Adrenoceptors Flashcards
What are they?
The adrenergic receptors (or adrenoceptors) are a class of G protein-coupled receptors that are targets of the catecholamines, especially norepinephrine (noradrenaline) and epinephrine (adrenaline)
• All the physiological effects of activation of the sympathetic nervous system are brought about by the action of the transmitter substances on specific cell membrane receptors (adrenoceptors) that convey the message from the outside to the inside of the cell.
Where do A and NA come from?
- Sympathetic nerves release NA
* Adrenal medullae release adrenaline and NA
Which receptors can CC bind to?
• 2 main subtypes of receptor to which CC bind
o alpha adrenoceptors
o B adrenoceptors
• These two groups can be further subdivided.
Adrenergic receptors: Agonist potency order
Different adrenoceptors have different binding affinities to the different CC’s:
e.g a1 –> NA,A, isoprenaline
a2 –> A,NA, I
Structure of adrenoceptors
- All adrenergic receptors are part of the family of G-protein coupled receptors (metabotropic receptors)
- Recruit intracellular proteins, known as G-proteins, in order to produce their cellular effects
- Integral membrane protein
- Single polypeptide chain: 400-500 aa
- Extracellular N-terminus, intracellular C-terminus
- 7 transmembrane a helices
- Binding site buried within a cleft between the a helices (i.e within the plane of a membrane)
- LARGEST SUPERFAMILY
- G-protein coupled receptors:- Intrinsic membrane bound proteins
G-protein coupled receptors
- Alpha and beta- adrenoceptors recruit different intracellular G-proteins
- Hence, alpha and beta adrenoceptors utilise different intracellular messaging systems to produce their cellular effects.
- Site-directed mutagenesis experiments have shown that the long third cytoplasmic loop is the region of the receptor that couples to the G-protein (although the C-terminus may also be involved)
- Differences in the aa sequence of the long third cytoplasmic loop are the basis by which alpha and beta adrenoceptors interact with different G-proteins, and produce different cellular effects.
- Each of these receptors active a different G-protein
• When agonist such as NA binds, GDP on alpha sub-unit phosphorylated to GTP, this makes this sub-unit unstable and it dissociates, and interacts with the target protein, modifying its activity and producing an effect.
A1 adrenoceptor: coupled to phospholipase C-
- SR- store to calcium in muscles
- NA binds, Gq-protein becomes unstable and its alpha sub-unit dissociates and activates its target, in this case the target is Phospholipase C.
- Phospholipase C synthesises a compound called IP3
- IP3 then binds to its receptor and causes the release of calcium from internal stores; causes muscle to contract, in other cells will have other effects.
- Phospholipase C also produces DAG, EFFECT in the cell
Alpha 2 adrenoceptors: Inhibition of adenylyl cyclase
- Similar mechanism, Gi protein binds instead (inhibitory)
- NA binds, G-protein becomes unstable
- Gi inhibits enzyme adenylyl cyclase
- AC normally produces cAMP therefore there will be a decrease in the signalling molecule cAMP
- Therefore there will be a decreased activity of protein kinase A
- Decreased phosphorylation of intracellular proteins
- EFFECT in the cell e.g inhibition of transmitter release from ANT’s
Yohimbine
- inhibitor/ antagonist of alpha 2 adrenoceptors
- Not used clinically anymore
- Used for treatment of Sexual dysfunction
B adrenoceptors: stimulation of adenylyl cyclase
- All three adrenoceptors act on the same G-protein
- G-protein = Gs
- Gs becomes unstable and dissociates, activated adenylyl cyclase
- Increase cAMP levels
- Increased activity of protein kinase A
- Increased phosphorylation of intracellular proteins
- EFFECT in the cell
- Action of acting an alpha 2 receptor is exactly the opposite of activating a B adrenoceptor
- Receptors themselves which determine whether or not the cell is going to be inhibited. NA can stimulate different receptors
- Key effects is to relax smooth muscle
- Whether or not NA has a positive or negative effect on the cell will depend on the receptors that the cell expresses.
Functions of adrenoceptors: Heart
Important cardiac adrenoceptors are the B1 subtype:
SAN: Increases HR
Atria: Increased contractility
Functions of adrenoceptors: Smooth muscle
BV’s: a1 constriction, b2 dilation
Uterus: a1 contract b2 relax
GI tract: contraction of sphincters (a1,2) relax (b2)
Functions of adrenoceptors: other tissues
Liver: a1,b2: glycogenolysis
Pancreatic islets: a2 reduced insulin secretion
NT: a2 (inhibition of NT release)
b2: enhanced release (sympathetic)
Selective agonists
A1: phenylephrine (nasal congestion)
A2: Clonidine (hypertension, migraine)
B1: Dobutamine (acute heart failure)
B2: Salbutamol (inhaler), terbutaline (inhaler)
B3-Mirabegron (overactive bladder syndrome)
Selective antagonists
A1: Prazosin; hypertension
A2: Yohimbine
B1: Atenolol; hypertension SE: bradycardia
B2: Butoxamine
