Cell Signaling Mechanisms

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					                  Cell Signaling

Learning Objectives
At the end of the lecture student should be able to understand;

•   Significance of cell signaling

•First and second messengers
•Cell surface types and different forms of intracellular receptors
•Four features of signal transducing system
•Six general types of signal transduction
•The first messengers classification
•G-protein linked signal transduction
•Ca+2 as an intracellular receptor
•Phospholipase C system of signal transduction
Cell Signaling: Responding
    to the outside w orld
•   Cells interact with their environment by interpreting extracellular signals via
    proteins that span their plasma membrane called receptors

•   Receptors are comprised of extracellular and intracellular domains

•   The extracellular domain relays information about the outside world to the
    intracellular domain

            Cell Signaling:
          responding to the
            outside w orld
•   The intracellular domain then interacts with other intracellular signaling

•   These intracellular signaling proteins further relay the message to one or
    more effector proteins

•   Effector proteins mediate the appropriate response
         Cell Signaling:
       responding to the
         outside world
•   This event is transduced into secondary responses within the cell that can
    be divided into four broad categories:

•   (1) ion channel activation,

•   (2) G-protein activation,

•   (3) activation of enzyme activity within the cell,

•   (4) direct activation of transcription

      Some signals to
     which cell respond
    Cell surface
•   Signaling molecules include peptide hormones,
    catechol-amines, insulin, growth factors, cytokines,

•   Binding, and subsequent events, triggers an  or 
    in the cytosolic concentration of a second
    messenger; or the activated,bound receptor acts
    as a scaffold to recruit and activate other
    intracellular proteins
•   Signaling molecules include steroid hormones,
    retinoids,thyroxine, etc

•   Receptor-hormone complex acts a transcription factor
    to alter transcription of certain genes

•   Participates in transduction of the signal from the external messenger to
    some component of the metabolic machinery

•   Has at least one additional functional site which is altered by ligand binding
    (allosteric site)

•   Extracellular ligands are called "first messengers" and the intracellular
    mediators are called "second messengers."
          Four features of signal
           transducing system

•   Each cell is programmed to respond to specific combinations of signaling

•   Different cells can respond differently to the same chemical signal
    Si x general types of si gnal transducers

•    Peptides or polypeptides - insulin, glucagon, growth hormone, insulin-like growth
     factors, vasopressin, prolactin….

•    Glycoproteins - follicle stimulating hormone (FSH), thyroid stimulating hormone

•    Steroids - glucocorticoids      (aldosterone,   cortisol),   steroids   (progesterone,
     testosterone), retinoic acid…

•    Amino acid derivat ives - epinephrine, norepinephrine, thyroxine, triidothyronine
Agonist         mimics a hormone in binding productively to a receptor

Antagonist          mimics a hormone stereochemically, but binds to the receptor

          non-productively, inhibiting the action of the natural hormone

          Agonist              Hormone

          e.g. important therapy binds  2 receptor in heart muscle  Antagonist

          in asthma              ncreased heart rate              ontrol heart beat
Three largest classes of
 cell surface receptors

  Ion Channel linked
        G protein-linked Membrane Receptors
      e.g. Glucagon, Epinephrine and Thrombin as
                    signaling molecules
  •    Activates a chain of events  alterat ions in concentrat ions of signal ing
elaborate sets of interact ing molecules that can relay s ignals from cel l surface
      to the nucleus

       C omponents:
  •    R eceptor; Transducer (G protein ):
  •    Effector (me mbrane-bound en zyme);
  •    Second messenger (e.g. cA M P);
  •     R esponse (casca de of hi ghly- regu lated protein
       phosphorylat ions, et c)

       R ECEPTOR:
  •     typica lly a seven transmembrane
  •     domain, integra l membrane

Characteristics of G proteins
  1. . G protein is an  trimeric protein which binds guanine nucleotides

  2. They function to couple integral membrane receptors to
     target membrane-bound enzymes

  3. They can be considered molecular switches where in
     GDP (inactive)   GTP (active) + 

  4. The dissociated  subunit expresses GTPase activity.
Enzyme linked cell surface receptor
   Phospholipase C mechanism

   Hormonal involvement in responses to a stimulus
         Ca+2 acting as an
       intracellular receptors
Cells must work very hard to maintain low intracellular [Ca 2+]
in order for Ca2+ to result in effective intracellular signaling.

Cellular mechanisms that maintain very low intracellular Ca 2+ concentrations
A: Ca2+ is actively pumped out of the cytosol.
B: Ca2+ is pumped into the ER and mitochondria.

Lingjuan Ma Lingjuan Ma