Receptor Mechanism Flashcards
What does acetylcholine do in the salivary gland?
Secretion
What does acetylcholine do in the heart muscle?
Decreased rate and force of contraction
What does acetylcholine do in the skeletal muscle?
Contraction
What model do receptors work under?
Lock and key model
What’s the fastest receptor?
Ligand gated ion channel
What’s the slowest receptor?
Nuclear
Give examples of ligand gated ion channel agonists
- nicotinic cholinoceptor 5HT3
- acetylcholine 5HT
- gamma amino butyrate acid (gaba) glycine
How many similar proteins does a ligand gated ion receptor have?
5
Where is the amino acid terminus in a ligand gated ion channel?
External
How many transmembrane domains do ligand gated ion channels have?
4
Which amino acids form domains and which form the chains between domains?
Hydrophobic amino acids form domains
Hydrophilic amino acids form the Chains
How many transmembrane domains do nicotinic acetylcholine have per protein?
4
What is the nicomic acetylcholine made up of?
2 alpha subunits
1 beta subunit
1 gamma subunit
1 delta subunit
How do the agonists activate the ligand gated ion channel?
Bind to the alpha subunits which causes a molecular kink
How do nicotinic and 5HT3 depolarise?
Na/Ca influx
How does GABAa and glycine hyperpolarise?
Chloride influx
What is the nicotinic acetylcholine receptor made up of in adult skeletal muscle?
Alpha 1 Epsilon Alpha 1 Beta 1 Delta
What is the nicotinic acetylcholine receptor made up of in foetal skeletal muscle?
Alpha 1 Gamma Beta 1 Alpha 1 Delta
What’s the difference in function between nicotinic acetylcholine receptors in adult and foetal skeletal muscle
Adult- channel is open longer and brings in different molecules
What is the nicotinic acetylcholine receptor made up of in the CNS?
Alpha 2-4 and beta 2-4
Give symptoms of myasthesia gravis
- muscle weakness
- drooping eyelids
- Fatigue
- difficulty swallowing or talking
- exertion is hard
What causes myasthesia gravis?
Muscle nicotinic acetylcholine receptors become degraded
What subunit does myasthesia gravis target?
The alpha 1 subunit
How much of the proteome is made up of G protein coupled receptors?
8%
Roughly what proportion of all pharmaceutical drugs target GPCRs?
30%
What subunits make up a GPCR?
Alpha, beta gamma (and GDP?)
What happens when the agonist binds to the GPCR?
There is a change in the affinity of the alpha subunit, so it binds to GTP which activates it
What happens when the alpha subunit is activated in GPCRs?
It dissociates from the beta gamma and interacts with other proteins
How many transmembrane domains do GPCRs have?
7
What does the alpha s do from GPCRs?
Stimulates
What does the alpha I do from GPCRs?
Inhibits adenyl cyclase
What does the alpha q do from GPCRs?
Interacts with the PLC beta
What does the alpha 12/13 interact with from GPCRs?
RhoGEF
What does adenylate cyclase do with alpha I?
Takes ATP-> activated pKA (v.basic)
What does phosphodiesterase break down?
cAMP
What does Gq/11 do?
Increased phospholipase C activity
What does PIP2 stand for?
Phosphatidylinositol
What does IP3 stand for?
Inositol triphosphate
What does DAG stand for?
Diacylglycerol
What is tyrosine receptor kinase involved in?
Insulin
Epidermal growth factor (EGF)
Platelet derived growth factor (PDGF)
What is JAK/STAT involved in?
Growth hormone
Interferon
What is serine threonine receptor kinase involved in?
TGF beta
What are nuclear receptors involved in?
Glucocorticoid
Thyroid hormone
What are enzyme-linked receptors involved in the regulation of?
Cell growth Division Differentiation Survival Migration
What is inappropriate enzyme linked receptor activity associated with?
Disease including cancer
What does activation of enzyme-linked receptors lead to?
Actuation of receptor kinases
Activation of multiple signalling pathways
What does dimerisation of tyrosine kinase linked receptors do?
Brings together two receptor molecules allowing autophosphorylation of specific tyrosine residues
Can all tyrosine residues be phosphorylated?
No
What does phosphorylation of tyrosine residues form?
Docking domains
What do the proteins that bind to the docking domain of tyrosine kinase linked receptors recognise?
A specific AA sequence that includes a phosphorylated tyrosine residue
What is a motif in tyrosine kinase linked receptors?
Specific AAs including a phosphorylated tyrosine residue
What happens when grb-2 binds to the tyrosine through its SH2 domains?
Undergoes a conformational change which allows it to bind to another protein called GEF through the SH3 domain
How is RAS GTP made from GEF?
RAS binds to GEF
GDP swapped for GTP
What is ras?
Membrane associated protein that is bound to GDP
What does PI3-kinase phosphorylate?
PIP2 to PIP3
What does the insulin receptor consist of?
2 alpha chains
2 beta chains
What are the subunits joined by in insulin receptors?
Disulfide bridges
What happens to the insulin receptors when the insulin isn’t bound?
It doesnt allow the phosphorylation of receptors
What happens in the insulin receptor when insulin is bound
There is a conformational change to the receptor which allows autophosphorylation to take place
How does the insulin receptor substrate bind in the insulin receptor?
SH2 domain
What do insulin receptors lead to in the liver and muscles?
Glycogen synthesis or protein synthesis
What can insulin receptors lead to?
Stimulation of glucose transporters which increase glucose uptake
What other proteins can insulin substrates recruit
Ras and phospholipase c
How are phosphatase activated?
As a result of the receptor activation
What do kinases add?
Phosphates
What do phosphatase remove?
Phosphates
What facilitates the inactivation of the molecules?
PTEN
What enzyme is ras acted on by to speed up the inactivation?
GTPase activating protein (GAP) binds to the activated Ras and stimulates the GTPases which leads to the dissociation of GTP
What can mutations in key regulatory mechanisms lead to?
Increase in receptor expression
Loss of phosphatase activity
Loss of GTPase activity
Loss of phosphatase activity
What is jak-STAT signalling pathway activated by?
Growth hormone
Give the JAK-STAT signalling pathway
Jaks cross-phosphorylate each other on tyrosine
Activated jaks phosphorylate receptors on tyrosine
STATs dock on phosphotyrosines and jaks phosphorylate them
STATs dissociate from receptors and dimerise via SH2 domain
Travels to the nucleus where it will stimulate and regulate the gene regulatory protiens
What does the serine-threonine kinase require the presence of?
Two different types of receptor
What is the serine-threonine kinase domain?
Type 2 receptor, by binding of TGF beta undergoes a conformational change
What are intracellular receptors activated by?
Molecules that readily pass across the cell membrane and are largely insoluble in aqueous environments
Give some intracellular receptor activators
Thyroid and steroid hormones and glucocorticoids
What are the intracellular receptor activators delivered bound to?
Globulin including vit D
In steroid receptors what does the binding of cortisol to a glucocorticoid receptor lead to?
Dissociation of the heat shock protein and the glucocorticoid receptor bound to the cortisol
What does the glucocorticoid receptor- cortisol complex do in the nucleus?
Binds with the glucocorticoid response element which leads to an increase in gene transcription
How do thyroid hormone receptors work?
T3 delivered to the cell bound to a binding globulin. Then it diffuses across the plasma membrane into the nucleus where it binds to the thyroid hormone receptor
