10/6/23
Lecture
Cell-cell communication or the cellular internet
Johan Renes
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Cellular communication
5 routes how cells communicate
Autocrine
The
picture
can’t
be
Response
displa
yed.
Cellular communication
Contents
• Direct cellular communication, contact dependent
(Cell-cell contact, Gap Junctions and juxtacrine)
• Cell-derived signals that influence remote cells
(diverse molecules secreted by cells)
• ‘External signals’ that effect cellular responses
(autocrine, paracrine, endocrine, synaptic)
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Cell-cell contact
Anchoring junctions
Contact-dependent
Anchoring junctions in epithelial tissue
Contact-dependent
Example of cell-cell anchoring junctions
Embryonic development
Coupled cells follow a similar
developmental pathway
e.g. neural tube development
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Contact-dependent
Gap Junctions
Vertebrates’ connexons composed
primarily of connexin proteins
Gap junctions are highly dynamic:
half-live of connexin proteins is a few hrs.
Contact-dependent
Gap Junctions, formation
Contact-dependent
Gap Junctions, formation and degradation
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Contact-dependent
Gap Junctions, function
(Da)
Pore size: ~ 1.4 nm
• Transfer of inorganic ions and small water-soluble molecules between neighboring cells
- Ca2+ (electrical signals)
- cyclic AMP, inositol triphosphate (intracellular mediators)
- nucleotides
- amino acids, small peptides
- vitamins
• No transport of larger molecules like proteins > 5 kD
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Contact-dependent
Functional Gap Junctions, examples
• Gap junctions required for normal development of ovarian follicles
• Mutations in connexin-coding genes cause infertility
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Contact-dependent
Functional Gap Junctions, examples
Liver function
Blood glucose ê
Noradrenaline release from
sympathic nerve endings é
Intracellular cAMP é GAP junctions
Glycogen breakdown é
Not all hepatocytes are connected to nerves
Glucose release in the blood cAMP serves as signal molecule via Gap junctions
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Contact-dependent
Regulation of Gap Junctions, cell permeability
• Gap junctions can switch between open/closed states in seconds
• By closing Gap junctions healthy cells can be protected from damaged neighboring cells
- Damaged cells > permeable > high influx of Ca2+ and leaking of valuable metabolites
- High Ca2+ influx immediately closes Gap junctions preventing spreading damaging
effects to neighboring cells
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Contact-dependent
Regulation of Gap Junctions, cell permeability
Neuron in retina
loaded with
fluorescent dye
control + dopamine
Reduction in Gap junction permeability > switching from rod photoreceptors to cone
receptors
> Switching eyes from low light detection to color and fine detail detection in bright light
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Contact-dependent
Direct cell-cell contact mediated by membrane-bound molecules
Also known as juxtacrine communication
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Contact-dependent
Direct cell-cell contact mediated by membrane-bound molecules
Signal-sending cell
NOTCH
signalling
Signal-receiving cell
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Contact-dependent
Notch signaling
• Embryonic development
• Angiogenesis
• Bone development
• Immune system
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Contact-dependent
Notch signaling
Faulty Notch signaling involved in
• Cancer
• T-cell acute lymphoblastic leukemia
• Multiple Sclerosis
• Tetralogy of Fallot
(congenital disorder)
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Contact-dependent
“Fighting infections’
White blood cells are attracted to tissue sites to ‘fight’ against pathogens
or to clean up dead cells
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Cellular communication
• Direct cellular communication
• Cell-derived signals that influence remote cells
(diverse molecules secreted by cells)
• ‘External signals’ that effect cellular responses
(autocrine, paracrine, endocrine, synaptic)
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Cell-derived signaling molecules
• Ions (e.g. K+, Na+, Ca2+)
• Amino acids
• Peptides
• Proteins
• Nucleotides (miRNA)
• Steroid hormones
• Fatty acid derivatives
• GASSES
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Cell-derived signaling molecules
Secretion mechanisms
Large molecules
- Proteins
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Cell-derived signaling molecules
Secretion mechanisms
Large molecules
- Proteins
Transmembrane proteins are ‘shaved’ by proteases
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Cell-derived signaling molecules
Secretion mechanisms
miRNA secretion
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Cell-derived signaling molecules
Secretion mechanisms
Gasses
Steroid hormones
Ions
Amino acids
Peptides
Fatty acid
derivatives
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Cellular communication
• Direct cellular communication
• Cell-derived signals that influence remote cells
(diverse molecules secreted by cells)
• ‘External signals’ that effect cellular responses
(autocrine, paracrine, endocrine, synaptic)
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Cellular communication
‘External’ signals
Molecules secreted by a cell react with this same cell
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Cellular communication
‘External’ signals
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Cellular communication
‘External’ signals
Protein
Fatty acid
Steroid
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Cellular communication
‘External’ signals
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Cellular communication
‘External’ signals
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Cellular communication
Cellular response on ‘external’ signals
Concentration of external signals
Is very low, usually ≤ 10-8 M
Affinity of receptors for ligands
is high, Ka ≥ 108 liters/mole
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Cellular communication
Cellular response on ‘external’ signals
Example, eye
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Cellular communication
Cellular response on ‘external’ signals
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Cellular communication
Cellular response on ‘external’ signals
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Cellular communication
Cellular response on ‘external’ signals
One signal molecule can have different effect on different tissues
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Cellular communication
Cellular response on ‘external’ signals
Effect of gasses as signaling molecules
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Cellular communication
Cellular response on ‘external’ signals
Effect of gasses as signaling molecules
NO gas
cGMP phosphodiesterase
-
VIAGRA
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Cellular communication
Cellular response on ‘external’ signals
Effect of gasses as signaling molecules
Prolyl-hydroxylation
O 2 gas
Ubiquitin
Blood vessel growth
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Need a break?
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Cells are exposed to hundreds of different cell signaling molecules 24/7
Still, cells don’t get crazy, why?
Cells specifically express only those receptors and intracellular signaling systems
that are required for the proper regulation of that cell 41
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Cellular communication
4 main mechanisms of signal transduction
• Nuclear receptors
• Ion channel coupled receptors
• G-protein coupled receptors
• Enzyme receptors
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Cellular communication
Nuclear receptors, ligands
Cholesterol
Tyrosine
Vitamin A 43
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Cellular communication
Nuclear receptors
• Present in cytosol
• Present in nucleus, bound to DNA
• From most nuclear receptors the ligand is known
• Receptors with unknown ligands are called Orphan receptors
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Cellular communication
Nuclear receptors, general working mechanism
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Cellular communication
Nuclear receptors, working mechanism
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Cellular communication
4 main mechanisms of signal transduction
• Nuclear receptors
• Ion channel coupled receptors
• G-protein coupled receptors
• Enzyme receptors
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Cellular communication
Ion-channel coupled receptors
Binding of an external signal molecule opens the ion channel
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Cellular communication
Ion-channel coupled receptors
• Also known as transmitter-gated ion channels
• Allows a quick and transient opening/closing of membranes
• Rapid change of ion permeability of the membrane and as such the excitability
of a target cell
• Rapid signaling between nerve cells and electrically excitable target cells,
like muscle and other nerve cells
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Cellular communication
Ion-channel coupled receptors, example
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Cellular communication
What can go wrong with neurotransmitters?
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Cellular communication
Mechanisms of signal transduction
• Nuclear receptors
• Ion channel coupled receptors
• G-protein coupled receptors
• Enzyme receptors
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Cellular communication
G-protein coupled receptors (GPCR’s)
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Cellular communication
G-protein coupled receptors (GPCR’s)
HOW DO THEY WORK?
https://www.youtube.com/watch?v=Glu_T6DQuLU
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Cellular communication
Generalized signal transduction pathway
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Cellular communication
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Cellular communication
Many intracellular proteins involved in signal transduction function as molecular ‘switches’
protein protein
In the human proteome: In the human proteome:
- 30% proteins contain phosphate - Trimeric GTP binding proteins (GPCR’s)
- 520 protein kinases - Monomeric GTP-binding proteins (GTPases)
- 150 protein phosphatases - Activated/inhibited by regulatory proteins
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Cellular communication
G-protein coupled receptors (GPCR’s)
Trimeric GTP-binding complex (G-protein)
Activation of further Strong upregulation of
downstream pathways Cyclic AMP levels
(e.g. by scaffold protein) 58
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Cellular communication
Generation of cyclic AMP (cAMP)
Extracellular signal
+
Activated receptor Activated G-protein
cAMP is a so-called second messenger
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Cellular communication
Generation of cyclic AMP (cAMP) is a quick process
Neuron treated with serotonin
Loaded with a fluorescent protein which changes its fluorescent emission upon cAMP binding
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Cellular communication
cAMP has many different effects in various cells
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Cellular communication
How does cyclic AMP transfer its signaling effect?
cAMP mediates its effects via activation of protein kinase A
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Cellular communication
Extracellular signal > activated GPCR > activated G-protein > activation
of adenylyl cyclase > increased cAMP levels > activation of PKA
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Cellular communication
How can an extracellular signal change gene expression?
Activation of ion channels
in olfactory neurons
Activation of monomeric GTPases
often involved in cell adhesionion
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Cellular communication
External signal
Activated GPCR’s
Second messengers
Direct regulation of
downstream pathways cAMP
Phosphatidyl-inositol-
4,5-bisphosphate (PIP2)
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Cellular communication
GPCR’s and PIP2
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Cellular communication
GPCR’s and PIP2
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Cellular communication
GPCR’s and PIP2
Fertilization of an egg cell
Sperm-specific PLC > production of IP3 > strong Ca2+ release > change of egg cell membrane
> blocking entry of other sperm cells
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Cellular communication
Mechanisms of signal transduction
• Nuclear receptors
• Ion channel coupled receptors
• G-protein coupled receptors
• Enzyme receptors
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Cellular communication
Enzyme receptors
Ligand binding> dimerization > activation
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Cellular communication
Enzyme receptors
HOW DO THEY WORK?
https://www.youtube.com/watch?v=LT_ws4Xvj7M
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Cellular communication
Enzyme receptors
Receptor dimerization
to relay the signal
RTK: receptor tyrosine kinase
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Cellular communication
Enzyme receptors
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Cellular communication
Enzyme receptors
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Cellular communication
Enzyme receptors
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Cellular communication
Enzyme receptors
GCPR vs. enzyme receptors
• GPCR span the plasma membrane 7 times
• Enzyme receptors span the membrane only once
• GCPR activates G-proteins and as such transduce the signal upon ligand binding
• Enzyme receptors transduce the ligand signal by dimerization and auto-phosphorylation
(receptor tyrosine kinases) or directly recruit cytoplasmic tyrosine kinases to relay the
signal
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Cellular communication
GCPR and Enzyme receptor activated pathways overlap
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Cellular communication
Enzyme receptors, insulin resistance
Cytokines
e.g. (TNF-α)
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Cellular communication
Take home messages
• Different types of cellular communication
- Direct cell-cell contact
- Auto- juxta-, para-, endo-, neurocrine
• Different signaling molecules secreted by cells
• 4 different mechanisms of signal transduction
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