Signal Transduction Ch. 11 videos 5&6

Calcium as secondary messenger

many pathways use calcium instead of cAMP or in addition to cAMP, as a secondary messenger

• Ca+ is small, water-soluble, and freely diffusible, making it a good second messenger

• There is a low concentration of it in the cytosol because Ca+ gets pumped out of the cell, as well as pumped inside storage organelles like the mitochondria or ER

• When Ca+ concentration DOES rise in cytosol, any protein dependent on calcium concentration can become activated

• Protein Kinase C is a protein responsive to calcium concentration

Where is Ca2+ located in the cell?

• mitochondria or ER until the channel opens

phospholipase C

• an enzyme linked to a pathway involving Ca ions.

• can cut phospholipids

• After first messenger binds to G protein receptor, the G protein will interact with the receptor and drop its GDP and gain GTP, which activates it to be mobile, and attach to phospholipase C.

Full Ca pathway

1. signal molecule attaches to receptor

2. receptor goes through a conformational change and will interact with G protein

3. interaction with G protein causes it to lose its GDP nad gain GTP, causing it to be mobile and travel to phospholipase C

4. phospholipase C activates, cuts PIP2 molecule creating IP3 molecule (the second messenger)

5. IP3 diffuses to a gated calcium channel and binds to it. the binding opens the channel

6. The channel opening allows the Ca2+ ions inside the ER to travel out to the cytosol

7. The ions can bind to many different protein types, and depending on what it bind to cause a specific cellular response

protein Kinase receptor

• class of cell surface receptors that play a crucial role in signal transduction pathways

• resposible for protein phosphorylation

• a specific one we will focus on is the receptor tyrosine kinases (RTK)

Receptor tyrosine kinase (RTK) structure

one RTK monomer has

• a binding site that the ligand can bind to

• a side in the cytoplasm that has RTK proteins on them to help with its enzymatic fuction

• The side in the cytoplasm has tyrosine proteins on them

RTK binding 

1. Either 2 signal molecules can bind to 2 independent RTK molecules, causing them to combine and turn into a dimer, OR 1 signal molecule can bring the two RTK molecules together and bind to both at the same time

receptor tyrosine kinases (RTK) process

• Their unactivated state is independent, but when activated, it combines with another RTK receptor

• The dimerization activates the molecule and goes through autophosphorylation, which means the two monomers put phosphate groups on each other’s tyrosine proteins

• the phosphates come from ATP, so at the end of the auto-phosphorylation, it converts its used ATP to ADP

• Now in its fully phosphorylated form, the dimer can bind with relay proteins

• the binding of the relay prtiens is the beginning of the tranduction

Scafollding peoteins

• multiple protein kinases can combine together with a scaffolding protein

• this increases the signal transduction efficiency because multiple proteins are already groped together and can bind to a receptor together 

Termination of Signals

After a signaling molecule sends a signal which brings about a response, and then it needs a way to end the signal.

→ They can use

• reversible binding

• turning off enzymes

reversible binding

1. The two molecules (ligand and receptor) will join together and come apart

(The signaling molecule diffuses away from the receptor)

2. After inactivating all the proteins affected by the initial binding inactivates as well

3. for example an activated G protein with a GTP will turn off by hydrolyzing the GTP and gaining GDP

GTPase

when a G protein can hydrolyze its bound GTP (turning off on its own)

whena g protein is not a GTPase, it will get assistance from an enzyme to shut off

Termanation of signal- what happens to the ezyme

• the protein will diffuse away from the enzyme, making it inactive again

• all the molecules made by the enzyme gets destroyed

phosphodiesterase

• An enzyme that destroys all the second messengers created by the enzyme after the enzyme is inactivated

What if the Termination of a signal does not occur? (example)

• Vibrio cholerae (cholera) produces a toxin that modifies a G protein so its stuck in active form

• this causes the protein to continually produce cAMP causing intestinal cells to secrete large amounts of salt into the intenstines

• water follows by osmoses

• an untreated person will lose salt and water and can die

how are cells different from eachother?

• Cells are different from each other because they have different collections of proteins

• They have different proteins within them because they have different genes being expressed

specificity of cell signaling

the arrival of the same signaling molecule in different cell types can bring about different effect

the different effects can be becuase

1. the proteins within the cells are different

2. a cross talk between two signal molecules binding can cause a new pathway

3. the signal molecule binds to a different receptor

Why does the Same signal-molecule/receptor binding bring different pathways for different cell types?

The proteins in the cells are different.

Cross-talk

• a cross-talk is when two different signaling molecules bind to their receptors, and the result of the two binds occuring leads to a new path

• a cross-talk is another reason why different cells can have different responces to the same signal molecule binding

different receptor

• different receptors will communicate with different relay protein

acetycholine binding with different cells

A. heart pacemaker cell- binds to G protein receptor cell. Upon binding it decreases the rate of firing

B. salivary gland cell- binds to G protein receptor cell. Upon binding, the cell secretes saliva

C. skeletal muscle cell- binds to an ion channel-coupled receptor. upon binding, it allows for contraction of the muscle

epinephrin binding to different cells

A. liver cell- binds to its beta receptor. upon binding breaks down glycogen and releases glucose

B. skeletal muscle blood vessel- binds to beta receptor. Upon binding, the vessel dilates

epinephrin binding to same cell different receptors

Receptors in the blood vessel

A. Beta receptor- upon binding, the vessel dilates

B. Alpha receptor- upon binding, the vessel contracts

Signal for apoptosis (example)

for soil worm caenorhabditis elegans

• apoptosis is triggered by signals that activate a cascade of “suicide” proteins

• when death signal is received, an apoptosis inhibiting protein (Ced-9) is inactivating allowing for the caspase “suicide” proteins to promote apoptosis

Ced-9 protein

protein inhibiting apoptosis. usually activated unless inactivated

Capases

proteins that carry out apoptosis

Apoptosis pathways and signals triggering them

• humans have several different pathways to carry out apoptosis

• apoptosis can be triggered by signals outside the cell or inside

• internal signals include- DNA damage, protein misfolding

apoptosis steps

1. initial- sudden release of cytochrome c from the mitochondria into cytosol

2. second- the lipid asymetry of plasma membrane breaks down (phosphatital serine is found in the cytosol, but during apoptosis it is found outside the cell and other cells such as macrophages can consume the content)

3. final- the plasma membrane becomes permeable to small molecules