Cell Signalling

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Cell Signalling
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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

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1. Direct Contact
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2. Local Signalling, 3. Distance signals
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• 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

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• 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

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II. Signal Reception

• A. Signal binds to receptor protein
• causes shape change
• B. Signal molecule specific to receptor
• C. Signal molecules called Ligands

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II. Signal Reception

• D. Signal receptors - mostly membrane proteins.
• 1. Large and water soluble
• 2. When activated (shape changed), can trigger
  changes within cell.

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II. Signal Reception

• E. Main types of receptors
• 1. Membrane receptors
• 2. Intra-cellular receptors

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• 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

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• 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

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• 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

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• 1. Membrane receptors (3 main ones)
• G-Protein-linked Receptor
• G-protein shut off
• GTP back to GDP
• Common roles
• Embyro development
• Sensory systems

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• E. Main types of receptors
• 1. Membrane receptors
• G-Protein-linked Receptor
• Tyrosine Kinase Receptor
• Used for triggering several pathways
• and coordinating many activities.

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• Tyrosine Kinase Receptor
• Parts of the Tyrosine Kinase Receptor
• Extracellular binding site
• Single alpha helix within membrane
• Intracelluar tail - tyrosine tails

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• Tyrosine Kinase Receptor
• Operation
• Ligands bind to two receptors
• Receptors aggregate togther
• Activated tails are phosphorylated

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• Tyrosine Kinase Receptor
• Operation
• Relay proteins are activated
• These lead to cell responses

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• 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

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• Ligand-gated ion channels
• Allows or blocks ion flow
• such as Na or Ca2
• Ligand binds to exterior
• Channel shape changes
• opens channel
• Ion flow occurs
• Ligand detaches,
• closing channel

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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

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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

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II. Signal Reception

• 2. Intra-cellular receptors
• Examples
• Hydrophobic steroids
• Thyroid hormones
• Testosterone
• binds to cytosol rec.
• Activated rec. enters
• nucleus
• turns on genes

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II. Signal Reception

• 2. Intra-cellular receptors
• Examples
• Turn on genes how?
• Act as transcription
• factors
• Controls which genes
• are transcribes to
• mRNA.

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III. Signal-Transduction Pathways

• A. Reason for Transduction?
• A Multi-step pathway!
• Advantages
• 1. Amplifies the signal
• One tiny signal to Many activated
  molecules

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III. Signal-Transduction Pathways

• A. Reason for Transduction?
• A Multi-step pathway!
• Advantages
• 2. Provide more coordination than a
  simpler system could accomplish

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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

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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

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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

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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.

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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

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• 3. Cyclic Amp
• This is a step for Sutherlands Epinephrine.
• Receptors 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 .

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• 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)

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• Uses of cAMP
• G-protein can pass signals this way
• G-protein activates Adenylyl cyclase
• Some systems inhibit Adenylyl cyclase
• enables regulation

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• 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

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• 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.

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• 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

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• 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.

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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

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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

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IV. Cellular Response to Signals

• A cells 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.

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IV. Cellular Response to Signals

• 3. Scaffolding proteins
• Link pathway steps together physically

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• 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

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• D. Disorders associated with disrupted signaling
• 1. Wiskott-Aldrich Syndrome (WAS)
• Absence of a relay protein
• disorganized cytoskeleton
• Leads to
• abnormal bleeding
• infections
• leukemia

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Summary

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