- Different cells can respond to the same signals differently. - The response depends on end target proteins present in each cell, as well as which cell surface receptor is involved.

lecture 7 - intercellular communication Flashcards by Maya Allison

Signalling molecules - examples

proteins
peptides
amino acids
nucleotides
steroids
retinoids
fatty acids
dissolved gases

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Receptors

Different cells can respond to the same signals differently.
The response depends on end target proteins present in each cell, as well as which cell surface receptor is involved.

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receptors ACH example

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Feedback

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diagram of receptor signalling

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4 types of intracellular signalling

Endocrine
Paracrine
Synaptic
Contact-dependent

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Contact-dependent signalling

Extracellular signal molecules remain bound to the surface of the signalling
cell and only influence cells that contact it
Need to be close to each other
Some cell extend long thin processes to make contact

Contact results in conformational change in the target cell protein, which active signal transduction pathways

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Contact-dependent signallingExample: Notch signalling

The signal cell expresses Delta
Target cell express Notch
Delta and Notch bind  conformational change in Notch
Notch gets cleaved
 Intracellular Notch
Extracellular Notch
Intracellular Notch translocates to the nucleus and act as a transcription factor.

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Paracrine signalling

Signalling cell secretes signal molecules, called local mediators, locally into the extracellular fluid.
Local mediators only act on cells in the near vicinity of the signalling cell
Cells may produce signals that they respond themselves on, called autocrine signalling

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Paracrine signallingExample: Hedgehog signalling

The secreting cell produces and secretes SHH
Shh (sonic)
Ihh (indian)
Dhh (desert)
The receiving cell is in the near vicinity of the secreting cell.
Targets include:
PTC
GLI

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Synaptic signalling

When a neuron is activated, an action potential is generated, which travels down the axon.
When an action potential reaches a neuron’s terminal, it stimulates the release of neurotransmitters stored in synaptic vesicles into the synaptic cleft.
Neurotransmitters travel across the synaptic cleft and bind to receptors on the postsynaptic target cell
Neurotransmitters are degraded or re-uptaken by the neuron or glial cells.
Allows for a quick and specific signalling

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Synaptic signalling - Form of paracrine signalling

Local environment: Synaptic cleft
Local mediators: Neurotransmitters

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Endocrine signalling

Endocrine cells secrete signal molecules, called hormones, into the bloodstream
The blood carries the hormones far and wide  can act on distant tissue and cells

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hormones in Endocrine signalling

Steroid hormones
Synthesised from cholesterol  not water soluble
Transported in blood by binding to carrier proteins
E.g. sex hormones and cortisol
Peptide hormones
Water soluble
E.g. Insulin
Modified amines (neurotransmitter)
A substance can act as a neurotransmitter in one part of
the brain, while acting as a hormone elsewhere
E.g. oxytocin

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Endocrine signallingExamples: insulin and growth hormone

Insulin
Pancreatic beta-islet cells secrete insulin in response to high glucose
Insulin acts distally in the liver, fat and muscles to control glucose uptake.
Growth hormone
Pituitary gland secretes growth hormone (GH) into the bloodstream.
GH acts in multiple tissues and organs distant from the brain to stimulate growth

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Cell surface receptors types

Ion-channel-coupled
G protein-coupled receptors (GPCRs)
Receptor tyrosine kinases (enzyme-linked) or RTKs

Ion-channel-coupled receptors

Also known as ionotropic receptors or X-gated ion channels.

They open in response to a specific stimulus:
Binding of ligand for ligand-gated ion channels.
Change in voltage for voltage-gated ion channels.
Mechanical stress for mechanically-gated ion channels.

They show ion selectivity.

They are gated: they open briefly then closes again.
Conformational change.
With prolonged stimulation, most ion channels become desensitised or inactive.

The ligand can be an extracellular mediator such as a neurotransmitter or an intracellular mediator such as an ion or nucleotide.

Ion-channel-coupled receptors process

Defective Ion channel-coupled receptor signalling

Epilepsy: Triggered by excessive uncontrolled stimulation of neurons in the brain.

Cardiac dysfunction:
Mutations in heart Na+ and K+ channels can lead to a cardiac channelopathy called Long QTsyndrome
Patients susceptible to cardiac arrhythmias following a trigger e.g. exercise

G protein-coupled receptors (GPCRs)

Large family of proteins
~3% of all human genes encode GPCRs in humans
Seven transmembrane domains
G-protein-coupled receptors act by indirectly regulating the activity of a separate plasma-membrane-bound target protein:
Mediated by a trimeric GTP-binding protein (G protein)

G protein-coupled receptors (GPCRs) - Targets:

Enzyme  changes in the concentration of one or more small intracellular signalling molecules
Ion channel  changes in the ion permeability of the plasma membrane
The small intracellular signalling molecules can have further downstream effect

process of G-protein coupled receptors

Ligand binding induces GDP to GTP exchange on the Gα subunit
Gα subunit dissociates from βy complex
Gα subunit and βy complex activate downstream targets
When bound to target GTPase activity of Gα subunit is increased leading to hydrolysis of GTP to GDP

The main g-protein subtypes

Adenylyl cyclase and cAMP diagram

what is cAMP

Synthesised from ATP by adenylyl cyclase Continuously degraded by Cyclic AMP phosphodiesterase Cyclic AMP is a second messenger protein. cAMP exerts its effect mainly by activating cAMP-dependent protein kinase (PKA)

how cAMP exerts its effect mainly by activating cAMP-dependent protein kinase (PKA):

PKA phosphorylates selected target proteins, regulating their activity Target proteins differ between cell types  different cell type respond differently to an increase in cAMP

serotonin and cAMP

Serotonin acts through a GPCR, causing an increase in cAMP This neuron has been injected with a fluorescent protein which changes its fluorescence when it binds to cAMP. Following the addition of serotonin, over 20x increase in cAMP level in the cell in 20 sec.

Adenylyl cyclase and cAMP diagram

cAMP diagram

Defective GPCR signalling

Can be caused by either loss of signalling or excessive signalling

Signalling can be compromised at all stages:

Increased signal initiation Essential Hypertension - mutations in G protein β subunits Decreased signal initiationWhooping Cough (Pertussis) - a bacterial toxin inhibits Gαi/o protein, causing reduced responsiveness of G proteins to receptor activation. Defective signal terminationCholera – G protein lose their ability to hydrolyse its bound GTP, due to alteration of Gα by cholera toxin.Adenomas - G proteins lose their ability to hydrolyse GTP through mutation Decrease in the production of G proteinsPseudohypoparathyroidism - genetic loss of Gαs protein a subunits results in no response to parathyroid hormone GPCRs (and kinases) are common drug targets

Enzyme (kinase) linked receptors

Enzyme-coupled receptors either function as enzymes or associate directly with enzymes that they activate. They are usually transmembrane proteins that have their ligand-binding site outside the cell and their catalytic or enzyme-binding site inside. In humans, the largest class is receptor tyrosine kinases (RTK) Great diversity: about 60 RTKs in humans

Enzyme (kinase) linked Receptors

The ligand binds to two adjacent receptors Receptors dimerise Activate intracellular domain or neighbouring enzymes that bind to the receptors

Kinase linked receptors

1 and 2. Ligand-binding leads to dimerization of receptors 3. Receptor dimers undergo auto-phosphorylation at tyrosine (Tyr) residues 4. pTyr sites recruit proteins with SH2 domains leading to activation of downstream signalling e.g. STAT transcription factors, members of the Ras/Raf/MAPK pathway

Downstream signalling: Ras

Downstream signalling: MAP kinase module

Both tyrosine phosphorylation and activation of Ras are usually short-lived. MAP (mitogen-activated protein) kinase module is key to having long lasting effects: MAPKKK (=Raf): activated by Ras, activates MAPKK MAPKK (=Mek): activates MAPK MAPK (=Erk): phosphorylates various proteins in the cell, including transcription regulators and other protein kinases

Defective RTK signalling

Cancer: Approximately 30% of human cancers have a mutation in Ras Mutation means Ras is permanently signalling Downstream of Ras are two main signalling pathways MAPK  changes in gene expression e.g. cyclin genes  proliferation PI3K/Akt  phosphorylates proteins e.g. Bad  promotes cell survival activates Tor kinase  cell growth