ELM1: Receptors 101 Flashcards
What do most drugs bind to?
Proteins
What part of the protein do drugs bind to?
The binding domain
What type of bond is formed between a drug and its target protein?
Reversible
Lots of different types of bond
What is the definition of a receptor?
A protein that binds a molecular message and passes the information on in a different form
What is a protein superfamily?
Broad grouping of proteins that are related in terms of structure and function
What is the hierarchy of protein superfamilies?
Superfamily
Family
Subfamily
What is the GPCR superfamily?
G protein coupled receptors
Biggest superfamily with over 800 members
What is the rhodopsin-like family?
Largest family in the GPCR superfamily
Over 600 members
19 subfamilies
How do superfamilies arise?
- A gene duplicates in cell division and makes two of the same gene
- One gene is mutated and have no effect
- The spare copy is mutated enough and gains a function
- This makes a new receptor
What are the evolutionary advantages of diversity?
Greater flexibility of organisms
Better adapt to environment
What is the beta1 subgroup of adrenoceptors?
Expressed in heart
Role in increasing heart rate and force of contraction
What is the beta2 subgroup of adrenoceptors?
Expressed in bronchial smooth muscle
Role in dilation of airways
What does the existence of the beta1 and beta2 subunits mean for the pharmaceutical industry?
The different types mean we can target each individually without affecting the other
This makes drug development easier
What are ligand gated ion channels?
Transmembrane proteins with a built in ion channel
Neurotransmitter ligand binds and opens the channel
What is the process of a ligand gated ion channel becoming activated?
- Agonist binds to receptor at two agonist binding sites
- Conformational change and channel opens so ions cross the membrane
- Ions dissociate from receptor which inactivates and closes
What are pentameric ligand gated ion channels?
Ligand gated
Superfamily
5 subunits in a ring around ion channel
4 transmembrane domains with N terminal extracellular domain
What are nicotinic acetylcholine receptors?
Ligand gated
Agonist is acetylcholine
Activated by nicotine
Allow sodium and calcium in to depolarise membrane
What is the physiological importance of nicotinic acetylcholine receptors?
Fast excitatory transmission between motor neurons and skeletal muscle
Fast synaptic transmission in autonomic ganglia
Modulate release of neurotransmitters in CNS
What is the pharmacological importance of nicotinic acetylcholine receptors?
In skeletal muscle are target of drugs to block neurotransmitter transmission
In brain are target of nicotine and drugs treat nicotine addiction
What is the structure of nicotinic acetylcholine receptors
16 subunits
5 classes of subunit
What are the 3 most important classes of nicotinic acetylcholine receptors?
GABAA receptors
Inotropic glutamate receptors
Brain nicotine binding site
What are GABAA receptors?
Pentameric ligand gated ion channels
Chloride channels
Hyperpolarises cell
What is the physiological importance of GABAA receptors?
Inhibitory transmitter in brain
Two classes A and B
What are GABAA receptors responsible for?
Fast synaptic transmission
What are GABAB receptors responsible for?
Slower inhibition
What is the pharmacological importance of GABAA receptors?
Target for drugs to decrease brain activity
What is the structure of GABAA receptors?
19 subunits
Mostly alpha beta and gamma
What are inotropic glutamate receptors?
3 families of NMDA AMPA and Kainate
Cation channels
Agonist of glutamate and aspartate
What is the physiological importance of inotropic glutamate receptors?
iGluRs do fast excitatory transmission
mGluRs do slower responses
What is the pharmacological importance of inotropic glutamate receptors?
Inhibition of them is involved in anaesthesia and ketamine
What is the structure of inotropic glutamate receptors?
Tetramers
What are enzyme linked receptors?
Transmembrane proteins that associate with an enzyme
What are receptor tyrosine kinases?
Enzyme linked receptor
Large proteins with single transmembrane domain
What are tyrosine kinases?
Enzymes that phosphorylate tyrosine residues on the target protein
How does the mechanism of receptor tyrosine kinases work?
- Agonist binds and RTK dimerises and tyrosine kinase domains activate
- Tyrosine kinase domains on each RTK phosphorylate tyrosine residues on partner RTK
- Activated receptor binds intracellular adaptor proteins and activates them by phosphorylating tyrosine residues
- Adaptor proteins link RTK to intracellular signalling pathways
What is the physiological significance of receptor tyrosine kinases?
Bind peptide signalling molecules with roles in regulating growth and metabolism
What is the pharmacological significance of receptor tyrosine kinases?
Drugs targeting them are insulin and insulin analogues
What are nuclear receptors?
Superfamily 48 in humans
Bind lipophilic agonists
What is the mechanism of nuclear receptors?
- Agonist crosses membrane and binds receptor
- Chaperones dissociate
- Receptor forms dimer and enters nucleus through pore
- Receptor dimer binds to hormone response element
- Receptor impacts transcription rate of target gene
What is the physiological significance of nuclear receptors?
Regulating body’s basic functions
What are some examples of steroid hormone receptors?
Glucocorticoid receptors
Mineral corticoid receptors
Thyroid hormone receptors
What are glucocorticoid receptors?
Steroid hormone receptor
Regulate glucose metabolism and inflammation and immune system
Agonist is cortisol
What are mineralcorticoid receptors?
Steroid hormone receptors
Regulate salt and water balance and blood pressure
Agonist is aldosterone
What are thyroid hormone receptors?
Regulate metabolism and development and heart rate
What is the pharmacological significance of glucocorticoid receptors?
Glucocorticoid steroids used for antiinflammatory
What is the pharmacological significance of mineralcorticoid receptors?
Target for cardiovascular conditions
What is the pharmacological significance of thyroid hormone recepotrs?
Treated with synthetic thyroid hormone
What is the general structure of steroid hormone receptors?
DNA binding domain linked to ligand binding domain by hinge region Ligand binding domain binds to agonist
What is the role of G protein coupled receptors?
To link an extracellular signal to intracellular signalling pathways
What is the structure of G proteins?
Trimeric membrane associated proteins
Alpha beta and gamma subunits with lipid tails after translation
Bound to a GDP molecule
What is the mechanism of GPCRs?
- Agnoist binds to GPCR
- Receptor is activated and interact with G protein
- Alpha subunit swaps GDP for GTP and G protein is activated
- G protein diffuses through membrane and activates more G proteins
- Alpha subunit dissociates and interacts with target protein to change activity and generate second messenger
How is the signalling of a GPCR terminated?
- Agonist dissociates and terminates signal randomly
- Agonist reuptaken into surrounding cells to stop rebinding
- Alpha subunit hydrolyses GTP into GDP and P to shut down system and rejoins beta and gamma
How are GPCRs arranged across the membrane?
Snake back and fourth across membrane 7 times
What is the role of cAMP?
Second messenger
Produced from ATP
Concentrations depend on adenylyl cyclase and phosphodiesterase
What is protein kinase A?
Activation changes the function of cAMP
Phosphorylates serine and threonine in target proteins
Found in cytoplasm
Inactive tetramer made of 2 catalytic and 2 regulatory subunits
How do the subunits of protein kinase A link to cAMP?
Regulatory subunits bind 2 molecules of cAMP
Catalytic subunits are released and become active
What is the role of Gs?
A G protein Stimulates adenylyl cyclase to increase cAMP concentration
What is the mechanism of Gs G protein?
- Agonist binds to GPCR and activates it
- GPCR interacts with G protein and GDP replaced with GTP to activate it
- Alpha subunit dissociates and binds to adenylyl cyclase which stimulates it
- cAMP increases
- Alpha subunit hydrolyses GTP to GDP and P and reassociates
- Adenylyl cyclase no longer stimulated cAMP goes to normal
What is the role of Gi/o?
Decrease activity of adenylyl cyclase to decrease cAMP concentration
What is the mechanism of G protein Gi/o
- Agonist binds to GPCR and activates it
- GPCR interacts with G protein and GDP replaced with GTP to activate it
- Alpha subunit dissociates and binds to adenylyl cyclase which inhibits it
- cAMP decreases
- Alpha subunit hydrolyses GTP to GDP and P and reassociates
- Adenylyl cyclase no longer inhibited cAMP goes to normal
What is the difference between the G proteins of Gq Gi/o and Gs
Gq is different as it couples to intracellular pathway using IP3 and DAG
Where does DAG act?
Remains in membrane and modulates membrane proteins
Where does IP3 act?
Released in cytoplasm and modulates proteins in endoplasmic reticulum
How is DAG and IP3 made?
- Membrane protein PIP2
- PLC cleaves head off PIP2 and makes diaglycerol and inositol trisphosphate
How does Gq activate phospholipase C to produce DAG and IP3?
- Agonist binds to and activates GPCR
- GPCR interacts with G protein and GDP is replaced by GTP which activates it
- Alpha subunit dissociates and binds to PLC
- PLC stimulated and cleaves PIP2
- DAG increases in membrane IP3 increases in cytoplasm
- Termination as normal
What is the effect of IP3?
- IP3 binds to IP3 receptor on ER
- Allows calcium to enter cytoplasm
- Opens ryanodine receptor and causes calcium induced calcium release
What is protein kinase C?
Cytosolic protein that becomes associated with membrane when it binds to calcium
Phosphorylates proteins on serine and threonine residues
Requires binding of DAG and calcium to activate
