Dit document bevat een samenvatting van de hoorcolleges van het vak 'Molecular biology of the cell' gegeven door professor Luc Leyns aan de Vrije Universiteit Brussel.
Evolution
- Bacteria were present 2.5 billion years before multicellular organisms
- Mechanisms enabling one cell to influence the behavior of another cell were probably already
present in unicellular organisms (e.g. the mating factor in budding yeast)
A simple intracellular signaling pathway
- Signaling molecules are released by signaling cells: signal is a ligand
- Ligand binds to specific receptor on target cell
Signal molecules typically act at low concentrations (< 10-8 M) and receptors have a high
affinity for it
- Ligand – receptor interactions: induce conformational or shape – change in the receptor
- Produces a specific response = cellular response
- Higher organisms: cells use very different type of signal molecules
Proteins, small peptides, amino acids, steroid, retinoids, fatty acid derivatives, nitric oxide
Cell-to-cell communication by extracellular signaling usually involves six steps
- Synthesis of the signaling molecule by the signaling cell
- Release of the signaling molecule by the signaling cell
- Transport of the signal to the target cell
- Detection of the signal by a specific receptor protein – receptor – ligand specificity
- A change in cellular metabolism, function or development = cellular response
Triggered by the receptor-ligand complex
Specific to the ligand-receptor complex
Specific to the responding cell
- Removal of the signal which usually terminates the cellular response – degradation of ligand
Binding to cell-surface or intracellular receptor
- Cell surface receptors
Hydrophilic molecules are the signals: binds to cell-surface receptor
- Intracellular receptors
Small hydrophobic signal molecule transported by carrier protein and can then cross the
membrane (without carrier protein): attach to intracellular receptor
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,Extracellular signals can act over long or short distances
- Contact-dependent
- Paracrine: uses local mediators to send messages from signaling cell to the target cell
Signal molecules are released into the surrounding fluids and then diffuse into nearby cells
Endocrine signaling: long distances – slow
- Releases hormones into blood stream
- Hormones are carried to the appropriate target cells
- Every target cell has a receptor
- Endocrine signaling is used when the transportation distance exceeds the ability of diffusion
Synaptic signaling: long distances – fast
- Neurons connect through synapses = small gaps between neurons
- Chemical substances are released from the pre-synaptic neuron to affect the post synaptic
neuron
- Post synaptic neurons have receptors that these chemical substances bind to
- Neuron can connect to other cells as well as to other neurons
- Long axons: neurotransmitter at end
- Fast due to electrical nature
Autocrine signaling
- Cell secretes signal molecules that bind to its own receptors
- Starting cell will trigger collective response
- Community effect: performed by a group of cells
- Used by cancer cells: produces own growth signals
Gap junctions allow sharing of signaling information
- Connection between 2 cells: allow exchange of small molecules (Ca2+, cAMP)
Each cell is programmed to respond to specific combination of signals
- Survive
- Divide
- Differentiate
- Die: apoptosis
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,Different cells can respond differently to the same signal
- E.g. acetylcholine
Heart muscle cell: decrease rate and force of contractions
Skeletal muscle cell: contraction
Salivary gland cell: secretion of saliva
Adjustment of the concentration of a signaling molecule
- Signal leads to changes
- Development: even when the signal is removed, the changes persist
- Adults: response generally fades when the signal disappears
- Generally signal is transient because it alters unstable molecules undergoing continuous
turnover
- Speed of cellular response to signal removal depends on turnover rate
Nitric oxide (NO)
- Diffuses to neighboring cells
- Binds to an intracellular enzyme
- In mammals: regulates smooth muscle contractions
NO gas produced by deamination of arginine catalyzed by NO synthase
Dissolved NO diffuses quickly
NO binds to iron in active site of guanylyl cyclase: forming of cGMP
Rapid relaxation of smooth muscle cell
Half-life is 5-10 seconds
cGMP has a high turnover because it is degraded by a cGMP phosphodiesterase
effect occurs in seconds: Viagra inhibits the cGMP phosphodiesterase in the penis therefore
cGMP level remains high longer, the blood vessels stay relaxed and more blood is coming
Nuclear receptors are ligand-activated gene regulatory proteins
- Some signal molecules are small hydrophobic molecules that can cross the cell membrane and
bind to intracellular receptor proteins
- Water-insoluble molecules persist generally longer than soluble ones and mediate generally
responses that last longer
Nuclear receptor superfamily
- After binding to the ligand, the receptors will bind to DNA to regulate the transcription of
specific genes
- Receptors structurally related: superfamily
Have DNA binding domain, ligand binding domain
- Ligand unknown for many receptors: ‘orphan ligands’
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, Hydrophobic molecules: hormones
- Transported in blood via carrier proteins
- Diffusion intro cells
- Inactive nuclear receptor: present in cytosol, present in nucleus
- Binds as homo- or heterodimer to DNA
- Inactive receptor is located in the cytoplasm (and then migrate to the nucleus) or is already
present in the nucleus
- Gene activation often depends on more than one signal
Three large classes of cell-surface receptor proteins
- Bind water-soluble signal molecules
- Act as signal transducers by converting an extracellular signal in an intracellular one
Ion-channel-linked receptors
G-protein-linked receptors
Enzyme-linked receptors
Intracellular signaling molecules
- Signal is relayed intracellulary to lead ultimately to alteration in target proteins
- Small intracellular mediators (second messengers)
Generated in large number, diffuses from the source and broadcast the signal to other part
of the cell
cAMP of Ca2+
Intracellular signalling proteins
- Extracellular signal molecules bind to receptor
- Scaffold protein: ensures that proteins are positioned locally: ready to answer quickly
- Amplifier: amplification of the signal: multiple effects
Contrary: nuclear: no amplifier!
- Small intracellular mediator: e.g. cyclic AMP, cyclic GMP…
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