Exam 2 Lecture 14 Flashcards
What is the largest family of membrane receptors in the human genome?
G-protein coupled receptors (GPCRs)
In what ways do GPCRs have a high degree of structural similarity?
They have 7 ðž-helical transmembrane regions that span the membrane, they have an extracellular N terminus and an intracellular C terminus, and they undergo a conformational change upon receiving a signal
GPCRs signal through what?
Heterotrimeric G-proteins
Why do GPCRs have no enzyme activity and no scaffolding like RTKs?
The ligand binds on the outside and changes the receptor conformation
What are some key events in the discovery of receptors?
1878: Langley concluded that there is some substance in nerve endings in which pilocarpine and atropine will interact with
1905: Langley proposed that nicotine and curare reacted with a reactive substance
1907: Enrich proposed the existence of chemoreceptor for drugs
1948: Anquist discovered that there are receptors for epinephrine that act on ð― and ðž receptors
1965: Propranolol is the first clinically active ð― blocker
GPCRs are also known as what?
7 transmembrane (7 TM) receptors
GPCRs all do what?
They all couple to G proteins to initiate downstream signal transduction
What is the key to initiating signaling?
The structure will change!
How is rhodopsin a bit different?
It is constantly on and then turned off unlike other receptors that are constantly off and then turned on
GPCRs represent what?
They represent the largest known class of biologically important transmembrane proteins conserved throughout evolution.
How many GPCRs are there?
There are 865 in humans but there are only 363 GPCRs (not counting olfactory GPCRs) that are targeted by general ligands in which about 120 GPCRs are orphans in which the endogenous ligand is not known and the physiological function is unknown but then only 46 GPCRs are targeted by drugs
What percent of drugs on the pharmaceutical market do GPCRs represent?
40%
In its active state, which subunit has GTPase activity?
Gðž
How many subtypes are there of each subunit?
Gðž has 20 distinct subtypes. Gð― has 5 subtypes. Gðū has 12 subtypes.
What happens when GDP is released for GTP to bind?
When GTP is bound, the ðž and ð― subunits dissociate from one another.
What happens during the activation of the G protein cycle?
GDP is released so GTP can bind
What happens during deactivation of the G protein cycle?
Hydrolysis of GTP to GDP
The main takeaway of the G protein cycle is:
If bound to GDP â is resting, the pathway is dead
If bound to GTP â have an activated GPCR
In its inactive state, where is GDP is bound in the G protein?
GDP is bound in the middle
A G protein consists of what 2 domains?
A Ras-like domain and an ðž-helical domain
What is the mechanism of G protein activation?
The ðž-helix moves and the helix from the Ras-like domain goes into the G protein â basically the ðž-helical domain swings out 120 degrees so that GDP gets released â pac-man
What is one of the ways that GPCR signal terminates?
Receptor desensitization/internalization:
- Phosphorylation of the C terminus of GPCRs by GRKs
- Binding of ð―-arrestin which leads to desensitization
- Recruitment to clathrin coated pits which leads to internalization
- Has 2 choices: recycling or degradation
How does internalization via clathrin coated pits work?
Goes into the pit and form a residue that pulls the receptor into the cytosol so that it can no longer be activated
ð―-arrestin can also do what?
It can also initiate signaling pathways on its own
