signal transduction


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signal transduction

  1. 1. Dr Sufyan Akram
  2. 2. Lecture outline• Introduction to Signal transduction pathways• Cellular receptors– Cell surface receptors• G protein coupled receptors• Tyrosine kinase receptors– Intracellular Receptors
  3. 3. Control systems of the bodyHuman body has thousands of control systems in itCellsGeneticcontrolTissuesTissuefactorsOrgans/Systemse.g. Pancreas(blood glucosesensing andrelease ofInsulin)Nervous SystemHormonesComplex,interconnectedcontrolmechanisms
  4. 4. Autocrine Paracrine Endocrine
  5. 5. What are hormones• Endocrine hormones are secreted by specializedglands/tissues• Carried by blood to cells throughout the body• Some have general effects, while others only affectspecific target organs• Hormonal effects on target cells depend upon presenceof specific receptors
  6. 6. General Mechanism of Hormone Action• Specificity of Hormone and Target Tissue interactionis dependent upon the location of cellular receptors:• Plasma membrane of cells (surface receptors)• In the cytosol or nucleus (intra-cellular receptors)
  7. 7. Hormone Receptors• The interaction is swift and reversible, allowing rapidonset and termination of hormone action• Receptor affinity for hormone must be high ashormones circulate in pico- or nanomoleconcentrations• Receptors are also specific
  8. 8. What are Receptors?• Usually proteins or glycoproteins• Ligand-receptor interaction brings aboutconformational change in the receptor leading toactivation of intracellular mediators (“secondmessengers”)• Second messengers, would then activate furthermolecules in the cell…
  9. 9. Two major types of Receptors
  11. 11. GDPGTPGTPATP cAMPActivation ofdownstream targetmolecules   Intracellular effectsG-proteins could be stimulatory(Gs) or inhibitory (Gi)Each hormone receptor interactsspecifically with either Gs or GiGsReceptorAdenylylcyclaseLigand
  12. 12. cAMP• Cyclic adenosine monophosphate (cAMP) is anucleotide generated from ATP through the action ofthe enzyme adenylate cyclase• The intracellular concentration of cAMP is increasedor decreased by activation of a variety of receptors• cAMP activates a large number of downstreamtargets
  13. 13. cAMP• Protein kinase A is normally in a catalytically-inactive state, but becomes active when it binds tocAMP• Upon activation, protein kinase A phosphorylates anumber of other proteins• Levels of cAMP decrease due to destruction bycAMP-phosphodiesterase and the inactivation ofadenylate cyclase
  14. 14. RTK• The receptors for several protein hormones arethemselves protein kinases which are switched onby binding of hormone. The kinase activityassociated with such receptors results inphosphorylation of tyrosine residues on otherproteins• Insulin is an example of a hormone whose receptoris a tyrosine kinase
  15. 15. RTK• The hormone binds to domains exposed on thecells surface, resulting in a conformational changethat activates kinase domains located in thecytoplasmic regions of the receptor• In many cases, the receptor phosphorylates itself aspart of the kinase activation process• The activated receptor phosphorylates a variety ofintracellular targets, many of which are enzymes
  16. 16. 2nd Messenger SystemsSecond Messenger Examples of HormonesCyclic AMPEpinephrine and norepinephrine, glucagon, LH,FSH, TSH, calcitonin, PTH, ADHReceptor TyrosineKinaseInsulin, GH, PRL, Oxytocin, erythropoietin, severalgrowth factorsCalcium and / orPhosphoinositidesEpinephrine and norepinephrine, angiotensin II,ADH, GRH, TRHCyclic GMP ANP, nitric oxide
  17. 17. Insulin-RTK Receptor (an example)
  18. 18. Insulin• Insulin is a hormone associated with energyabundance• In the case of excess carbohydrates, it causes themto be stored as glycogen mainly in the liver andmuscles• Excess carbohydrates that cannot be stored asglycogen are converted into fats and stored in theadipose tissue• In the case of proteins, insulin has a direct effect inpromoting amino acid uptake by cells
  19. 19. Insulin• To initiate its effects on target cells, insulin first bindswith and activates a membrane receptor protein(RTK)
  20. 20. PPInsulinInsulinReceptorTranscriptionof TargetGenesβ βα α-S-S-S-S- -S-SProteinSynthesisFatSynthesisGlucoseSynthesisGlucoseTransportGLUTGlucoseIRS (Insulin Receptor Substrates)Phosphorylation of Enzymes
  22. 22. Intracellular Receptors• Steroid and thyroid hormone receptors are membersof a large group ("superfamily") of transcriptionfactors. All of these receptors are composed of asingle polypeptide chain that has three distinctdomains
  23. 23. Intracellular Receptors• The amino-terminus: this region is involved inactivating or stimulating transcription by interactingwith other components of the transcriptionalmachinery.• DNA binding domain: Amino acids in this region areresponsible for binding of the receptor to specificsequences of DNA.• The carboxy-terminus or ligand-binding domain:This is the region that binds hormone
  24. 24. Hormone-Receptor Binding andInteractions with DNA• Being lipids, steroid hormones enter the cell bysimple diffusion across the plasma membrane.Thyroid hormones enter the cell by facilitateddiffusion• The receptors exist either in the cytoplasm ornucleus, which is where they meet the hormone.When hormone binds to receptor, a characteristicseries of events occurs…
  25. 25. • Receptor activation is the term used to describeconformational changes in the receptor induced bybinding hormone. The major consequence of activationis that the receptor becomes competent to bind DNA• Activated receptors bind to hormone response elements,which are short specific sequences of DNA which arelocated in promoters of hormone-responsive genes• Most commonly, receptor binding to DNA stimulatestranscription. The hormone-receptor complex thusfunctions as a transcription factor
  26. 26. In Summary• Receptors are specific proteins which can beactivated by various factors (ligands)• Once activated, the receptors activate furthermolecules leading to a chain of events (signalingcascade)• The effects could be immediate (like changes inmembrane permeability to certain ions) or long-term (like transcription of genes)