W6 - GPCR's + Flashcards
What are the 4 major drug targets
Enzymes
Transporters
Ion channels
Receptors
What is a receptor
Receptors are target molecules through which soluble physiological mediators can produce their desired biological effects
What are the 4 different types of receptor
G protein coupled receptor (Metabotropic receptor)
Ligand gated ion channel
Enzyme coupled receptors
Nuclear receptors
What is a metabotropic receptor
A type of membrane receptor that initiates a number of metabolic steps to modulate cell activity.
What is a G Protein Coupled Receptor
A G protein coupled receptor is a transmembrane receptor that has seven domains which couple to g proteins to initiate signal transductions.
What is the GPCR activated by
Photons
Hormones
Peptides
Peptidases
Why are G protein coupled receptors important
- They are the largest family of cell surface receptors (approx 800genes)
Represent more than 50% of the current drug targets in a variety of fields ranging from stomach ulcers to migraines.
What are the 6 Classes GPCR
Class A - Rhodopsin like Class B - Secretin like Class C - Metabotropic Glutamate pheromone Class D - Fungal pheromone Class E - cAMP receptors Class F - Frizzled/Smoothoned
Describe the structure of a typical class a gpcr
There are 7 transmembrane domains which have a short N terminus and a c terminal tail. The domains are connected by intra and extra cellular loops.
What do agonists bind to on a Class A gpcr
agonists bind to the extracellular loops and transmembrane domains
Describe the structure of a typical class b gpcr
there are 7 transmembrane domains connected by intra and extra cellular loops.
Unlike class A it has a larger globular N terminus. In addition to this it has the familiar C terminal tail
What is the role of the larger globular N terminus in class b gpcr’s
plays a role in agonist binding
Describe the structure of a Class C gpcr
again it is made up of 7 transmembrane domains which are connected via intra and extra cellular loops. As well as having the C terminal Tail
What separates this is the large N terminal domain
What is the role of the large N domain
binds agonists and form obligatory dimers
What is a Dimer
is an oligomer consisting of two monomers joined by bonds that can be either strong or weak, covalent or intermolecular.
What is the same in Class A Class B and Class C gpcr’s
7 Transmembrane domains
Connected via intra and extracellular loops
C terminal tail.
Process by which GPCR’s are activated
Agonist binds to the receptor
receptor undergoes conformational change
increases affinity for heterotrimeric g protein
What is the result of a GPCR being activated
There is an exchange of GDP to GTP from the G protein
The Subunits then dissociate and signal to different effectors.
What does heterotrimeric g protein mean
Large 3 subunit g protein
Alpha subunit
Beta subunit
Gamma subunit
What are the three major signaling events
Gas
Gai/o
Gaq/11
describe the process of the Gas event occurring
The Gas subunit has a positive effect on adenylate cyclase which converts atp to cAMP. This means more cAMP is being produced which then interacts with protein kinase A.
describe the process of the Gai/o event from occuring
Gai/o has an inhibitory effect on the adenylate cyclase catalytic domain. This means less cAMP is produced meaning that there is less interaction at the Protein kinase A structure
describe the process of the Gaq/11 subunit
Hint
Cleave
Inner Membrane
Outer Membrane
Gaq/11 activates phospholipase which cleaves pip2 (fatty acid) into DAG and IP3.
DAG which remains in the membrane, acts as a tethering agent for PKC which moves to the membrane and becomes active.
IP3 binds to receptors on the endoplasmic reticulum as it moves to the cytosol, this increase the level of intracellular calcium
What is desensitization
molecular mechanism that prevents continuous activation of GPCR’s.
Achieved by phosphorylation and or internalization
Critical to prevent uncontrolled signalling
What is homologous desensitization
Effects are restricted to agonist acting through a specific receptor
What is heterologous desensitization
effects can affect receptors that share a component of the same signaling code
What is down regulation
reduction in number of functional receptors (permanent so new must be synthesized)
How is GPCR desensitized
B arrestins bind to the receptor which recruit clathrin
which is involved in the internalization which puts the receptor in a endosome.
This is so that it can be either recycled or degraded in a lysosome
What is tolerance
tolerance is the progressive reduction in the effectiveness of a drug, usually occurring over days or hours which is distinct from desensitization and down regulation
