receptors Describe the cAMP, cGMP, PLC, Smad and Ras pathways

More Related