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Topic 10. Pharmacodynamics : Signal Transduction. 713 311 PRINCIPLES OF VETERINARY PHARMACOLOGY Dr. Korawuth Punareewattana. Faculty of Veterinary Medicine, Khon Kaen University. Topics on Signal Transduction. Cell signaling General principles Signaling molecules and their receptors

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pharmacodynamics signal transduction

Topic 10

Pharmacodynamics: Signal Transduction

713 311 PRINCIPLES OF VETERINARY PHARMACOLOGY

Dr. Korawuth Punareewattana

Faculty of Veterinary Medicine, Khon Kaen University

topics on signal transduction
Topics on Signal Transduction
  • Cell signaling
    • General principles
    • Signaling molecules and their receptors
  • Signal transduction
    • General concepts
    • Mechanism of transduction
cell signaling general principles
Cell Signaling: General Principles

Cell Signaling (Communication between cells)

  • receive a signal
    • Recognition of stimulus at outer cell surface by specific membrane-embedded receptor
    • Transfer of signal across membrane to cytoplasmic surface
  • transmit the signal within the cell (signal transduction)
    • Transmission of signal to specific effector molecules on inner membrane surface or in cytoplasm that trigger cell response
  • alter behavior to fitsignal
signaling and signal transduction
Signaling and Signal transduction

Signaling

is about communication between different groups of cells and tissues…how one group of cells informs another group of cells what to do.

Signal transduction

refers to how the presence of an extracellular signal can produce a change in the intracellular state of the cell without the initial signal crossing the membrane.

Or a step of cell signaling within target cells

signal transduction
Signal Transduction

Cell Signaling

general principles signaling molecules ligands drugs and their receptors
General Principles; signaling molecules (Ligands, Drugs) and their receptors

Extracellular Signals

  • recognized by specific receptors.
  • 2 types of Signals
  • Hydrophilic; unable to cross the plasma membrane - bind to cell-surface receptors

Example: growth factors

  • Hydrophobic; pass across the cell membrane and directly regulate the activity of an intracellular receptor.
  • Example: Steroid hormones, thyroid hormones, retinoids, and vitamin D bind to intracellular receptors that are ligand-activated transcription factors.

cell

surface

receptors

cell

intra-

cellular

receptors

cell

slide7

Cell surface receptors: Getting the Message Across

Extracellular ligand-binding domain

  • Many signals (e.g. peptide growth factors) cannot cross the plasma membrane.
  • Cells get round this problem by utilising transmembrane receptors.
  • These are proteins that sit in the membrane with the ligand* binding domain outside the cell and an intracellular domain that couples to the next step in the signalling pathway
  • *Ligand – a molecule that binds to, and is recognised by a receptor

Plasma membrane

outside

inside

Transmembrane domain

Intracellular domain – couples to next step (may have enzymatic activity)

intracellular receptors
Intracellular receptors

Steroid hormones such as cortisol

  • diffuses across the plasma membrane,
  • binds to a intracellular receptor protein,
  • enters the nucleus, and
  • activates specific transcription.
signal transduction1
Signal Transduction
  • Signal transduction is a process that relay signal or information or instruction from cell surface receptor to effectors inside the cells.
  • Steps of signal transduction
    • Activation of intracellular domain of receptors
    • Signal transduction
      • Cascade of phosphorylation
      • Use 2nd messengers
    • Activation of effectors
  • Patterns of signal transduction
    • Depends on the types of cell-surface receptors
slide10

Signal molecule

binds

receptor

activates

Intracellular signaling pathway

Target protein

alters cell behavior

A simple intracellular signaling pathway activated by an

extracellular signal molecule influences cell behavior.

cell surface receptors
Cell-surface receptors

There are three known classes of cell-surface receptor proteins:

  • Ion-channel-linked receptors also known as transmitter-gated ion channels.
  • G-protein-linked receptors also known as serpentine receptors
  • Enzyme-linked receptors
    • enzymes; tyrosine kinases
    • directly associate with an enzyme that they regulate
types of receptor signal transduction
Types of receptor & Signal transduction

Types of receptor

  • Cell surface receptorLigands (Drug)
    • Classical receptors activate signal transduction
    • Ion-channel receptors activate or block ion movement
    • Uptake carriers block transport
  • Intracellular receptor
    • Enzymes block enzyme function
    • Transcription factor activate or block
cell surface receptors1
Cell-surface receptors
  • act as signal transducers: they bind the signaling ligand with high affinity and convert this extracellular event into one or more intracellular signals that alter the behavior of the target cell.
  • Activated cell surface receptors trigger a phosphorylation cascade which results in signal relay through the cell and to the nucleus.
    • Some pathways using 2nd messengers (eg. cAMP) to amplify the signals
slide14

Phosphorylation cascade

Many enzymes are regulated by covalent attachment of phosphate, in ester linkage, to the side-chain hydroxyl group of a particular amino acid residue (Ser, Thr, or Tyr).

  • A protein kinase transfers the terminal phosphate of ATP to a hydroxyl group on a protein.
  • A protein phosphatase catalyzes removal of the Pi by hydrolysis.
major signaling mechanisms share common features
Major signaling mechanisms share common features

In both receptor tyrosine kinase signaling and G-protein-mediated signaling,

  • a signaling protein is activated by the addition of a phosphate group (phosphorylation) and inactivated by the removal of the phosphate.

Signaling by

phosphorylation

Signaling by phosphorylation of

GTP-binding protein

second messengers
Second Messengers
  • Several different molecules act as second messengers including:
    • Cyclic AMP (cAMP)
    • Cyclic GMP (cGMP)
    • Ca2+ ions
    • Inositol phosphates (IP3)
    • Lipids; eg. Diacylglycerol (DAG)

Signal amplification is an important feature of signal cascades:

  • One hormone molecule can lead to formation of many cAMP molecules.
  • Each catalytic subunit of Protein Kinase A catalyzes phosphorylation of many proteins during the life-time of the cAMP.
g protein linked receptors
G-protein-linked receptors

Receptor

  • The interaction between the G-protein-linked receptor and the target is mediated by a trimeric GTP-binding regulator protein(G-protein).
  • All of the G-protein-linked receptors belong to a large superfamily of homologous, seven-pass transmembrane proteins.

Trimeric GTP-binding

protein

receptor tyrosine kinases
Receptor tyrosine kinases

Receptor tyrosine kinases

  • single-pass transmembrane proteins
    • ligand-binding site outside the cell
    • catalytic site inside
  • The binding of growth factors such as insulin, epidermal growth factor, and platelet-derived growth factor to the extracellular domain of their receptors switches on the kinase activity of their catalytic domain and triggers phosphate group additions to a network of intracellular proteins to transduce the signal.
examples of signal transduction systems
Examples of Signal Transduction Systems
  • Receptor tyrosine kinase or Enzyme-link receptor
    • Kinase cascade
    • or Phosphorylation cascade
  • G-protein link receptor
    • using 2nd messenger (cAMP)
  • Steroid hormone receptor
    • Simple signaling system
signal integration
Signal Integration
  • Complex cell behaviors are generally regulated by specific combinations of signals rather than by a single signal acting alone.

ways to integrate combinations of signals

previous example of

complex cell behavior

How are multiple signals

understood by the cell?

signal transduction general principles summary
Signal Transduction: General Principles Summary
  • Cell signaling requires both
    • extracellular signaling molecules and
    • a complementary set of receptor proteins in each cell.
  • Most signaling molecules are hydrophilic and
    • activate cell surface receptors.
  • There are three main families of cell surface receptors.
  • The highly regulated phosphorylation cascade stimulated by activated receptors
    • relays the signal through the cytoplasm and to the nucleus to alter cellular behavior
slide25

Signaling molecules (ligands)

- hydrophobic

- hydrophilic

Receptors

- specific

- intracellular

- cell surface

Ion-channel-linked receptors

G-protein-linked receptors

enzyme-linked receptors

Intracellular signaling proteins

- receive and transduce the signal

- short half-life

- molecular switches

On and Off states

Phosphate group additions and loss relays signal

2 types of signal transduction

1) Phosphorelation cascade

2) Phosphorelation and 2nd messengers

slide26

P

Nucleus

A Simple Signalling System

INFg receptor

Interferon (IFN) g

Activated IFNg receptor recruits JAK kinase

Phosphorylation causes STATs to dimerise and migrate to nucleus…

…where they initiate transcription

ADP

ATP

JAK phosphorylates STAT monomer

STAT transcription factor

JAK tyrosine kinase

slide27

Cascading Kinases

Binding of epidermal growth factor to its receptor activates ras

Ras activates the serine/threonine kinase raf

Erk-1 phosphorylates the transcription factor myc and activates transcription

ras

raf

raf

ras

GTP

GDP

ADP

ATP

Raf phosphorylates and activates the dual-specificity kinase Mek-1

P

Mek1

Mek1

Nucleus

ATP

P

Erk1

ATP

ADP

ADP

P

P

P

Erk1

Erk1

Mek-1 phosphorylates the serine/threonine kinase Erk-1 which migrates to the nucleus

slide28

MLK3

raf

Mekk1

ATP

ATP

ATP

ADP

ADP

ADP

Mek1

MKK4

MKK7

ATP

ATP

ATP

ADP

ADP

ADP

Erk1

Jnk2

Jnk1

Cascading Kinases

The raf Mek-1 Erk-1 cascade is one example of a MAP kinase cascade. A number of these cascades have been described, and although they utilise specific kinases, the pathways are very similar…

N.B. Mode of activation of the first kinase in the cascade is variable and depende on the signal

Growth Factor

Stress

Cytokines

MAP kinase

kinase kinase

Serine/threonine kinase

MAP kinase

kinase

Dual-specificity kinase

Serine/threonine kinase

MAP kinase

slide29

Using Second Messengers

Binding of adrenaline to its receptor activates a G protein

G protein a subunit mediated activation of adenylate cyclase leads to cyclic AMP (cAMP) production

PKA catalytic subunit phosphorylates CREB* and activates transcription

a

b

g

ATP

GTP

2Pi

Inactive protein

kinase A (PKA)

Free PKA catalytic subunit migrates to nucleus

Nucleus

ATP

ADP

P

P

Regulatory subunit of PKA binds cAMP…

…which dissociates from the catalytic subunit