JC2: Signalling, receptors, and pharmacology (2) Flashcards
What are hormones?
Molecules that are released from one site for action at another
What do cells require to respond to extracellular signalling molecules? Why?
The appropriate receptor
This ensures the extracellular signalling molecules are in the correct place and performing the correct action
Where are the majority of cellular receptors found? Why?
At the cell surface because the majority of extracellular signalling molecules do not readily cross the plasma membrane
What are the four receptor subtypes? Give an example of each.
- Ligand-gated ion channels, e.g. nicotinic acetylcholine receptors
- Receptors with intrinsic enzymatic acticivty, e.g. receptor tyrosine kinases (e.g. insulin receptor)
- G protein-coupled receptors, e.g. muscarinic acetylcholine receptors
- Intracellular receptors, e.g. steroid receptors, thyroid hormone receptors
How do ligand-gated ion channels work?
The ligand binds and causes a conformational change of the ion channel, so ions can move into or out of the cell
How does an insulin receptor work?
Ligand binding activates an enzyme activity that phosphorylates the receptor and other substrates
This causes the receptor to dimerise
This is known as autoactivation
How do intracellular (nuclear) receptors work?
The ligand binds to the receptor in the cytoplasm, causing dissociation to a dimer
The dimer moves from the cytoplasm to the nucelus and binds directly to points on the DNA
This regulates gene transcription
What percentage of available prescription drugs exert their therapeutic effects directly or indirectly at GPCRs?
Approx. 30%
What is the difference between an agonist and an antagonist?
Agonists bind to the receptor and activate it
Antagonists bind to the receptor but to not activate it
What do antagonists prevent?
Endogenous activation of receptor
What do sensory GPCRs sense?
Light, odours, tastes
What can GPCRs respond to?
- Ions
- Neurotransmitters
- Peptide and non-peptide hormones
- Large glycoproteins
What is the common structure of GPCRs?
- Single polypeptide chain
- 7 transmembrane-spanning regions
- Extraceulluar N-terminal
- Intracellular C-terminal
What are the two different regions of GPCRs that can be responsible for ligand binding?
- 2-3 of the transmembrane domains
- N-terminal region and other extracellular domains
How do GPCRs respond to ligands?
By changing conformation
What does the G in ‘G protien’ stand for?
Guanine nucleotide-binding
What must an activated GPCR interact with?
A G protein
What are the subunits of G proteins?
α, β and γ
Why is a G protein heterotrimeric?
It has three different subunits
How do GPCRs alter cellular activity?
The G protein binds and causes the α subunit to release GDP and replace with GTP (GDP-for-GTP exchange)
The α-βγ complex immediately dissociated (into α-GTP and βγ) and each can then interact with effector proteins
Describe the process of termination of G protein signalling
The α-GTP and/or βγ interaction with effectors lasts until the α subunit GTPase activity hydrolyses GTP back to GDP
α-GDP and βγ subunits then reform an inactive heterotrimeric complex
How many different α, β, and γ proteins are encoded by the human genome?
How many possible Gα-βγ combinations are there?
20 Gα, 5 Gβ, 12+ Gγ
>1000 possible Gα-βγ combinations
What governs receptor-G protein selection?
Activated GPCRs preferentially interact with specific types of G protein, with the Gα subunit being the primary determinant
Gα subunits and Gβγ subunits interact with specific effector proteins
Complete this table.
