Why do cells need to communicate with each other?
Single celled organisms: social life(mating)
Multicellular organisms: development, growth, day to day physiology
Long range communication
1-Endocrine: - through the bloodstream
- hormone enters stream, it’s travels, binds to the receptor and leaves
2-Neuronal:- connected by wires, travels through axon and reaches neurotransmitter and synapses to target cell
Shorty range communication
1-Paracrine:- diffusion, one cell signal released
- hormone released from signaling cell to target cell
2-Contact-dependent:- signaling cell attaches the hormone to the target cell
What is the signalling Pathway?
1- signalling molecule synthesized and released by signalling cell
2- signal molecule travels to target cell
3- signal binds to receptor protein on/in target cell
*signal transduction
4- changes in protein activity( activation/inactivation)
- changes in gene expression
5- changes in cell shape, movement, metabolism, secretion etc
How is cell behaviour driven by multiple signals?
1- survive( one cell -> one cell)
2- grow and divide (one cell-> two cells)
3-differentiate (one cell -> one specialized cell ie changed shape)
4-die (one cell -> apoptosis)
How can a cells response be fast or slow?
Fast: when the ligand binds to the receptor it goes through intracellular signalling pathway to an altered protein (enzyme)
Slow: when the ligand binds to the receptor it goes to the nucleus to the dna and transcripted to rna and translated through altered protein synthesis
Both then go to altered cytoplasmic machinery to altered cell behaviour
Where can receptors on cells be found?
1- cell surface receptors: on the surface
2- intracellular receptors: on the nucleus inside the cell, drives gene transcription
- small hydrophobic signal molecules enter the cell and bind to receptors that regulate gene transcription ( ie. steroids )
What is the steroid hormone mechanism of action?
1- cortisol crosses through the plasma membrane
2- nuclear receptor protein binds to the cortisol which activates the protein
3- the activated receptor-cortisol complex moves ito the nucleus through nuclear imports
4- the activate protein bind to the regulatory region of the target gene and activate transcription
What proteins affect cell responses?
Metabolic: altered metabolism
Cytoskeleton: a;termed cells shape or movement
Transcription: altered gene expression
What is a second messenger?
Small molecules that relay signals from the cell surface receptors too target molecules within cell
Signalling by phosphorylation vs signalling by GTP-binding protein
Phosphorylation:
1- protein is OFF
2- signal goes into the cell and ATP donates a phosphate
3- the protein turns ON
4- the phosphate is removed and the protein turns off
GTP:
1- the g-protein is OFF and has a GDP attached
2- signal goes into the protein and the GDP is removed and GTP is added
3- the addition of GTP: activates the g-protein
4- a phosphate is removed and the g-protein with GDP is inactivated
Regulation of proteins by phosphorylation
- turning OFF is as important as ON
- each step that is activated needs too be inactivated
- proteins regulate by phosphorylation are kinases, phosphorylation cascades
- not random
- tyrosine kinases ->phosphorylation hydroxyl groups of tyrosine
Cell surface receptors
- Ion channels
- binding of ligand opens or closes the ion channel
- flow of ions change the voltage across membrane( electrochemical gradient) - GPCR
- binding of ligand activates trimeric(three) GTP binding proteins which activate the enzyme in the membrane
- half of all known drugs act via GPCR - Enzyme coupled receptors
- the receptors are enzymes or associated with enzymes
Activation of a GPCR
- Type receptor is inactive within the membrane along with the trimeric g-protein
- The signal molecule binds to the receptor and activate it, the trimeric g-protein binds to the receptor on the cytosolic side
- The GDP attached to the g-protein is released and GTP is added
- The activated receptor and g-protein separate into the receptor, alpha protein and the beta and gamma subunit
How does the alpha subunit turn itself off?
- The activated unit binds to an enzyme or target protein (which activates the enzyme ) and a phosphate is removed
- The removal of the phosphate detaches the alpha protein to the enzyme which deactivates them both
- The alpha and the beta and gamma subunit bind together
How long does the alpha signal last?
As long as the alpha is bound to GTP which usually lasts a few seconds
Disruptions of alps function
- Cholera->bacterium produce two in that enter intestinal cells altering alpha
-prolonged secretion into gut (diarrhea0 - Whooping cough ->bacterium colonize the lungs, produce toxin that enters cells
-prolonged signal that causes cough
Down stream targets of G-proteins
1.ion channels
- (k+ in heart cells)
- the activated beta gamma subunit binds to the channel and opens it allowing the flow of ions
- Membrane bound enzymes which catalyze 2nd messengers
- the alpha subunit binds to th enzyme activating it
-the signal from the activated enzyme catalyses then releases messengers through cell
What ligands reposed to what effects?
Epinephrine: skeletal, cardiac and adipose:fight or flight( glycogen breakdown, inc in HR, fat breakdown)
ACTH: adrenal: cortisol secretion
TSH:thyroid: thyroxine secretion
FSH/LH: gonads:steroid secretion
How does epinephrine breakdown glycogen in the muscles?
- Activates the GPCR
- Binds to the target protein in the membrane
- The target membrane activates and sends signal to convert ATP to cyclic cAMP
- CAMP binds to in active PKA (protein kinase A) and activate its
- The active PKA sends signal to activate phosphorylase kinase with the addition of a phosphate
- The activation of the phosphorylase kinase sends signal to activate glycogen phosphorylase with the addition of a phosphate
- Th active glycogen phosphorylase cause s the breakdown of glycogen
How does cAMP drive transcription
- The cAMP binds to PKA to activate it
- The activated PKA moves through the nucleus and sends signal to active the transcription regulator by the addition of a phosphate
- The activated transcription regulator starts transcription
How do GPCR activate phospholipase C?
- The signal binds to the GCPR and activates it
- The g-protein is activated and seperated into monomeric proteins
- The beta gamma subunit binds to the phosphlipase C and activates it
- The Signals from the phospholipase cut an inositol phospholipid leaving the diacylglycerol and one groups and the inositol 1,4, 5-triphosphate (2nd messenger) (ip3)
- The IP3 bind to ion channels on the ER and opens the Ca +2 channel, releasing Ca+2 into the cytosol
- The Ca+2 (used as 2nd messenger) binds to PKC, which is attached to the diacylglycerol in the plasma membrane
- With the PKC binder to both it is fully activated
NOTE: C-C-C
Phospholipase C-Ca+2-pkC
Ca+2 as a intracellular signal
- ca+2 is rapidly released
- causes the opening of channels on the plasma membrane and the ER
- binding of Ca+2 activates many different proteins
- ca+2 activates calmodulin(CaM)
How is RTK activated?
- RTK (receptor tyrosine kinase) within the membrane binds to a signal molecule in the shape of a dimer and activates
- The active RTKs are bonded with phosphates in a particular order (become very activated)
- The very activated RTK with phosphates become bonded to helper proteins, which in turn become activated by the phosphates
- The third protein binds to Ras-GEF
- The Ras-GEF send s signals to turn inactive Ras protein n to and activated Ras protein by the removal of GDP and the addition of GTP
- The signals from the activated Ras-protein sends continuous signals along multiple pathways
NOTE: Ras is a small monomeric protein bound to inner membrane by a lipid tail
- mediates cell growth, differentiation and survival
- most commonly mutated gene
- mutation causes cancer
