s2-L21-GPC receptors & second messengers Flashcards
(28 cards)
What is the example of the G protein couple receptor you need to know ? and why are they important?
-Adrenoceptors
-GPC receptors are receptor subtypes or super families of receptors.
More explanation about adrenoceptors
-Adrenoceptors are the receptors for noradrenaline.
-Autonomic nervous system has 2 neurones coming from the central nervous system out into the peripheral organs. Adrenoceptors detect the noradrenaline released from sympathetic post ganglionic neurones.
How are the effects of the activation of S.N.S brought ?
All the physiological effects of activation of the sympathetic nervous system are brought about by the action of transmitter substance (noradrenaline) on specific cell membrane receptors(adrenoceptors) that convey the message from the outside to the inside of the cell.
What does the adrenal medullae(located above the kidney) release? and another name for them?
Adrenaline(hormone) and noradrenaline
OR
catecholamines
What are the 2 main subtypes of receptors that these 2 catecholamines bind to ? and why did they make history?
-alpha adrenoceptors
-beta adrenoceptors
Both have differential response to different agonists.
Both alpha adrenoceptors and beta adrenoceptors can be subdivided, therefore what is the agonist potency order for all 5 divisions? a1,a2,b1,b2,b3
Agonist potency order has now been determined for all 5 main types of adrenoceptors.
Describe the structure of adrenoceptors
-All adrenergic receptors are part of the family of G protein-coupled receptors( metabotropic receptors).
-GPC receptors recruit intracellular proteins known as G proteins, in order to mediate/produce their cellular effects.
-They are all integral membrane proteins, they are all stuck in a membrane.
-consist of a single polypeptide chain(400-500 a.a)
-they are orientated to have a extracellular N-terminus and a intracellular C-terminus.
-also made up of 7 transmembrane alpha helices. - cross the membrane 7 times
-Their binding site is buried within a cleft between the alpha helices( ie: within the plane of the membrane).
Name the differences between the alpha and beta adrenoceptors. and why are they different?
-alpha and beta adrenoceptors recruit different intracellular G-proteins.
-So, they both utilise different intracellular messaging systems to produce their cellular effects.
-Different bc, differences in the a.a sequence of the long 3rd cytoplasmic loop is the reason why alpha and beta adrenoceptors interact with different G proteins, and produce different cellular effects.
What are the 3 main G-protein coupled signalling pathways you need to know?
1). alpha 1 adrenoceptors - coupled to phospholipase C-Beta
2). alpha 2 adrenoceptors - inhibition of adenylyl cyclase
3). Beta adrenoceptors - stimulation of adenylyl cyclase
Name the steps of a GENERAL GPC signalling pathway.
- GPC receptor is found as a 7 transmembrane protein with the extracellular N-terminus(sticking outwards from the plasma membrane) and intracellular C-terminus (sticking inwards from the plasma membrane).
- Ligand binding domain for noradrenaline is also located within the plane of 7 transmembrane.
- There is also the long 3rd cytoplasmic loop of the receptor which has the G protein coupling domain(for the G protein to bind to mediate their function).
- Agonist( noradrenaline) binds to the receptor, causing the G protein to phosphorylate. This converts GDP into GTP.
This phosphorylation step makes the G protein unstable. - This causes the alpha subunit to dissociate from beta and gamma subunit and move in the membrane and interact with a target protein. This mediate various effects within the cell.
What are the 3 subunits of G proteins ?
-alpha
-beta
-gamma
What is the state of G when it is bound to the receptor?
G is for Guanosine
- it’s in its di phosphate state.
Name the steps for the first “ 1). alpha 1 adrenoceptors-coupled to phospholipase C-Beta” signalling pathway.
What are the 2 divisions from the target protein if its the Gq protein that the receptor binds to.
- GPC alpha-1 receptor is found as a 7 transmembrane protein with the extracellular N-terminus(sticking outwards from the plasma membrane) and intracellular C-terminus (sticking inwards from the plasma membrane).
- Alpha-1 receptor couples to Gq protein(with the 3 subunits G protein).
- When Noradrenaline binds, alpha subunit of the Gq protein dissociates and binds to the Phospholipase C protein(target protein) and activates it.
- Phospholipase C(PLC) is an enzyme that acts on the membrane phospholipid PIP2 which produces 2 products:
- Inositol-3-phosphate (IP3)
-diacylglycerol (DAG) - IP3 then travels in the cell and binds to its IP3 receptor located in the endoplasmic reticulum.
- These IP3 receptors in E.R are ligand gated ion channels that are selective for Ca2+.
- These ion channels open up and allow Ca2+ release from the intracellular stores. (important functional change in the cell for either muscle contraction or secretion).
- Those Ca2+ will cause a particular effect in terms of the cell type its in. If its a muscle > for contraction and if its a secretory organ >it will secrete.
Here step 4 can also be another division:- Phospholipase may also release DAG(Diacylglycerol) which activates protein kinase C. (phosphorylates various cellular proteins).
Name the steps for the second “ 2). alpha 2 adrenoceptors-inhibition of adenylyl cyclase” signalling pathway.
- GPC alpha-2 receptor is found as a 7 transmembrane protein with the extracellular N-terminus(sticking outwards from the plasma membrane) and intracellular C-terminus (sticking inwards from the plasma membrane).
2.Alpha-2 receptor couples to Gi protein(with the 3 subunits G protein).
- When Noradrenaline binds, alpha subunit of the Gi protein dissociates and binds to the Adenylyl cyclase-AC-(target protein) and inhibits it.
4.When inhibited, it causes decreased cAMP levels.
👇
5. Decreased activity of protein Kinase A(PKA)
👇
6. Decreased phosphorylation of intracellular proteins
👇
7. produces the final effect - inhibition of transmitter release from autonomic nerve terminals.
- Alpha-2 receptors are found in the Autonomic nerve terminals and since nAh is also released from autonomic nerve terminals, this pathway works back on receptors in the terminals and inhibit further neurotransmitter release from themselves.
What is the normal role of the adenylyl cyclase ?
Converts cellular ATP into cyclic AMP (cAMP) as a second messenger in the cell
Name an example of a drug that affects these receptors.
Yohimbine - alpha 2-adrenoceptor antagonist
- in herbal and pure form, used for the treatment of sexual dysfunction.
- Yohimbine will inhibit the the response and will amplify the sympathetic function.
- normally a2-adrenoceptors found on the sympathetic nerve terminals will tend to inhibit sympathetic transmission.
Name the steps for the third “ 3).Beta adrenoceptors - stimulation of adenylyl cyclase “ signalling pathway.
- GPC beta receptor is found as a 7 transmembrane protein with the extracellular N-terminus(sticking outwards from the plasma membrane) and intracellular C-terminus (sticking inwards from the plasma membrane).
2.Beta receptor couples to Gs protein(with the 3 subunits G protein).
- When Noradrenaline binds, alpha subunit of the Gs protein dissociates and binds to the Adenylyl cyclase-AC-(target protein) and stimulates it.
- When inhibited, it causes increased cAMP levels.
👇 - increased activity of protein kinase A. (PKA)
👇
6.increased/enhanced phosphorylation of CERTAIN intracellular proteins.
👇 - Produces the final effect - depends on what protein that cell expresses - ie: relaxation of smooth muscle 💪
What can say about the effect from Gi protein and Gs protein?
Any receptor that couples with Gs protein will all have the OPPOSITE EFFECT of the response to the receptor Gi coupled receptor have.
Bc Gs 👉 s=stimulation
and
Bc Gi 👉 i= inhibition
What does alpha-2 and beta adrenoceptors do differently in smooth muscles?
-If Alpha-2 adrenoceptors are expressed in the smooth muscle cells 👉 cause contraction bc alpha-2 are Gi coupled
-If beta adrenoceptors are expressed in the smooth muscle cells 👉 cause relaxation bc beta are Gs coupled.
Functions of beta-1 adrenoceptors in various locations of the heart -4 locations
- beta-1 found in the SA node 👉 increases heart rate
- beta-1 found in the AV node 👉 increases conduction velocity
-beta-1 found in the atria 👉 increases contractility
-beta-1 found in the ventricles 👉 increased contractility and enhance automaticity(electrical activity).
Other functions of adrenoceptors in various other organs- smooth muscle, and others
Blood vessel > a1(a2) > constriction
> b2 > dilation
Bronchi > b2 > dilation
GI tract > a2,a2 > contraction of sphincters
> b2 > relax
Uterus > b2 > relax
bladder detrusor > b2,b3 > relax
Adipose tissue > b3 > lipolysis, thermogenesis
Name examples of agonists(drugs that activate these receptors):-a1,a2,b1,b2,b3
a1- phenylephrine
a2 - clonidine
b1 - dobutamine , in the heart
b2 - salbutamol, terbutaline, salmeterol, in the lungs - smooth muscle of airways to relax- asthma
b3 - mirabegron, in fat and bladder - relaxing the wall of the bladder.
Name examples of antagonists (drugs that inhibit these receptors):-a1,a2,b1,b2 and
what is propranolol
a1 - prazosin, doxazosin in blood vessels
a2 - yohimbine, idazoxan
b1 - atenolol, metoprolol
b2 - butoxamine
Propranolol is a non-selective Beta-adrenoceptor antagonist.
Uses of adrenoceptor agonists -
1. name the properties of Adrenaline
Adrenaline - also known as epinephrine
- mixed a and b receptor agonist
- cardiac arrest( to help restore cardiac rhythm)
- acute anaphylaxis( type I hypersensitivity)
- severe asthma ( emergency treatment) - airway closing, blood pressure
- prolongation of local anaesthetic action
- poorly absorbed by GIT( not orally)
- given intramuscularly or subcutaneously
- rapidly removed by tissues
- adrenaline is metabolised by enzymes in cells MAO and COMT
- DO NOT last longer, easily broken down
- plasma half life in order of minutes
- tachycardia, vasoconstriction, hypertension, cardiac arrhythmias
