Molecular Targets and Signal Transduction

Question 1

What is a molecular target?

Answer 1

The molecule (nearly always a protein) that interacts specifically with a drug and mediates its pharmacodynamic response

Question 2

What is a typical drug target?

Answer 2

Can be an enzyme, receptor or other protein, or very rarely a nucleic acid

Question 3

What are the majority of existing drugs targeted at?

Answer 3

Enzymes or receptors

Question 4

what are GPCRs

Answer 4

G-protein coupled receptors

Question 5

What do GPCRs connect within the cell?

Answer 5

they connect the outside of the cell with the inside of the cell, and the drug affects the signaling pathway that GPCRs mediate within the cell

Question 6

What is the structure of GPCRs

Answer 6

7 transmembrane a-helices that form a bundle which is the site of ligand binding
The intracellular loops couple with G-proteins on the inside of the cell

Question 7

What is an agonist (full or partial)

Answer 7

binds to and activates the receptor

Question 8

What is an antagonist?

Answer 8

binds to the receptor but cause no activation (also known as blockers)

Question 9

What does it mean if its a ligand?

Answer 9

It means its anything that binds a receptor. So anything that can bind is considered a ligand

Question 10

What are adrenergic receptors?

Answer 10

GPCR that works for norepinephrine and epinephrine and are catecholamine neurptransmitters
Most important for sympathetic nervous system

Question 11

What are the most common adrenergic receptors

Answer 11

Alpha 1 and 2

beta 1 and 2

Question 12

What are signaling molecules?

Answer 12

First messengers (hormones, neurotransmitters) deliver the message to the cells by interacting with proteins on the cell membrane, t

Question 13

What are the second messengers?

Answer 13

They take the signal from the first messengers and move them to the proper components inside the cell

Question 14

What is signal transduction?

Answer 14

it refers to the process of first and second messengers and how they transfer the messages of whats needed to the correct place

Question 15

What is the adenylate cyclase system?

Answer 15

The binding of first messengers to membrane receptors (GPCR) which triggers an increase of decrease in the activity of adenylate cyclase

Question 16

What do G-proteins designated as Gs do?

Answer 16

they have a stimulatory effect on adenylate cyclase (AC)

Question 17

What do G-proteins designated as Gi do?

Answer 17

they inhibit the activity of AC.

Question 18

What is adenylate cyclase?

Answer 18

its a membrane-bound enzyme that converts ATP to 3’-5’-adenosine monophosphate (cAMP)

Question 19

What does cAMP activate?

Answer 19

Particular protein kinase which phosphorylates specific enzymes that produce the ultimate response

Question 20

How does the adenylate cyclase system work with epinephrine?

Answer 20

Epinephrine (first messenger) can stimulate or inhibit the production of cAMP depending on whether it binds to alpha or beta adrenergic receptors
cAMP can then act to stimulate a protein kinase that will phosphorylate proteins to activate or inactivate them: This regulates the activity of the cell

Question 21

What happens to cAMP in the cell?

Answer 21

it is broken down to AMP by enzymes known as phosphodiesterases (PDEs)

Question 22

What determines the amount of cAMP will be in the cell?

Answer 22

The activity of AC (the messenger system) and PDEs (enzyme that breaks down cAMP)

Question 23

What do inhibitors of PDEs cause?

Answer 23

It will act to cause an increase in the amount of cAMP in the cell, this makes PDEs viable molecular targets for therapeutic intervention

Question 24

What happens when glucagon activates the adenylate cyclase pathway?

Answer 24

it will increase the cAMP production. They are Gs type proteins

Question 25

what is the phospholipase C/Ca2+ system?

Answer 25

Uses G-proteins (Gq) to activate phospholipase C

These are membrane-bound

Question 26

What happens when phospholipase C is activated

Answer 26

It cleaves membrane-bound phosphatidylinositol 4,5-bisphopgare (PIP2) into insitol (IP3) and DAG which act as second messengers

Question 27

What happens to IP3 when it gets created?

Answer 27

Its water-soluble allowing it to diffuse through the cytosol and bind to receptors on the endoplasmic reticulum, which causes a rapid release of Ca2+ from intracellular stores

Question 28

What happens when DAG is created?

Answer 28

Its nonpolar and lipid soluble
It activates a membrane-bound protein kinase C which is responsible for phosphorylating and regulating (activating or deactiving) target enzymes that lead to cellular response

Question 29

What and where is Nitric Oxide (NO) synthesized

Answer 29

Its a diatomic gas within endothelial cells by an enzyme known as NO synthase

Question 30

How does Nitric Oxide (NO) move in the body?

Answer 30

Its so small, it can diffuse out of the endothelial cell membranes and bind to proteins either in neighboring cells

Question 31

What is the target for NO?

Answer 31

Guanylate cyclase and enzyme that generates the second messenger cyclic GMP (cGMP)