Cell Signalling

							Cell Signalling
           I. Introduction
A. Conversion of a signal to a response -
    Signal-Transduction Pathway
B. Communicating cells may be close or far
 apart
    1. Direct Contact
    2. Local regulators
    3. Hormones
         Endocrine cells to blood to
         target cells
1. Direct Contact
2. Local Signalling, 3. Distance signals
C. Three stages of cell signalling
 1. Reception - signal binds to protein on
 cell surface
 2. Transduction - change in receptor
 triggers a series of changes - pathway
     sometimes in form of a cascade
 3. Response - cell activity results
D. Pioneer of cell signalling research
     E.W. Sutherland
         Studied epinephrine (hormone)
         effects on glycogen breakdown

      Epinephrine activates
        Glycogen phosphorylase (enzyme)

        Sutherland discovered that there is
        a series of intermediate steps
       II. Signal Reception
A. Signal binds to receptor protein
     causes shape change
B. Signal molecule specific to receptor
C. Signal molecules called Ligands
       II. Signal Reception
D. Signal receptors - mostly membrane
 proteins.
     1. Large and water soluble
     2. When activated (shape changed), can
     trigger changes within cell.
        II. Signal Reception
E. Main types of receptors
    1. Membrane receptors
    2. Intra-cellular receptors
E. Main types of receptors
1. Membrane receptors (3 main ones)
  G-Protein-linked Receptor
     protein spans membrane
     cytoplasmic end
     associates with a
     G-Protein
1. Membrane receptors (3 main ones)
  G-Protein-linked Receptor
     Normally in
     inactive states
     Signal binds to
          receptor
     Receptor activated
     Receptor binds to
          G-Protein
1. Membrane receptors (3 main ones)
  G-Protein-linked Receptor
    Activates G-protein
          GDP to GTP
    G-protein binds to
       other membrane
       protein (enzyme)
     Leads to cell
          response
1. Membrane receptors (3 main ones)
  G-Protein-linked Receptor
     G-protein shut off
     GTP back to GDP

 Common roles;
 Embyro development
 Sensory systems
E. Main types of receptors
1. Membrane receptors
G-Protein-linked Receptor

Tyrosine Kinase Receptor
 Used for triggering several pathways
    and coordinating many activities.
Tyrosine Kinase Receptor
 Parts of the Tyrosine Kinase Receptor
    Extracellular binding site
    Single alpha helix within membrane
    Intracelluar tail - tyrosine tails
Tyrosine Kinase Receptor
 Operation
    Ligands bind to two receptors
    Receptors aggregate togther
    Activated tails are phosphorylated
Tyrosine Kinase Receptor
 Operation
    Relay proteins are activated
    These lead to cell responses
E. Main types of receptors
1. Membrane receptors
G-Protein-linked Receptor
Tyrosine Kinase Receptor
Ligand-gated ion channels
  Protein pores that open
  or close in response to
  a signal
Ligand-gated ion channels
Allows or blocks ion flow
  such as Na+ or Ca+2
Ligand binds to exterior
Channel shape changes
  opens channel
Ion flow occurs
Ligand detaches,
  closing channel
       II. Signal Reception
E. Main types of receptors
    1. Membrane receptors
          G-Protein linked
          Tyrosine Kinase
          Ligand gated ion channels
    2. Intra-cellular receptors
          Found in cytosol or nucleus of
          target cells
        II. Signal Reception
2. Intra-cellular receptors
  Operation
      Signals pass through cell membrane
      Can bind to receptors in cytosol
           causing cytosol transduction
           or relay signal to nucleus
      Can directly enter nucleus, binding to
           nuclear receptors
        II. Signal Reception
2. Intra-cellular receptors
  Examples
  Hydrophobic steroids
  Thyroid hormones
  Testosterone
      binds to cytosol rec.
      Activated rec. enters
           nucleus
           turns on genes
        II. Signal Reception
2. Intra-cellular receptors
  Examples
  Turn on genes how?
      Act as transcription
           factors
      Controls which genes
      are transcribes to
      mRNA.
III. Signal-Transduction Pathways
A. Reason for Transduction?
    A Multi-step pathway!
        Advantages
              1. Amplifies the signal
                     One tiny signal to Many
                     activated molecules
III. Signal-Transduction Pathways
A. Reason for Transduction?
    A Multi-step pathway!
        Advantages
              2. Provide more coordination
                        than a simpler
                        system could
                        accomplish
III. Signal-Transduction Pathways
B. Relay of signal down a chain
    Activated receptor activates protein A
    Protein A activates protein B
    Protein B activates protein C
    Protein C activates protein D …..

  At each step, signal is transduced to a
  different form -
      usually a change in protein shape
III. Signal-Transduction Pathways
C. Protein phosphorylation - common in
 transduction
 Activated protein kinase
     phosphorylates an inactive protein
     kinase
              This adds P to it
              This activates it
III. Signal-Transduction Pathways
C. Phosphorylation
     Usually at Serine or Threonine of
     substrate.
     May lead to a cascade
     Each phosphorylation =
          Shape change due to interaction of
          Phosphate groups and aminoacids
     A single cell has 100s of protein kinases
          specific to a substrate
III. Signal-Transduction Pathways
D. Turning off activation -
     Protein phosphatases
               Remove Phosphate groups
     Regulation depends on balance of
         Kinases and Phosphatases
     During times of “No signal”
         Phosphatatases predominate and
         pathway is shut down.
III. Signal-Transduction Pathways
E. Important small molecules in pathways
  Second Messengers - non-protein
  1. Diffuse rapidly through cell
  2. Used to spread signal from both
          G-protein linked receptors
          Tyrosine kinase receptors
     Can be found as steps in many
     pathways
3. Cyclic Amp
     This is a step for Sutherland’s
     Epinephrine.
     Receptor’s activation leads to increase
     of Cyclic AMP concentration (cAMP)

Start of chain or Embedded in chain
Receptor          Receptor
  cAMP                Kinase Phos. Chain
     Kinase Phos. Chain    cAMP
                              Kinase ….
How does this step work?
    Receptor activates adenylyl cyclase
    Adenylyl cyclase converts ATP to cAMP
    cAMP short-lived as Phosphodiesterase
        cAMP passes the signal by
              activating other kinases ….
    cAMP rapidly back to AMP (inactive)
Uses of cAMP
 G-protein can pass signals this way
    G-protein activates Adenylyl cyclase
 Some systems inhibit Adenylyl cyclase
    enables regulation
Cholera - disruption of
    G-protein - cAMP mechanism
    Vibrio cholerae invades Sm Intestine
          Modifies a G-protein that controls
               salt and water secretion
          G-protein is stuck as active form
          Over production of cAMP
          Intestine cells secrete too much
               water
          Extreme diarrhea and dehydration
4. Ca+
  Can be a second messenger in
         G-protein systems and
         Tyrosine Kinase systems
  Mechanism
     Ca+ concentration usually low inside
         Cells transport it out or into E.R.
     Signal triggers release of Ca+ from E.R.
4. Ca+
     Ca+ release caused by other second
     messengers
         DAG (Diacylglycerol)
         IP3 (Inositol trisphosphate)
     How?
         Receptor activates Phospholipase
         This cleaves a phospholipid
         Releases DAG and IP
         IP opens gated channel in ER
4. Ca+
     Effects of Ca+ release
          Activates transduction pathway
          via Calmodulin
               Ca+ binds to Calmodulin
          Calmodulin passes signal to next
               in chain, often a kinase.
IV. Cellular Response to Signals
A. Many types of responses possible
 1. Regulation of cell activities
         Change in an ion channel
         Change in cell metabolism
              epinephrine activates enzymes
                   breakdown of glycogen
 2. Synthesis of enzymes or other proteins
 3. Transcription factors that turn on genes
IV. Cellular Response to Signals
B. Pathways to amplify and specify response
 1. Multistep pathways
          Amplification via cascade
               one signal ….. Many activated
 2. Different types of cells may have
 different responses to the same signal
     epinephrine - liver and muscle
                         glycogen breakdown
                  - Cardiac muscle
                         contraction
IV. Cellular Response to Signals
 A cell’s specific response to a signal
    depends on its specific collection of
    receptor and relay proteins
          single pathway in one cell type
          multi-pathway in another type
          The two may interact
               important for regulation and
               coordination.
IV. Cellular Response to Signals
3. Scaffolding proteins
     Link pathway steps together physically
C. Importance of Inactivating mechanisms
     Molecular changes due to signals are
          short-lived
          Locking in a new mode can disrupt
           the cell.
     Changes in receptors and relay proteins
          are reversible. They often return to
          original state after they pass it on.
     Some are inactivated by specific
      proteins
     Inactivation prepares cell for a fresh
     signal
D. Disorders associated with disrupted
 signaling
     1. Wiskott-Aldrich Syndrome (WAS)
          Absence of a relay protein
              disorganized cytoskeleton
          Leads to
              abnormal bleeding
              infections
              leukemia
              Summary

Reception
    Membrane Receptors
    Intra-cellular receptors
Transduction
    Single pathways
    Cacades
    Methods - Phosphorylation, cAMP, Ca+
Response