Cell Signalling Lecture Sep 24

Question 1

What are the 5 universal features of chemical messengers?

Answer 1

1. They are secreted by specific cells
2. They diffuse or are transported to target cells
3. They bind to their receptor
4. They elicit a response
5. The signal is terminated eventually

Question 2

Describe the nicotinic acetylcholine receptor. What kind of receptor is it?

Answer 2

The nicotinic acetylcholin receptor is a ligand-gated channel.

THe presynaptic nerve terminal holds Ach in synaptic vesicles near the synapse. In response to Ca+ flow during an action potential, the Ach vesicles will fuse with the membrane and the Ach will diffuse through the synapse.

On the other side of the synapse are the Nicotinic acetylcholine receptors. THese are ligand gated channels, so when the Ach binds to the receptor, a conformation change occurs resulting in the opening of the challen and Na+ will flow in while K+ flows out.

Question 3

What are the four general types of chemical signalling?

Answer 3

endocrine

paracrine

autocrine

juxtacrine (contact dependent)

Question 4

What are the 4 main classes of chemical messengers with examples?

Answer 4

1. ENdorine system: insulin, glucagon, steroid hormones
2. Growth Factors: nerve GF, platelet derived GF, etc.
3. Nervous system: GABA, ACh, NO
4. Immune system: cytokines

Question 5

How is NO synthesized?

Answer 5

1. ACh is released by nerve terminals in blood vessel walls.
2. The ACh receptor on the endothelial cell will activate NO synthase
3. Activated NO synthase will convert arginine to NO in two steps: first it converts the arginine to hyedroxyarginine, which is then cleaved to form citrulline and NO. Both of these steps use NADPH

Question 6

What does NO release from endothelial cells do to smooth muscle cells?

Answer 6

NO can rapidly diffuse across cell membranes

1. It will bind to and activate guanylyl cyclase within the cytoplasm
2. Guanylyl cyclase will produce cyclic GMP.
3. cGMP triggers a response in the smooth muscles to relax - leading to vasidilation and enhancement of blood through the blood vessel

Question 7

How is NO utilized to treat angina?

Answer 7

Nitroglycerin is given to patient with angina because it will dissociate to NO in the body and the NO will increase the production of cGMP to induce vasodilation and increased blood flow to the heart

Question 8

How can NO be used to treat erectile dysfunction?

Answer 8

It isn’t using NO directly, but it promotes the product of NO in the body:

Viagara blocks the breakdown of cGMP to GMP (which is inactive), so that levels of cGMP stay higher longer

This allows vasodilation to last longer in the penis, increasing blood flow and erection

Question 9

What are some examples of steroid hormones?

Where are the receptors for steroid hormones?

Answer 9

Steroid hormones include cortisol, aldosterone, thryoid hormone, vitamin D (kinda), retinoids, retinoic acid

Their receptors are free floating in the nucleus.

The steroid hormones can reach receptors in the nucleus because they are lipophyllic

Question 10

What do steroid hormones need in order to dissolve and circulate in the blood?

Answer 10

Because they are so lipophyllic, they require carrier proteins in order to be transported in the blood.

Carriers include albumin, steroi hormone-binding globulin (SHBG), and thyroid hormone0binding globulin (TBG)

Question 11

What do all steroid hormone receptors do?

Answer 11

They are all intracellular (and most are in the nucleus)

They are all trasncription factors when bound

Question 12

Drugs tha target the nuclear steroid hormone receptors treat what?

Answer 12

they are targets for lipid lowering drugs

Question 13

What are the three major classes of plasma membrane receptors?

Answer 13

1. Ion channel receptors (Nicotinic ACH receptor)
2. Receptors that are kinases or bind kinasea a.k.a enzyme-linked receptors (JAK-STAT receptors, tyrosine kinase receptors, serine threonine-kinase receptors)
3. Heptahelical receptors-work through second messengers (GPCRs)

Question 14

Describe the enzyme linked receptors. What are the three kinds?

Answer 14

These are the growth factor and cytokine receptors:

THey either have their own kinase activity on the inner side of the membrane OR they bind kinases.

These are the TYrosine-kinase receptors

JAK-STAT receptors

Serine-threonine kinase receptors

Question 15

Describe the heptahelical receptors

Answer 15

They have 7 transmembrane sections

They are the GPCRs.

They bind to small G proteins, which become active when the receptor binds its ligand

Question 16

What are the 3 types of heptahelical receptors?

Answer 16

1. Ion channel (Ach binds to GPCR, the G protein alpha subunit becomes activated and will open a K+ channel)
2. Activators of Adenyl cyclase and cAMP ( in the fasted state, epinephrine is released and binds to its receptor, which activates a G protein to activate adenyl cyclase to increase cAMP production. cAMP is the second messenger)
3. Activators of Phosphatidyl inositol: THe ligand binds the GPCR, which activates the G protein, which is phospholipase C in this case. Phospholipase C cleaves the PIP2 into IP3 and DAG. IP3 goes to the ER and releases calcium. The calcium and DAG activate PKC which is another secondary messenger.

Question 17

What causes diarrhea in cholera?

Answer 17

The cholera bacteria attacks gut epithelial cells.

1. The bacteria secretes an AB toxin
2. The B subunit of the toxin facilitates the binding of the toxin to the cell and entrance throguh endocytosis
3. THe A subunit of the cell binds to adenyl cyclase and keeps it in the activated form
4. intracellular levels of cAMP rise dramatically
5. the cAMP activates the CFTR, promoting the release of Cl- from the cell
6. Water leaves the gut epithelial cell through osmosis, resulting in diarrhea

Question 18

What is the concern about the ryanodine receptor?

Answer 18

The Ryanodine receptor is similar to the IP3 receptor in that it will allow Ca2+ to leave the ER when activated.

It’s a concern because in some people, the receptor is hypersensitive to drugs–anesthtics in particular

This causes a massive efflux of calcium. THis results in excessive ATP hydrolysis and heat release, causing malignant hyperthermia

Question 19

What second messenger becomes activated in response to Ca2+ release?

Answer 19

Calmodulin will bind to the cytosolic calcium

This will then activate calmodulin-activated kinase which acts as a second messenger

Question 20

How do tyrosine kinase receptors work?

Answer 20

The unbound, inactive receptor is a monomer.

When the signal molecule binds to the receptor, the receptor dimerizes, which leads to autophosphorylation of the OH gruops on tyrosine residues, resulting in activation of the kinase activity

Signalling molecules are then attracted to the receptors and activated.

This is how growht factors do it.

Question 21

What is the difference between an ionotropic and a metabotropic receptor?

Answer 21

Ionotropic receptors produce very quick responses by opening ion channels - the response is amost instantaneous (as in Ach receptors)

Metabotropic receptors take longer - hours even - because the receptors act through G-proteins which will need to activate other secondary messengers etc., so there’s just more steps.

Question 22

How does Ras signalling work?

Answer 22

This works on a tyrosine kinase receptor pathway…

The receptor dimerizes and the kinase activity is initiated

An adaptor proteins with a Ras-activating protein binds to the active recepotor ad is activated.

This takes inactive Ras and binds it to GTP to make it active Ras.

Active Ras then acts as a secondary messenger and through the MAP Kinase pathway causes changes in protein activity and changes in gene expression in such a way that promotes DNA replication, proliferation and differentiation

Question 23

How can mutations in Ras lead to cancer?

Answer 23

Mutations in Ras that make it unable to hydrolyse GTP which mean the Ras is always active and will always promote DNA replication proliferatoin and differentiation. this is cancer

Question 24

Why is Ras considered an oncogene?

Answer 24

Ras is an oncogene because the normal function is for controlled DNA replication, proliferation and differentiation.

Thus, one mutation would be all it would take to make these things occur all the time, leading to cancer.

Question 25

What oncogene was found in relation to the RSV virus in chickens?

Answer 25

the Src gene is an oncogene which will result in cancer if mutated

Question 26

Describe how JAK-STAT receptors work.

Answer 26

1. Receptor binds cytokines (or other ligands)
2. The receptor dimerizes and binds JAKs (Janose Kinases)
3. the JAKs phosphorylate each other and the receptor.
4. The phosphorylated receptor binds and phoshorylates STATs
5. The STATs dissociate from the receptor, dimerize and translocate to the nucleus where they act as transcription factors.

Question 27

Describe serine/threonine kinase receptors

Answer 27

These are basically the same as the JAK-STAT, only the serine and threonine OH residues are what gets phosphorylated inthis case.

When one receptor binds its ligand, it will phosphorylate another receptor

The phosphorylated receptor will activate R-Smad

R-smad will dimerize and go to the nucleus to affect gene transcription