06-Cellular Reception and Drug Action Flashcards
What is a G-protein?
Protein that stimulates effectors to produce intracellular changes
What are the G-protein subgroups?
Gs, Gi and Gq
What is Gs?
Stimulatory
What is Gi?
Inhibitory
What is Gq?
We don’t know what these do
How is our ability to see light and smell linked with these g-protein coupled receptors?
- Receptors that interact with the G-proteins include those for light, odorants, hormones, neurotransmitters and prostaglandins
- Ability to see light and smell are all involved in complex biological processes
What does the binding of a ligand to its receptor cause?
Causes the g-protein to stimulate an effector
What are some examples of effectors?
Ion channels: - Ex. cardiac muscarinic receptor Adenylyl cyclase: - This enzyme makes cAMP from ATP - cAMP is a second messenger (involved in the cAMP signal transduction pathway) Phospholipase C (PLC): - PLC acts to cleave PIP - THe cleaved PIP yields IP3 and DAG - IP3 and DAG are both second messengers (involved in the phophatidylinosital signal transduction pathway)
Muscarinic receptors are…?
Cholinergic -> Acetylcholine is their endogenous ligand
Adenylyl cyclase is always associated with…?
Gs and Gi
Phospholipase C is always associated with…?
Gq
Ligand binding at a receptor site leads to what?
G-proteins will then stimulate an effector
Cardiac Atrial Muscarinic Receptor
- Coupled to a G-protein that is connected to a K+ channel
- When acetylcholine binds to the muscarinic receptor the associated G-protein is stimulated
- The G-protein activates the K+ channel to open
- K+ leaves the cell, hyperpolarizing the cellular membrane and slowing the heart rate
Muscarinic receptors are associated with…?
Parasympathetic nervous system, rest, rumination, relaxation and reproduction
G-proteins linked to adenylyl cyclase: How does the Gs protein link to it?
- Stimulates Adenylyl cyclase
- Adenylyl cyclase converts ATP into cAMP
- cAMP is a second messenger that binds to and activates protein kinases
- Protein kinases activate enzymes by adding a phosphate group
G-proteins linked to adenylyl cyclase: How does the Gi protein link to it?
- Inhibits adenylyl cyclase
- Activation of Gi leads to a decrease in cAMP since no new cAMP is made
- Less protein kinases, less intracellular phosphorylation
- Shifts can lead to greater/lesser physiological response
When an agonist binds to a receptor what happens?
Stimulates Gs protein, stimulates AC then increases cAMP, activates protein kinases and leads to biological effects. COMPLEX PROCESS
What is albuterol/salbutamol?
- Bronchodilator
- Specific beta2-adrenergic receptor agonist
- Binding to the receptor activates adenylyl cyclase via the Gs protein
- Increase in cAMP causes the activation of enzymes that sequester calcium
- Decreased calcium levels lead to relaxation of the bronchial smooth muscle
- Increase in cAMP causes an increase in protein kinases, enzyme phosphorylizes the pump, brings calcium into the sarcoplasmic reticulum, less calcium in smooth muscle and leads to relaxation
Why are calcium levels important to muscle contraction?
- More calcium = more muscle contraction
- Less calcium = less muscle contraction
When we give an agonist to a receptor associated with Gs, what is the net biological effect?
Inhibitory, it inhibits muscle contraction
Gi linked to adenylyl cyclase: Misoprostol (peptic ulcer drug)
- Prostaglandin E1 receptor in the gut
- Misoprostol binds to the E1 receptor, stimulates the Gi protein, inhibits AC, decreases cAMP, less phosphorylation, enzymes in pump producing stomach acid are no longer active
- Protective for ulcer
Why is misoprostol not to be given to pregnant patients?
Binds to EP3 in uterus, decrease cAMP, increase of calcium, therefore muscle contractions occur in the uterus. This can cause spontaneous miscarriage, can be used for pharmacological abortion
How is G1 linked to phospholipase C?
- PLC activated by Gq
- PLC cleaves PIP
- Cleaved PIP yields 2nd messengers (IP3 and DAG)
- IP3 binds to the sarcoplasmic reticulum and stimulates the release of calcium into the cytoplasm (IP3 activates pumps associated with Ca+, reverses it, moves calcium into the cytosol to facilitate contraction)
- Calcium influx into the cytoplasm produces the biological response
How is Gq linked to phospholipase C?
- Ergonovine binds to Gq protein linked prostaglandin E1, receptors in the uterus and Gq proteins linked a1 adrenoceptors in the blood vessels
- Receptors binding stimulates PLC to produce IP3 and DAG
- IP3 binds to the sarcoplasmic reticulum and induces release of calcium into the cytoplasm
- Induces contraction of the uterus and blood vessels
Why must the uterus continue to contract post delivery?
Promote formation of therapeutic clots to stop blood flow
Ergonovine is not specific for EP1 and also has affinity for A1 in the vasculature
Causes vasoconstriction and increases blood pressure. Need to monitor patient for hypertensive crisis
Why do we give an IM injection of oxytocin after birth?
Bypass worry all together, the uterus will contract and save the patients life
T/F: the endogenous ligand is water soluble for intracellular receptors
(if F, correct)
- F
- ligand is always fat soluble
T/F: on membrane spanning enzymes, the endogenous ligand stimulates the receptor
(if F, correct)
-TRUE
T/F: G-protein coupled receptors activate G-proteins which activates an effector activating protein kinases
(if F, correct)
-TRUE
Give 4 examples of receptors that interact with G-proteins…
- odorants
- hormones (water soluble)
- neurotransmitters
- prostaglandins
With what receptor is the Gprotein effector an ion channel (give an example)?
-cardiac muscarinic receptor
What is always the ligand for a muscarinic receptor?
acetyl choline
Describe the use of a Gprotein with the cardiac atrial muscarinic receptor…
- ACh binds to the receptor, stimulating the Gprotein
- Gprotein activates the K channel to open
- K leaves the cell, hyperpolarizing the membrane to slow HR
T/F: all G proteins use adenylyl cyclase as the effector…
if F, correct
- F
- only Gs and Gi use adenylyl cyclase
- Gq uses PLC
Explain the process of Gs proteins
- effector is stimulated by binding of endogenous ligand
- adenylyl cyclase turns ATP into cAMP
- cAMP activates protein kinases which in turn yields the biological effect
T/F: cAMP is a 2nd messenger for protein kinases.
if F, correct
-TRUE
By which mechanism are protein kinases activated?
-cAMP uses enzymes to phosphorylate (add phosphate) to the protein kinases
T/F: stimulating Gs proteins always result in the cell doing more of something
(if F, correct)
- F
- stimulating Gs could also result in the cell doing less
How is the Gi process different from the Gs?
- Gi inhibits the effector (adenylyl cyclase)
- less cAMP and less phosphorylation of protein kinases
Explain the process of albuterol (a bronchodilator) using the Gs pathway
- activate effector
- increased cAMP activates enzymes that sequester Ca (smooth muscle) and inactivate MLCK leading to smooth muscle relaxation
T/F: administering through an IV makes it harder to target just one tissue for the drug to effect.
(if F, correct)
-TRUE
Why would it be dangerous to administer ventolin (used for bronchodilation) using an IV for a woman in labour?
- uses the Gs pathway
- Gs in many different tissues, the IV would not specify which tissue to have an effect
- would shut down the labour as it relaxes smooth muscle
Explain the process of misoprostol (peptic ulcer drug) using the Gi protein system
- cAMP decreases
- protein kinases not activated (less stomach acid produced and pumped)
- stomach mucosa now has less acid and can heal itself
T/F: You should never give msioprostol to someone who is pregnant…
(if F, correct)
- TRUE
- causes uterine contraction!!
Explain the Gq protein system
- Gq protein activates the effector of phospholipase C (PLC)
- PLC cleaves PIP and yields 2 2nd messengers (IP3 and DAG)
What effect does the 2nd messenger of IP3 have?
-binds to the sarcoplasmic reticulum and stimulates the release of Ca into the cytoplasm (increase Ca in smooth muscle)
What effect does the 2nd messenger of DAG (diacylglycerol) have?
-binds to Ca channels on cell membrane, facilitates the movement of extracellular Ca into the smooth muscle cell
When is the drug ergonovine used?
- to reduce the risk of post-partum hemmorhage (after the birth; helps to push out the placenta)
- normally only used in developing countries
Explain the process of administered ergonovine using the Gq pathway..
- after birth
- Gq stimulates PLC to cleave PIP and yield IP3 and DAG
- IP3 and DAG cause more Ca in the cytoplasm of cell; causing uterine and BV contraction
What naturally occurring hormone contracts the uterus?
-oxytocin
Why is the mother urge to breastfeed the baby as soon as possible after birth?
- feeding releases oxytocin which naturally contracts the uterus and helps to push out the placenta
- reduce risk of hemmorhage
What is normally administered intramuscularly no matter the blood flow at birth?
oxytocin!
Why is ergonovine a dangerous drug? why is it still used in some countries?
- oxytocic drugs only have eyes for the uterus but ergonovine contracts everything (BP skyrockets)
- CHEAPER than oxytocic drugs
