Cell Signalling

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Cell Signalling
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signal transduction systems
Steroid hormones
hormones
ion channels
Seven-spanning G protein-linked receptors
adenylate cyclase
G proteins
cAMP
kinases
phosphatases
Tyrosine Phosphorylation
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Cells constantly communicate with one another,
through direct contact and by chemical
messengers, such as hormones.
This communication is cell signaling.
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Cell signaling involves A. Recognition of
stimulus at outer cell surface by specific
membrane-embedded receptor. B. Transfer of
signal across membrane to cytoplasmic
surface. C. Transmission of signal to specific
effector molecules on inner membrane surface or
in cytoplasm that trigger cell response.
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Signal Transduction
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Communication by extracellular signals usually
involves six steps 1) synthesis and 2)
release of signaling molecules by the signaling
cell 3) transport of the signal to the target
cell 4) detection of the signal by a specific
receptor protein 5) and change in cellular
metabolism or gene expression triggered by the
receptor-signaling molecule complex 6) removal
of the signal, often terminating the cellular
response
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Signaling is about communication between
different groups of cells and tissueshow 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.
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Endocrine signaling signaling molecules act on
target cells distant from their site of synthesis
by cells of endocrine organs Paracrine
signaling signaling molecules released by a
cell only affect target cells in close proximity
Autocrine signaling cells respond to
substances that they themselves release
The Signal
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Signal molecules move between cells

• Growth factors promote survival and stimulate
  cell proliferation.
• Acetylcholine is a neurotransmitter.
• Thyroid hormone stimulates metabolism.
• Nitric oxide relaxes muscle cells in vessels.
• Testosterone induces secondary male sexual
  characteristics.

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How are signals transmitted into the cell?

• Hydrophobic signal molecules such as testosterone
  or gaseous signal molecules such as nitric oxide
  can cross the membrane.
• Most signal molecules bind to a cell-surface
  receptor protein where the information is
  converted from one form to another in a process
  called signal transduction.

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Steriod Hormones

• Steriod hormones such as cortisol diffuses across
  the plasma membrane
• Binds to a intracellular receptor protein, enters
  the nucleus
• Activates specific transcription.

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Nitric Oxide

• In response to a signal from nerve cells,
  endothelial cells that line blood vessels make
  and release nitric oxide.
• Nitric oxide enters muscle cells in the vessel
  wall causing them to relax and dilate.
• Blood flow increases and more oxygen can reach
  organs such as the heart.
• The 1998 Nobel prize was awarded to two U.S.
  scientists for discovering this mechanism.

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Receptors

• Signal molecules that do not enter the cell bind
  to cell-surface receptors.
• Signal molecules that enter the cell bind to
  intracellular receptors.

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Three classes of cell-surface receptors

• Ion-channel-linked receptors open an ion channel
  in response to the signal molecule.
• G-protein-linked receptors activate an
  intracellular G-protein that in turn activates
  intracellular enzymes.
• Enzyme-linked receptors directly activate a
  membrane bound enzyme.

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The Second Messenger
Examples of Signal Transduction Systems Ca2/calm
odulin adenylate cyclase/cAMP NO PLC/PKC PI/IP3/DA
G membrane receptors G proteins steroid hormones
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The Response
Depending on type of cell and stimulus, the
response might involve 1. Change in gene
expression. 2. Alteration of activity of
metabolic enzymes. 3. Reconfiguration of
cytoskeleton. 4. Change in ion permeability. 5.
Secretion of a hormone or protein. 6. Activation
of DNA synthesis. 7. Death of cell.
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cAMP
Adenylyl cyclase is a membrane-bound enzyme that
synthesizes cyclic adenosine monophosphate (cAMP)
from adenosine triphosphate (ATP). Cyclic AMP
functions as a "second messenger" to relay
extracellular signals to intracellular effectors
such as protein kinase A.
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• Signal transduction across the plasma membrane
  can cause a cascade of events that amplify the
  signal and distribute it to influence several
  cell processes in parallel.

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Enzymes activated by G-proteins catalyze the
synthesis of second messengers.
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G-protein linked receptors
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G-protein-linked receptors -functionally
diverse but share a common structure
extra-cellular
Serpentine
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G-protein-linked receptors function through
trimeric G-proteins

• G-protein-linked receptors
• mediate their intracellular actions
• through target ion channels or enzymes.
• pathway involves activation of one or more
• guanine nucleotide-binding regulatory proteins (G
  proteins).

• G proteins consist of three protein subunits.
• The G alpha binds a guanyl nucleotide.

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Trimeric G-proteins functionally couple the
receptor to adenylyl cyclase to regulate the
production of cAMP
Adenylyl cyclase is the integral membrane protein
that catalyzes the cyclization of ATP.
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The activation of PKA

• cAMP
• Binds to regulatory subunits of PKA
• induces a conformational
• change

inactive
PKA
inactive

• Protein kinase A (PKA)
• Serine/threonine kinase
• phosphorylates target proteins.

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How does a rise in cAMP levels lead to altered
gene transcription?

• Increase in cAMP activates PKA
• PKA catalytic subunits move into
• the nucleus
• PKA phosphorylates the transcription
• factor CREB (cAMP response
• element binding protein).
• Phosphorylated CREB binds to the co-
• activator CBP
• Transcription is activated.

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Enzyme-linked cell surface receptors
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General structure of receptor tyrosine
kinases(RTKs)
Common general architecture for this family of
receptors
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Ligand activation of RTKs
Ligands are often dimers Ex platelet-derived grow
th factor (PDGF) is a covalently linked
dimer. -directly cross-links two receptors -autoph
osphorylation is the first step in the signal
cascade.
ATP
ADP
P
phosphorylated tyrosines
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What is the role of autophosphorylation?

• Phosphorylation of tyrosines within the kinase
  domain
• increases the kinase activity of the enzyme
• 2. Phosphorylation of tyrosines outside the
  kinase domain creates
• high-affinity binding sites for a number of
  intracellular signaling
• proteins

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The same signal molecule can induce different
responses in different cell types
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Why do cells communicate?

• During development, cells differentiate to adopt
  specialized roles.
• Cells need to know whether to live, die, or
  divide.
• Neurotransmission.
• Regulation of metabolism.
• Contraction-expansion.
• Secondary sexual characteristics.

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• Nitric oxide binds directly to an intracellular
  enzyme causing a rapid response.

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Fast and slow responses
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review

• Why do cells communicate?
• How are signals transmitted between cells?
• How are signals transmitted across cell membranes
  into the cell interior?
• How are signals transmitted within a cell?
• How do signals affect cell function?