CBG Lecture 10: Cell Signalling Flashcards
what happens if there are holes in a membrane
cell tends towards thermodynamic equbm, resting potential dissipates (0mV) creates action potential
give an example of a signal that indicates death
oxidised fat leakage - nearby cells recognise it and activate their defences
give generalised flowchart of cell signalling
signal (ligand) - receptir (transmembrane/cytosolic) - cascade (sometimes, amplification,switches) - gene expression (TFs) - enzyme activity
what 4 ways of signalling are
juxtacrine
autocrine
paracrine
endocrine
which types of cell signalling are short disctance
autocrine
juxtacrine
which types of cell signalling are long distance
endocrine
paracrine
what is juxtacrine signalling
cell directly interacts with other cell via membrane bound ligands
give an example of juxtacrine signalling
Th cell stimulation of B cell,
gap junctions
plasmodesmata
which type of signalling requires direct contact with other cell
juxtacrine
what is autocrine signalling
self stimulation
give an example of autocrine signalling
selinterleukin 2 from a stimulated T cell causes that T cell to proliferate monoclonally
positive feedback loop
what type of signalling is self stimulation
autocrine
what is paracrine signalling
signalling to other nearby cells
local cells
which type of signalling is done to nearby cells
paracrine
give an example of paracrine signalling
neuronal signalling
many growth factors
what is endocrine signalling
distant cells secrete signalling molecules into transport systems
what is the longest distance cell signalling
endocrine
give an example of endocrine signalling
insulin via blood in mammals
gibberellin via xylem in plants
give an example of when the same ligand has different effects on different cells
ACh on…..
1. heart muscle: decreased contraction
- Salivary glands: secretory enzymes
- Skeletal muscle: contraction
how does ACh have different effects?
different cells/different receptors
eg. heart/salivary glands/skeletal muscles
what is an agonist
opens the ligand gated ion channel
what is an antagonist
closes the ligand gated ion channels by blocking them : paralysis
what are the main classes of cell signalling receptors
- nuclear receptor
- Gprotein coupled receptor
- enzyme coupled receptor
- ligand gated ion channels
- adhesion receptors
give an example of a ligand gated ion channel
nicotinic ACh receptor is a ligand gated Na+ channel : musculoskeletal junctions. CNS synapses
what is the agnonist in ligand gated ion channel
nicotine
what is an antagonist of Nicotinic Ach receptor
curare
what effect does curare have on a nicotinic ACh receptor
its an antagonist
what are nuclear receptors
ligand modulated gene regulatory proteins that bind hydrophobic signalling molecules
where are nuclear receptors
cytosolic
what features do nuclear receptor ligands tend to have
small, hydrophobic as need to directly cross cell membran
give some examples of ligands for nuclear receptors
oestrogen - a steroid sex hormone
retinoic acid
thyroxine
what happens when ligand hormones bind to nuclear receptors
they bind DNA
outline structure of nuclear receptors
have a three part structure
what could be a us for steroid receptor antagonists
used in chemo for breast cancer
also tamoxifen blocks oestrogen receptors because most breast cancer cells require oestrogen to divide
what is estradiol
a form of oestrogen - female sex hormone
give an example of hormones used in chemotherapy for breast cancer
steroid receptor antagonists like tamoxifen used against breast cancer by blocking oestrogen receptors (most breast cancer cells require oestrogen to divide)
what are G proteins?what are they involved in
timed delayed biological switches
involved in cell signalling, im/export proteins in nucleus/vesicular traffic
what do G proteins bind to when active
bind to GTP
what is GAP
a GTPase Activating Protein
what is inactive form of G-protein bound to
GDP
what do GPCRs act as
ligand modulated GEFs
give an example of a GPCR
beta andrenergic receptor - adrenaline
outline what happens in the adrenaline cascade
adrenaline interacts with the beta andrenergic receptor which is a GPCR
conformational change, alpha unit of GPCR swaps GDP for GTP and causes alpha unit to dissociate
alpha unit then binds to adenyl cyclase, interacts with eachother and converts ATP to cAMP
flood cell with cAMP: amplificaiton
cAMPs target is PKA (protein kinase A) a heterotetramer in inactive form
when PKA binds 4xcAMP, releases active form of PKA
Activated PKA phosphorylates CREB - TF can enter nucleolus and bind to cAMP response element = start transcription
what is CREB
cAMP response element binding protein
what happens in the conformational change of GPCR when adrenaline binds
alpha subunit of GPCR swaps GDP for GTP causing alpha to dissociate
what is the GPCR adrenaline reacts with
beta-andrenergic receptor
what binds to adenyl cyclase? what happens
alpha subunit binds to adenyl cyclase - convert AMP to cAMP
what is cAMPs target in adrenaline cascade
PKA - protein kinase A: a heterotetramer in inactive form
how many cAMPs does PKA need to bind to be active
4
what does acivated PKA do in the adrenaline cascade
phosphorylates CREB (cAMP response element brinding protein)
what is CREB - what does it do
cAMP response element binding protein
piece of DNA that can bind TF that starts transcrption
what enzyme is a G protein like
a weak GTPase
what are GPCRs made of - which type of receptor are they
ubiquitous 7-transmembrane receptors
they are all-trans-Retubak
what do GPCRs act through
second messengers
name some second messengers that GPCRs act through
cAMP
IP3/DAG
in a trimeric G protein, what does each subunit do
alpha does the work
beta and gamma can open ion channels
what are the characteristics of the cAMP signalling system
- amplification
- sharp response
- short duration
what features of the cAMP signalling system show amplification
small signal leads to much cAMP
what features of the cAMP signalling system show sharp response
4 cAMP needed to release PKA
what features of the cAMP signalling system show short duration
PKA activates phosphodiesterase which rapidly removes cAMP
how many times do receptor tyrosine kinases pass through membrane
singlepass enzyme coupled transmembrane receptors
what are RTKs
receptor tyrosine kinase - ligand modulated kiases
what are RTKs involved in
epidermal growth factors
insulin
how do RTKs respond
dimerise and act through phosphorylation cascades
briefly describe structure of RTKs
extracellular receptor domain, transmembrane domain and intracellular tyrosine kinase domain
what is the extracellular receptor domain of RTK like
cysteine-rich or globulin like
what is the difference between RTKs and GPCRs
RTKs dont self destruct but do act as biologival switches
show does ligand activate RTK
cross links them and brings them close to one another
what do RTKs respond to
large extracellular peptides: growth factors
what signalling are RTKs involved in
paracrine signalling
what type of receptor is insuline
RTK
what two proteins are the main proteins involved in most growth factor cascades
RTKs and Ras
what is Ras
a protooncogene
where is Ras-GAP mutated
in neurofibromatosis
what happens when Ras-GEF is mutated
Ras is constituently activated -whether theres TF or not
how many cancers are Ras mutants
a quarter
how can a signal be amplified
through use of secondary messengers
outline steps of a generalised RTK cascade
1, ligand eg.EGF binds to EGF RTK and causes cross linking
- mass of phosphorylation at bottom EGF RTK causes adaptor to bind a Ras-GEF protein to recognise phosphotyrosine
- adaptor recruits GEF and Ras
- Ras-GEF causes Ras GDP to swap out GDP for GTP
- Ras activates MAPKKK (Raf)
- Raf actuvates P onto MAPKK (Mek)
- MEK adds P onto MAPK (Erk)
- Erk phosphorylates Myc (gives 2 Ps) results in increase transcription of genes, by binding to enhancer box sequence after entering nucleus
- Myc switches on transcription of cyclin genes
give an example of a ligand in RTK
epidermal growth factor
how do RTKs crosslink
each one of pair can phosphorylate eachother
what does mass of phosphorylation at bottom of EGF RTK cause
causes adaptor to bind a Ras-GEF protein to recognise phosphotyrosine
what does adaptor protein do
recruits GEF and Ras
what does RAS=GEF do
causes Ras to swap GDP for GTP
what is MAPKKK aka
Raf
what is Raf aka
MAPKKK
what does Raf do
activates a P onto MAPKK (MEK)
what is Mek
MAPKK
what does MAPKK do
MEK adds P onto MAPK (ERK)
what is ERK aka
MAPK
what does ERK do
phosphorylates Myc by giving it 2 Ps and results in increase transcripitoin of genes by binding to enhancer box sequence after entering nucleus
what does Myc do
Myc switches on transcription of cyclin genes