Cell signalling 1


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Cell signalling 1

  1. 1. Cell signalling <ul><li>By: </li></ul><ul><li>Khuram Aziz </li></ul><ul><li>M.phill biochemiatry </li></ul>
  2. 2. <ul><li>Cellular Signaling </li></ul><ul><li>Many living organisms contain billions of cells that carry out diverse functions. In order for the cells to cooperate, cells need to be able to communicate with each other. Many of the genes that cells are capable of synthesizing are thought to be involved in cellular signaling. </li></ul>
  3. 3. Environmental stimuli <ul><li>With  single-celled organisms , the variety of signal transduction processes influence its reaction to its environment. </li></ul><ul><li>With  multicellular organisms , numerous processes are required for coordinating individual cells to support the organism as a whole; the complexity of these processes tend to increase with the complexity of the organism. Sensing  of environments at the cellular level relies on signal transduction;  many disease processes, such as  diabetes  and  heart disease  arise from defects in these pathways, highlighting the importance of this process in biology and medicine. </li></ul>
  4. 4. <ul><li>Various environmental stimuli exist that initiate signal transmission processes in multicellular organisms; examples include  photons  hitting cells in the  retina  of the eye,  and  odorants binding to  odorant receptors  in the  nasal epithelium .  Certain microbial molecules, such as viral  nucleotides  and protein  antigens , can elicit an  immune system  response against invading  pathogens  mediated by signal transduction processes. </li></ul>
  5. 5. Types of cellular signaling <ul><li>Extra cellular signaling or chemical signaling </li></ul><ul><li>Cell”s direct signaling or intracellular signalling </li></ul>
  6. 6. Ectracellular signaling <ul><li>signaling by extracellular, secreted molecules can be classified into three types — endocrine, paracrine, or autocrine — based on the distance over which the signal acts. </li></ul>
  7. 7. <ul><li>In  endocrine signaling , signaling molecules, called  hormones , act on target cells distant from their site of synthesis by cells of endocrine organs. In animals, an endocrine hormone usually is carried by the blood from its site of release to its target. </li></ul>
  8. 9. <ul><li>In  paracrine signaling , the signaling molecules released by a cell only affect target cells in close proximity to it. The conduction of an electric impulse from one nerve cell to another or from a nerve cell to a muscle cell (inducing or inhibiting muscle contraction) occurs via paracrine signaling.  </li></ul>
  9. 11. autocrine signaling , <ul><li>cells respond to substances that they themselves release. Many  growth factors  act in this fashion, and cultured cells often secrete growth factors that stimulate their own growth and proliferation. This type of signaling is particularly common in tumor cells, many of which overproduce and release growth factors that stimulate inappropriate, unregulated proliferation of themselves as well as adjacent nontumor cells; this process may lead to formation of tumor mass. </li></ul>
  10. 14. Cell direct contact signalling <ul><li>Three types </li></ul><ul><li>Gap junctions </li></ul><ul><li>Surface protein interactions </li></ul><ul><li>Receptors </li></ul>
  11. 15. Receptors <ul><li>In  biochemistry , a  receptor  is a  molecule  found on the surface of a  cell , which receives specific chemical signals from neighbouring cells or the wider environment within an organism. These signals tell a cell to do something—for example to divide or die, or to allow certain molecules to enter or exit the cell. </li></ul><ul><li>Receptors are  protein  molecules, embedded in either the  plasma membrane  ( cell surface receptors ) or the  cytoplasm  ( nuclear receptors ) of a cell, to which one or more specific kinds of signaling  molecules may attach.  </li></ul>
  12. 16. <ul><li>A molecule which binds (attaches) to a receptor is called a  ligand , and may be a  peptide  (short protein) or other small molecule, such as a neurotransmitter , a  hormone , a pharmaceutical drug, or a toxin. Each kind of receptor can bind only certain ligand shapes. Each cell typically has many receptors, of many different kinds. Simply put, a receptor functions as a keyhole that opens a biochemical pathway when the proper ligand is inserted. </li></ul>
  13. 17. Structure <ul><li>The shapes and actions of receptors are studied by  X-ray crystallography ,  dual polarisation interferometry ,  computer modelling , and structure-function studies, which have advanced the understanding of  drug action  at the binding sites of receptors. Structure activity relationships correlate induced conformational changes with biomolecular activity, and are studied using dynamic techniques such as  circular dichroism  and  dual polarisation interferometry . </li></ul>
  14. 18. Binding and activation <ul><li>Ligand binding is an  equilibrium  process. Ligands bind to receptors and dissociate from them according to the  law of mass action . </li></ul><ul><li>One measure of how well a molecule fits a receptor is the binding affinity, which is inversely related to the  dissociation constant   K d . A good fit corresponds with high affinity and low  K d . The final biological response (e.g.  second messenger cascade , muscle contraction), is only achieved after a significant number of receptors are activated. </li></ul>
  15. 19. <ul><li>The receptor-ligand affinity is greater than enzyme-substrate affinity.  Whilst both interactions are specific and reversible, there is no chemical modification of the ligand as seen with the substrate upon binding to its enzyme. </li></ul>
  16. 20. Constitutive activity <ul><li>A receptor which is capable of producing its biological response in the absence of a bound ligand is said to display &quot;constitutive activity&quot;.  The constitutive activity of receptors may be blocked by  inverse agonist  binding. Mutations in receptors that result in increased constitutive activity underlie some inherited diseases, such as precocious puberty (due to mutations in luteinizing hormone receptors) and hyperthyroidism (due to mutations in thyroid-stimulating hormone receptors). </li></ul>
  17. 21. Ligands <ul><li>(Full)  agonists  are able to activate the receptor and result in a maximal biological response. Most natural ligands are full agonists. </li></ul><ul><li>Partial agonists  do not activate receptors thoroughly, causing responses which are partial compared to those of full agonists. </li></ul><ul><li>Antagonists  bind to receptors but do not activate them. This results in receptor blockage, inhibiting the binding of other agonists. </li></ul><ul><li>Inverse agonists  reduce the activity of receptors by inhibiting their constitutive activity. </li></ul>
  18. 22. Cell surface receptor <ul><li>Cell surface receptors  ( membrane receptors ,  transmembrane receptors ) are specialized  integral membrane proteins  that take part in communication between the cell and the outside world. Extracellular  signaling molecules  (usually  hormones , neurotransmitters ,  cytokines ,  growth factors  or  cell recognition molecules ) attach to the  receptor , triggering changes in the function of the  cell . This process is called  signal transduction :  </li></ul>
  19. 23. <ul><li>The binding initiates a chemical change on the  intracellular  side of the membrane. In this way the receptors play a unique and important role in cellular communications and signal transduction. </li></ul>
  20. 24. Types <ul><li>Receptors can be roughly divided into two major classes:  intracellular  receptors and  extracellular  receptors. </li></ul>
  21. 25. Extracellular receptors <ul><li>Extracellular receptors are  integral transmembrane proteins  and make up most receptors. They span the  plasma membrane  of the cell, with one part of the receptor on the outside of the cell and the other on the inside. Signal transduction occurs as a result of a ligand binding to the outside; the molecule does not pass through the membrane. This binding stimulates a series of events inside the cell; different types of receptor stimulate different responses and receptors typically respond to only the binding of a specific ligand. Upon binding, the ligand induces a change in the  conformation  of the inside part of the receptor. These result in either the activation of an enzyme in the receptor or the exposure of a binding site for other intracellular signaling proteins within the cell, eventually propagating the signal through the cytoplasm. </li></ul>
  22. 27. <ul><li>These are transmembrane recptors of various types </li></ul><ul><li>Having 3 domains </li></ul>
  23. 28. The extracellular domain <ul><li>The extracellular domain is the part of the receptor that sticks out of the membrane on the outside of the cell or  organelle . If the polypeptide chain of the receptor crosses the bilayer several times, the external domain can comprise several &quot;loops&quot; sticking out of the membrane. </li></ul>
  24. 30. the transmembrane domains <ul><li>In the majority of receptors for which structural evidence exists,  transmembrane alpha helices  make up most of the transmembrane domain. In certain receptors, such as the  nicotinic acetylcholine receptor , the transmembrane domain forms a protein-lined pore through the membrane, or  ion channel . Upon activation of an extracellular domain by binding of the appropriate ligand, the pore becomes accessible to ions, which then pass through. </li></ul>
  25. 32. <ul><li>  In other receptors, the transmembrane domains are presumed to undergo a conformational change upon binding, which exerts an effect intracellularly. In some receptors, such as members of the  7TM superfamily , the transmembrane domain may contain the ligand binding pocket </li></ul>
  26. 33. intracellular (or  cytoplasmic ) domain <ul><li>The intracellular (or  cytoplasmic ) domain of the receptor interacts with the interior of the cell or organelle, relaying the signal. There are two fundamentally different ways for this interaction: </li></ul><ul><li>The intracellular domain communicates via specific protein-protein-interactions with  effector proteins , which in turn send the signal along a signal chain to its destination. </li></ul><ul><li>With  enzyme-linked receptors , the intracellular domain has  enzymatic activity . Often, this is a  tyrosine kinase  activity. The enzymatic activity can also be located on an enzyme associated with the intracellular domain. </li></ul>
  27. 35. <ul><li>processes through membrane receptors involve the External Reactions, in which the ligand binds to a membrane receptor, and the Internal Reactions, in which intracellular response is triggered. </li></ul>
  28. 36. <ul><li>Based on structural and functional similarities, membrane receptors are mainly divided into 3 classes: The  ion channel-linked receptor ; The  enzyme-linked receptor  and  G protein-coupled receptor . </li></ul>
  29. 37. Ion channel linked receptors <ul><li>Ion channel linked receptors  are ion-channels (including cation-channels and anion-channels) themselves and constitute a large family of multipass transmembrane proteins. They are involved in rapid signaling events most generally found in electrically excitable cells such as  neurons  and are also called  ligand-gated ion channels . Opening and closing of Ion channels are controlled by  neurotransmitters . </li></ul>
  30. 39. Enzyme-linked receptors <ul><li>Enzyme-linked receptors  are either enzymes themselves, or are directly associated with the enzymes that they activate. These are usually single-pass transmembrane receptors, with the enzymatic portion of the receptor being intracellular. The majority of enzyme-lined receptors are protein kinases, or associate with protein kinases. </li></ul>
  31. 42. G protein-coupled receptors <ul><li>G protein-coupled receptors  are integral membrane proteins that possess seven membrane-spanning domains or transmembrane helices. These receptors activate a  G protein  ligand binding. G-protein is a trimeric protein. The 3 subunits are called α 、 β and γ. The α subunit can bind with  guanosine diphosphate , GDP. This causes phosphorylation  of the GDP to  guanosine triphosphate , GTP, and activates the α subunit, which then dissociates from the β and γ subunits. The activated α subunit can further affect intracellular signaling proteins or target functional proteins directly. </li></ul>
  32. 43. G Protein-Linked Receptors
  33. 46. <ul><li>Signal transduction through membrane receptors usually requires four characters: </li></ul><ul><li>Extracellular signal molecule: an extracellular signal molecule is produced by one cell and is capable of traveling to neighboring cells, or to cells that may be far away. </li></ul><ul><li>Receptor protein: the cells in an organism must have cell surface receptor proteins that bind to the signal molecule and communicate its presence inward into the cell. </li></ul>four Stages of Signal Transduction
  34. 47. <ul><li>Intracellular signaling proteins: these distribute the signal to the appropriate parts of the cell. The binding of the signal molecule to the receptor protein will activate intracellular signaling proteins that initiate a signaling cascade (a series of intracellular signaling molecules that act sequentially). </li></ul><ul><li>Target proteins: the conformations or other properties of the target proteins are altered when a signaling pathway is active and changes the behavior of the cell. </li></ul>
  35. 48. Three Stages of Signal Transduction
  36. 49. NEXT <ul><li>Detailed role of G-protein in signal transduction </li></ul>
  37. 50. <ul><li>Thanks </li></ul>