adrenoreceptors 2 Flashcards
structure of adrenoreceptor ?
The adrenoreceptor contains a basic amino acid structure with 7 Transmembrane domains that extend all the way through the lipid bilayer. In regard to the extracellular components, there is an Amine group and 3 extracellular loops , and intracellularly there is 3 intracellular loops and a carboxyl group which is important in signalling. The transmembrane domains are labelled 1 to 7.
20122 robert J leftowitz
In 2012 Robert J Lefkowitz and Brian K Kobilka resolved the beta 2 adrenoreceptor crystal structure and they won a Nobel prize for it. This had challenges as it was difficult to isolate the receptor out with the bilayer and keep it intact. It was also needed that the drug that bound to the receptor remained bound during isolation so that we could study how the drug interacted.
Crystallisation allows a 3-dimensional structure of the receptor be to be viewed and where all the domains are and drugs bind.
what isomer of adrenorecepor bound specifically to adrenoreceptor L or D ?
L isomer
site dependent mutagenesis ?
Site dependent mutagenesis was used to allow the amino acids in the side chain to be determined and altered one amino acid at a time.
benezene ring ?
It was discovered that the benzene ring of the catechol group bound to phenylalanine at position 290. The amino group also binds at 2 places: asparagine 312 and aspartic acid 113.The hydroxyl group at the 3rd and 4th position are essential for the adrenoreceptors. Within the beta receptor you have a hydroxyl group while the alpha receptors are missing this hydroxyl group.
why would you modify the parent compound ?
Taking the parent compound we then can modify this, to increase potency or solubility, ideally it would be both. A compound must be soluble to allow it to enter tissues in the body.
G proteins structure and importance as part of the receptor ?
G proteins are components that connect the receptors to a signalling pathways. The G proteins are heterotrimeric as they contain an alpha, beta and gamma subunit. However, It is normally the alpha subunit that determines the signalling. When an agonist binds to an adrenoreceptor it is coupled to the G protein and strongly activates down stream signalling.
beta adrenoreceptor ?
The beta adrenoreceptors are coupled to Gs which causes activation of the effector enzyme adenyl cyclase and this stimulates the formation of secondary messengers and ATP is transformed into cAMP. The cAMP then activates protein Kinase A, and this leads to protein phosphorylation.
alpha 2 receptors ?
The alpha 2 adrenoreceptors are linked to Gi, this turns off the effector enzyme adenyl cyclase which lowers cAMP production. This in turn causes less protein Kinase A in the system.
alpha 2 receptor smooth muscle ?
In smooth muscle the activation alpha 2 leads to Gi/o, this also causes contraction of the smooth muscle overall. However, this is not in the same way as alpha one receptor. The alpha 2 is linked to a different G protein, Gi/o which leads to activation of calcium channels to increase calcium influx causing smooth muscle contraction
cardiac beta 1 receptor ?
In terms of cardiac muscle , the Beta 1 adrenoreceptor is linked to Gs , this stimulates the effector enzyme adenyl cyclase, which in turn produces cAMP as a secondary messenger. CAMP activates protein Kinase A which phosphorylates the L type calcium channels, this generates a calcium influx and there is an increase in the force of contraction
smooth muscle beta 2 receptor ?
The smooth muscle for example in the airways contains beta 2 adrenoreceptors which is linked to Gs protein , this stimulates effector enzyme adenyl cyclase. This results in the generation of secondary messenger cAMP which activates protein Kinase A. This phosphorylates myosin light chain kinase (MLCK) and leads to relaxation of the airways.
alpha one receptor ?
Alpha one is coupled to Gq which leads to activation of effector enzyme phospholipase C (PLC). This generates 2 important second messengers IP3 and DAG , DAG leads to activation of Protein Kinase C while IP3 mobilises intracellular stores of Calcium in the endoplasmic reticulum. This leads to contraction in the smooth muscle system.
NEURONES ALPHA TWO
In neurones , the alpha 2 adrenoreceptor is linked to Gi/o and Go in nerve cells. It is linked to 2 secondary messengers signalling which have complimentary effects. When coupled to Go this lowers calcium influx and decreases transmitter release from the nerve. When coupled to Gi/o this increases potassium efflux which leads to hyperpolarisation and a decrease in nerve activity is seen.
parent compound for beta adrenoreceptor ?
This is the beta adrenoreceptor. The parent compound of noradrenaline has the benzene ring , amine group and hydroxyl group. If a chemist modifies this compound and removes the hydroxyl group this makes dopamine and we lose the activity of the adrenoreceptor receptors.
