Molecular Targets and Signal Transduction Flashcards
What is a molecular target?
The molecule (nearly always a protein) that interacts specifically with a drug and mediates its pharmacodynamic response
What is a typical drug target?
Can be an enzyme, receptor or other protein, or very rarely a nucleic acid
What are the majority of existing drugs targeted at?
Enzymes or receptors
what are GPCRs
G-protein coupled receptors
What do GPCRs connect within the cell?
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
What is the structure of GPCRs
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
What is an agonist (full or partial)
binds to and activates the receptor
What is an antagonist?
binds to the receptor but cause no activation (also known as blockers)
What does it mean if its a ligand?
It means its anything that binds a receptor. So anything that can bind is considered a ligand
What are adrenergic receptors?
GPCR that works for norepinephrine and epinephrine and are catecholamine neurptransmitters
Most important for sympathetic nervous system
What are the most common adrenergic receptors
Alpha 1 and 2
beta 1 and 2
What are signaling molecules?
First messengers (hormones, neurotransmitters) deliver the message to the cells by interacting with proteins on the cell membrane, t
What are the second messengers?
They take the signal from the first messengers and move them to the proper components inside the cell
What is signal transduction?
it refers to the process of first and second messengers and how they transfer the messages of whats needed to the correct place
What is the adenylate cyclase system?
The binding of first messengers to membrane receptors (GPCR) which triggers an increase of decrease in the activity of adenylate cyclase
What do G-proteins designated as Gs do?
they have a stimulatory effect on adenylate cyclase (AC)
What do G-proteins designated as Gi do?
they inhibit the activity of AC.
What is adenylate cyclase?
its a membrane-bound enzyme that converts ATP to 3’-5’-adenosine monophosphate (cAMP)
What does cAMP activate?
Particular protein kinase which phosphorylates specific enzymes that produce the ultimate response
How does the adenylate cyclase system work with epinephrine?
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
What happens to cAMP in the cell?
it is broken down to AMP by enzymes known as phosphodiesterases (PDEs)
What determines the amount of cAMP will be in the cell?
The activity of AC (the messenger system) and PDEs (enzyme that breaks down cAMP)
What do inhibitors of PDEs cause?
It will act to cause an increase in the amount of cAMP in the cell, this makes PDEs viable molecular targets for therapeutic intervention
What happens when glucagon activates the adenylate cyclase pathway?
it will increase the cAMP production. They are Gs type proteins
what is the phospholipase C/Ca2+ system?
Uses G-proteins (Gq) to activate phospholipase C
These are membrane-bound
What happens when phospholipase C is activated
It cleaves membrane-bound phosphatidylinositol 4,5-bisphopgare (PIP2) into insitol (IP3) and DAG which act as second messengers
What happens to IP3 when it gets created?
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
What happens when DAG is created?
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
What and where is Nitric Oxide (NO) synthesized
Its a diatomic gas within endothelial cells by an enzyme known as NO synthase
How does Nitric Oxide (NO) move in the body?
Its so small, it can diffuse out of the endothelial cell membranes and bind to proteins either in neighboring cells
What is the target for NO?
Guanylate cyclase and enzyme that generates the second messenger cyclic GMP (cGMP)
