Receptors Flashcards
Describe signal transduction
Receptor proteins bind “signals” i.e. drugs & endogenous ligands with high affinity Conforma)onal changes in the structure of the receptor protein then convert the chemical signal into one or more intra-cellular signals.
3 types of naturally occurring chemical messengers
Hormones
Neurotransmitters
Local chemical mediators
Not natural - clinically useful drugs
Receptors are embedded where?
Protein membrane/bilayer
3 families of plasma membrane receptors
G protein coupled - associated with GTP
Tyrosine kinase receptors- property of phosphorlyating tyrosine residues
Ligand gated ion channels
Receptor tyrosine kinases are activated by what?
cytokines, peptide hormones, growth factors
What do tyrosine kinase proteins do/regulate?
Regulate cell proliferation, differentiation and function
What are implicated as oncogenes?
anti cancer drug targets
Protein tyrosine kinases
Describe the basic structure of RTK (receptor tyrosine kinase)
3 essential components
1) ligand binding site (extracellular domain)
2) transmembrane domain (alpha helix)
3) Domain with tyrosine kinase activity (cytosolic)
Describe RTK in absence of a bound ligand
- generally monomeric
- poorly active kinases
Describe RTK when there is a bound ligand
Conformational change and a formation of a dimer receptor
Phosphorlyation of tyrosine residues
Describe the EGF receptor in one word
epidermal growth factor
bivalent
Describe the insulin receptor
dimer of two identical units
disulphide bond linked
insulin binding activates the kinase
Describe the process that occurs when insulin binds to its receptor
phosphorlyation of activation receptor
activates insulin receptor tyrosine kinase
phosphorylated sites then act as docking sites
IRS-1 binds what?
1) phosphotyrosine
2) and IRS-1 is phosphorylated by the receptor
3) PI-3 binds phosphorylated IRS-1… PIP2 phosphorlyated to PIP3
4) PIP3 binds PDK1 which is a kinase. Phosphorylation of Atk1 occurs
5) Movement of GLUT4 to cellular membrane occurs. transport of glucose into cell
Kinase activity is implicated in which diseases?
rheumatoid arthiritis
asthma
neurological disorders
cancers
How can the modulation of kinase activity be achieved?
disrupt protein-protein interactions
inhibit phosphorylation activity (prevent ATP binding)
Downregulate kinase gene expression
Tell me about a drug that works by blocking ligand binding
TK receptor
Bevacizumab binds to growth factors thus preventing their binding to receptors
This interferes with tumour blood vessel development
First line of treatment for colorectal cancers
How does imatinib mesylate work? What is it used for?
Targets ATP binding
chronic myeloid leukaemia and acute lymphoblastic leukaemia
How does Gefitinib work?
targets ATP binding to EGFR
EGFR is overexpressed in many solid tumours
Ion channels can be controlled by…. (2)
Ligands - ligand-gated ion channels
membrane potentials - voltage gated ion channels
Describe the general structure and gating of ion channels
5 protein subunits with receptor sites on 1 or more subunits
Ligand gated channel or lock/gating mechanism
receptor protein sensitive a chemical messenger
induced fit binding leads to conformational change which allows for ion passage
Cationic channels are for which ions?
Give one example of an ion channel of this type
Na+, K+, Ca2+
nicotinic acetylcholine receptor (role in synapes)
Anionic channels are for which ions?
Give one example of an ion channel of this type
Cl-
GABA and glycine gated Cl- channels
associated with many inhibitory synapses
How do local anaesthics work?
hint: think about ion channels
block conductance of Na+ and reduce pain perception
how do benzodiazipines work?
hint: think about ion channels
increase the availability of GABA to conduct Cl- across membranes
This drives the membrane potential away from its threshold of activation
this reduces communication between neurones and hence sedation
Define receptor
a protein which acts as a sensing element of a cell, allowing cells to receive messages to one another
Define agonist
mimic function of messenger by binding to receptor and causing normal response
Define antagonist
Binds receptor but fails to produce a response. Acts as an inhibitor for other possible chemicals that may want to bind to the receptor
Describe a G protein coupled receptor
Family of receptors associated with GTP binding proteins
The receptor has 7 transmembrane helices
Give 4 examples of substances that activate G protein coupled receptors
GABA, acetylcholine, dopamine, noradrenaline
Give 1 example/role of G protein receptors
beta-adrenergic receptor
target of beta blocker drugs such as propanolol, which is used to treat heart problems
GPCR activates which 2nd messengers? (2)
cyclic AMP
The enzyme adenylate cyclase products cAMP which then activates a kinase
phospholipase C
this causes inositol phospholipid cleavage to produce IP3 and DAG
What is the main clinical use for beta-adrenergic agonists?
ashtma
to relax the smooth muscle of the bronchi
e.g. salbutamol
How does cholera mediate use G proteins to mediate its infection of the body?
toxin production which stabilises GTP bound form of the G protein subunit
continual activation of protein kinase A
opens Cl- channels
diarrhoea occurs as Cl- escapes into colon, water follows due to osmosis
watery stool
epinephrine + beta-adrenergic receptor causes
energy store mobilisation
insulin + insulin receptor causes
increased glucose uptake into cells
epidermal growth factor + EGF receptor causes
expression of growth-promoting genes
Intracellular receptors are also known as
nuclear transcription factors
nuclear hormone receptors
Describe the basic structure of an intracellular receptor
single protein containing a ligand binding site at the C terminal and a binding region for DNA near the centre (zinc fingers)
Drug targeting oestrogen receptors
Tamoxifen
works via competitive inhibition of oestrogen binding to the receptor
inhibits expression of oestrogen regulated genes
advanced breast cancer treatment and primary breast cancer treatment - FDA approved
