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31 Cards in this Set

  • Front
  • Back
Regulation of cell functions:
1. Endogenous mechanisms: e.g: Haiflick limit
2. Exogenous mechanisms: intercellular communication
What is "Hayflick limit"?
It is the number of times a normal cell population will divide before it stops, presumably because the telomers reach a critical lenght.
Intercellular communication (3):
1. Direct connection of cytoplasms through gap junctions
2. Interaction of plasma membrane molecules (immune system)
3. Mediated intracellular communication: Signal molecules.
Chemical character of signal molecules: (3)
1. Proteins, peptides
2. Low molecular weight substances: AAs, nucleotides, streroids, retinoids, FA derivatives
3. Gases; NO, CO
Types of signaling by signal molecules (4):
1. Endocrine: hormones
2. Paracrine; local mediators where target cell is near the signal releasing cell (cytokines, GF, clotting factors, retinoic acid)
3. Autocrine; Local mediators where the signal acts on the same cell as the signal is released
4. Synaptic: neurotransmittors
Do all cells respond in the same way to the same signal?
No. Each cell is programmed to respond in a specific way to specific combination of signals
3 ways of signal transfer across membranes:
1. Diffusion of gas molecules
2. Diffusion of hydrophobic molecules by binding to a intracellular receptor
3. Interaction with membrane receptor
Diffusion of NO across plasma membrane: (3)
1. Produced by deamination of arginine catalyzed by NO synthase--> NO ---> diffuses
2. NO--> direct contact with relevant enzyme (guanylyl cyclase)
3. ---> Relaxation of smooth muscle cells and activates macrophages
Diffusion of hydrophobic molecules across plasma membrane:
1. Which molecules?
2. Meachanism:
1. Molecules:
- Steroid hormones
- Thyroid hormones
- Retinoids (related to Vit A)
- Vit D
2. Diffusion---> interaction with intracellular receptor--> binding to DNA==> regulation of gene expression
Gross structure of membrane receptors:
a) Are proteins
b) Have 3 domains:
1. Extracellular domain
2. Transmembrane region
3. Cytoplasmic domain
e.g: Ig- like domain in extracellular part & protein kinase domain, death domain in intracellular part
3 kinds of membrane receptors for signal transfer:
1. Ion channel- linked receptors
2. G protein- linked receptors
3. Protein kinase- linked receptors
Ion channel linked receptors:
- Ligand gated ion channel receptors
- Uses neurotransmitters
- Synaptic signaling: signaling between electrically excitable cells (conversion of chemical signal into electrical signal)
G protein- linked receptors:
- Associated with G protein
- 7 membrane alpha helical regions
- 1 signal molecule binding site (extracellular) and a segment that interacts with G protein (intracellular)
- Binding of first messenger---> Conformational change--> Cytoplasmic part binds inactive G protein---> displacing GDP and binding GTP (activation of G protein)
Protein kinase linked receptors:
1. Receptors with intrinsic kinase activity: receptor kinases
2. Receptors associated with kinases
Receptor desensitization:
Negative feedback
Receptor down- regulation:
Receptor internalization (receptor mediated endocytosis)--> recycling and degradation
3 ways to transfer signal across a membrane associated with G protein
1. Activation of phospholipase C (PLC- β)
2. Activation of adenylyl cyclase
3. Activation of cGMP phosphodiesterase
Activation of phospholipase C (PLC- β) and then PKC:
1. Signal molecule (first messenger) + G protein- coupled receptor==> activation of G protein (GTP) --> activation of phospholipase C
2. Phospholipase C cleaves PIP2 to IP3 and DG
3. IP3--> Ca channel in ER==> Release of calcium (2nd messenger)
4. DG--> activates protein kinase C (calcium dependent)
5. PKC (+Ca) phosphorylates target proteins:
- Raf kinase (joining IP3/DG pathway to kinase cascade Raf- MAPKK- MAPK)
- Membrane receptors: Receptor internalization
- Other membrane proteins: Ca- ATPase, Na+/H+ exchanger
Activation of adenylyl cyclase: (6)
1. First messenger (e.g adrenalin) binds to a G protein- coupled receptor
2.--> GTP binds G protein instead of GDP which activates adenylyl cyclase
3. Adenylyl cyclase removes two Pi from ATP and forms cAMP, and hydrolyses GTP on G protein forming GDP and making it inactive
4. cAMP (2nd messenger) activates Protein Kinase A
5. PKA phosphorylates target proteins:
- Activation of glycogen phosphorylase (induction of glycolysis)
- Creb protein--> binding to DNA---> gene expression regulation/ activation of transcription genes responding to cAMP
6. cAMP phosphodiesterase: cAMP---> AMP (inactivation)
Activation of cGMP phosphodiesterase :
Guanylyl cyclase: GTP---> cGMP
cGMP--> GMP--> conversion of the signal into electrical signal (photoreceptors)
2 receptor kinases:
1. Tyrosine kinases (most of growth factors: e.g: EGFR, FGFR)
2. Serine- threonine kinases (TGF-βR)
Structure of tyrosine kinase receptor:
1. Inactive monomers of polypeptides containing 3 tyrosines in the cytoplasmic part.
2. Alpha helix part in the membrane part
3. Ligand binding site in the extracellular part
Mechanism of tyrosine kinases:
1. Signaling molecules bind to ligand receptors
2. Homodimerization---> phosphorylation and activation of cytoplasmic domain
Example of signal transfer by EGFR:
1. GRB2- SOS- Ras----> kinase cascade Raf---> MAPKK---> MAPK---> target protein phosphorylation
MAP kinase function/ mechanism:
Phosphorylation of nuclear protein Elk-1---> phosphorylated ELK- 1 & SRF---> transcription of c- fos gene---> proteins Fos & Jun---> transcription factor AP- 1
Signal transfer by receptors associated with kinases:
1. Family of Src kinases (some of receptor kinases: e.g: EGFR, PDGFR)
2. Family of Jak kinases (interferon receptors and other cytokine receptors: e.g: IFN- γR)
Activation of Src kinases:
Src--> SHC---> GRB2 (joining pathway GRB2- SOS- Ras--> Raf)
Activation of Jak kinases--->
Phosphorylation of cytoplasmic STAT proteins (e.g: INF- α/βR)---> transition to the nucleus---> regulation of the transcription/ gene expression regulation (genes responding to INF- α/β)
Ions and intracellular signal transfer:
1. Calcium
- Normal level maintained by Ca2+ ATPase (pumps Ca2+ into ER)
- Phospholipase C--> IP3--Ca from ER
2. Na+/H+:
Na+ antiimport pumps H+ out of the cell and Na+ in---> pH increases. (Na+/H+ exchanger is activated by phosphorylation by PKC)
Why is increased intracellular pH by Na+/H+ important for the cell?
Because the increase in intracellular pH from 7.0-> 7.3 is indispensable for accomplishing stimulation of proliferation (DNA synthesis)
What is calmodulin and how does Ca2+ affect it?
Calmodulin is a Ca2+ binding protein.
Ca2+- calmodulin complex activates Ca2+- calmodulin dependent kinase (CAMK)---> phosphorylation of target protein!