16 - Introduction to GPCR Signalling Flashcards
What Nobel Prizes were awarded regarding the importance of GPCRs?
- The Nobel prize in physiology or medicine, 1971 to Earl W. Sutherland, Jr, “for his discoveries concerning the mechanisms of the action of hormones”
- The Nobel prize in physiology or medicine, 1994 to Alfred G. Gilman and Martin Rodbell “for their discovery of G-proteins and the role of these proteins in signal transduction in cells”
- The Nobel prize in Chemistry, 2012 to Robert J. Leftkowitz and Brian K. Kobilka “for studies of G-protein-coupled receptors”
How many genes in the human genome code for GPCRs?
Almost 800 genes - slightly over half of these are the olfactory receptors that enable us to smell
How many classes can GPCRs be grouped into and what are they?
6 classes:
o Class A- Rhodopsin-like
o Class B- Secretin receptor family
o Class C- Metabotropic glutamate/pheromone
o Class D- Fungal mating pheromone receptors
o Class E- Cyclic AMP receptors
o Class f- Frizzled/smoothened
What are GPCRs grouped based on?
Sequence homology and functional similarity
What are GPCRs targets of?
GPCRs are the targets of over half of the drugs currently used
Give an example of a GPCR that drugs target
The beta2 adrenergic receptor is the target of anti-asthma drugs, including salbutamol (Ventolin)
o Agonist to adrenaline receptors
o Mimics fight or flight which open the bronchi
What is the basic structure of GPCRs?
- they have a very common transmembrane structure so all 800 genes code for receptors which have these seven transmembrane passes (each of these passes is helical), and extracellular domain
- the amino acid sequence weaves in and out of the membrane creating intracellular and extracellular loops and then we have the intracellular terminal region
- lipid anchors link the tail of the receptor to the plasma membrane, and on the extracellular domain we have glycosylation
What is the basic structure of GPCRs?
- they have a very common transmembrane structure so all 800 genes code for receptors which have these seven transmembrane passes (each of these passes is helical), and extracellular domain
- the amino acid sequence weaves in and out of the membrane creating intracellular and extracellular loops and then we have the intracellular terminal region
- lipid anchors link the tail of the receptor to the plasma membrane, and on the extracellular domain we have glycosylation
What do kinases and G proteins do to GPCRs?
Kinases phosphorylates the intracellular loops & G proteins contact with multiple areas of the intracellular portions
How are the helical regions arranged?
The 7 helical regions cluster together in a circular orientation
What is the common feature of GPCRs?
The common feature of GPCRs is they activate heterotrimeric G proteins
o Have three subunits: the alpha, beta, and gamma
o Beta: propellar shape
o Gamma: forms a peptide and interacts with the beta subunit (beta gamma subunit)
o The alpha subunit can dissociate easily- binds GDP and GTP
What do small G proteins (like Ras) do?
Small G proteins-like Ras- bind GTP (on) and GDP (off)- not regulated by GPCR directly
Regulation of G-proteins by GPCRs
- when a signalling molecule interacts with the receptor, e.g., adrenaline interacting with the adrenergic receptor, it causes the receptor to interact with the alpha subunit, resulting in GTP to change to GDP causing activation of the subunit and dissociation of the beta gamma subunit
- these can now interact with effector molecules (attached to the cell membrane)
Give an example of the regulation of G proteins
In this particular situation, the alpha subunit is acted on to exchange GDP for GTP which requires a number of enzyme activities for example the GPCRs themselves have catalytic activity in the cytoplasmic tail (GEF activity) on alpha subunits
* There are 16 types of alpha subunit which regulate a different effector
* To switch off the activated alpha subunit, GAP activity is required§
What do GAP and GEF stand for?
- GTPase-activating protein
- Guanine nucleotide exchange factor