cell receptors and signalling by phil and alex. basics signalling controls all aspects of cell...
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CELL RECEPTORS AND SIGNALLINGBy Phil and Alex
Basics• Signalling controls all aspects of cell behaviour:
• Growth• Differentiation• Metabolism
• 3 main types of signalling:Paracrine
Endocrine
Cell signalling• 3 types of effects:
1. Altered gene transcription
2. Alter ion balance across the plasma membrane
3. Alter activity level of existing enzymes (by phosphorylation)
Types of receptors• Receptor Tyrosine Kinases:
• Transmembranal – bit outside the cell binds the ligand
• Upon binding dimerization (2 separate parts make 1) activation of kinase domain phosphorylation of intracellular proteins signalling cascade
• Example:• Erythropoietin acts on Jak-Stat
Types of receptors• Intracellular Receptors
• Ligand crosses plasma membrane binds to receptor • Small, uncharged, lipophilic molecules
• E.g. Steroids
• Receptors: Transcription factors or enzymes• When activated they turn gene transcription on or off
• Some examples of steroids…• Progesterone• Testosterone• Cortisol• Aldosterone
Types of receptors
• GPCR• Alpha, beta and gamma subunits• `ON` state = GTP bound• `OFF state = GDP bound
• When ligand binds to the receptor GDP released, GTP binds downstream signalling via stimulation of enzymes and release of secondary messengers
Enzymes affecting second messengers levels
• Sometimes these happen after a ligand binds to a GPCR:• Examples:
Active subunit Protein affected Action Example
Gα s Adenylate cyclasestimulated
↑ cAMP smooth muscle relaxation
Salbutamol
Gα i Adenylate cyclase inhibited
↓ cAMP Adrenaline in some tissues
Gα q Phospholipase C stimulated
PIP2 to IP3+DAG ↑Ca2+ smooth muscle contraction
Vasopressin
Types of receptors• Ion channel receptors
• A channel which will open or close depending on whether a ligand is/isn’t bound to it, or is sensitive to voltage.
• E.g.• GLUT 4 is insulin dependent in skeletal muscle and adipose tissue
MEMBRANE TRANSPORT
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SIMPLE DIFFUSION• When things are so small and/(or) hydrophobic that they
just whizz straight through the cell membrane.• Always goes DOWN their concentration gradient.
• What does hydrophobic mean?• It means things that don’t like (phobic) water (hydro) (or
actually any charged things).
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Cell membrane
FACILITATED DIFFUSION• To help stuff go through the membrane quicker than it
normally would if it was just ‘simple diffusion’. (Especially if it can’t go through by simple diffusion in the first place).
• Needs a protein channel/carrier/transportery thing to help it on its way
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Cell membrane
ACTIVE TRANSPORT• Needs a protein to help• KEY POINT: goes against the concentration gradient.
Therefore it needs ENERGY
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Cell membrane
TYPES OF TRANSPORTER• Channels
Stuff just smashes straight through – therefore they’re pretty quick• Carriers
The protein needs to re-jig itself – which takes slightly longer• Ligand-gated
A ‘ligand’ needs to bind before it can open (a ligand can be any sort of small molecule) • Voltage-gated
Only opens if the charge across the membrane is right
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THE ONES LADDSY WANTS YOU TO KNOW
• Passive transporters (i.e. driven by concentration gradients).
• 1. Glucose transportersGLUT1-4 and SGLT1(1 - intestine) +2(2 - kidneys) are the main onesThe allow glucose into cells. GLUCOSE CAN KEEP GOING DOWN A CONCENTRATION GRADIENT BECAUSE AS SOON AS IT ENTERS THE CELL IT GETS TURNED INTO GLUCOSE-6-PHOSPHATE.
• 2. Anion exchanger (Cl-/HCO3-)
Regulates cell pH (by pumping HCO3- out). Does what it
says on the tin
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• Active transporters (uses energy).• 3. Plasma membrane Ca2+-ATPase.Maintains low cytoplasmic Ca2+ concentration• 4. Sarcoplasmic/endoplasmic reticulum Ca2+-ATPase.Same again• 5. Plasma membrane Na+:K+-ATPase.3 sodium in 2 potassium out. Helps maintain concentration gradient• 6. Plasma membrane H+:K+-ATPase.1 proton out 1 potassium in. Maintains acidic envirnment int the stomach• 7. V-type and F-type H+-ATPases.V is vacuolar (creates an acidic environment). F is in the mitochondria – is SUPER IMPORTANT because is the only one which instead of USING ATP it MAKES ATP for everyone else. • 8. ABC transporters.ABC = ATP Binding Cassette (basically a section where ATP can bind which a lot of proteins use). These do loads of random jobs.
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• Co-transport systems
• 9. Na+:glucose, Na+:AA, Na+:Cl- and Na+:HCO3-
symporters.
In the intestinal epithelium• 10. Na+:H+ and Na+:Ca2+ antiporters.
Regulate cell volume and pH. Important for action potentials
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MEMBRANE POTENTIAL• What is membrane potential?
It’s the difference in charge across the membrane
• In human cells, the INSIDE of the membrane is always MORE NEGATIVE than the outside.
• Therefore, membrane potentials are always negative numbers
• DEPOLARISATION
The inside of the membrane gets LESS NEGATIVE (more positive).• HYPERPOLARISATION
Cytoplasmic side becomes MORE NEGATIVE
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What goes where?
• Voltage gated Na channels open at the arrival of the action potential
• Na enters the cell and so depolarises the membrane even more (cause it’s a positive ion going on to the negative side)
• Once you get past a threshold there’s an ‘explosion’ of Na ions entering the cell
• It all slows down once Na ions get close to their equilibrium (and the channels close)
• When the membrane depolarises enough the K channels open. (Positive stuff going out means the membrane potential Repolarises).
• Back to square one.
Na+ influx into cell
K+ efflux out of cell
1 2 3 40
Time (ms)
+20
0
-20
+40
-40
-60Pote
ntia
l (m
V)
Resting potential
Action potential