signal transduction (Spooner) Flashcards
why do regulatory feedback pathways exist?
positive feedback may be the response so need to control this and damp down signals or turn off receptor
signals are usually….
ligands that bind to something like receptor (except for light)
agonists
antagonists
ligands that stimulate pathways, most natural ligands like serotonin
ligands that inhibit pathways, most drugs like antihistamine
direct contact
direct contact - ligand on signalling cell binds receptor on target cell, important in development
gap junction
exchange signalling molecules, like in neurones
autocrine
ligand induces response only in signalling cell
self-stimulation - cell that makes signal is one that responds to signal
autocrine ligands rapidly degraded so short half life and can’t travel far
reinforce developmental decisions
common features of cancers
eicosanoids
autocrine ligands derived from fatty acids
aggregation of platelets in immune system
pain and inflammation
contraction of smooth muscle
paracrine
ligand induces response in target cells close to signalling cell
limited diffusion of ligand, destroyed by extracellular enzymes
e.g. neuromuscular junction
endocrine
ligand by endocrine cells and carried in blood (hormones)
distant target cells
systemic effect
what class of signals does acetylcholine belong to?
paracrine but also can be endocrine
so distinction between classes not always clear
specificity: cell-type specific
certain receptors only present on certain cells
molecules downstream of receptor only present in some cells (sometimes have receptor but don’t respond because lack further components)
because of differential gene expression by activators and repressors
specificity: high affinity interaction
precise molecular complementarity between ligand and receptor mediated by non-covalent forces
association depends on concentration
what is dissociation dependent on?
independent of conc of free reactants but dependent on conc of complex
1st order vs second order reaction
1 reactant vs 2 reactants
high affinity
low affinity
highly specific
less specific, sticky
signalling is incredibly…..
sensitive
desensitisation
continuous signal
cross-talk
pathways share common components so shared response
integration
multiple signals produce unified response
net response depends on integrated output of both receptors
takes strength of each into account
intrinsic enzyme activity
ligand binding activates enzyme activity
e.g. insulin receptor
insulin
glucagon and epinephrine (adrenaline) and cortisol
lowers blood sugar levels
raises blood sugar levels
islets of Langerhans:
alpha
beta
gamma
secrete glucagon
secrete insulin (more beta cells than alpha)
secrete somatostatin
IR
insulin receptor
associated into dimers
alpha subunit pointing out from membrane, beta in cytosol
IRS-1
insulin receptor substrate 1
Grb2
Sos
binds phosphate on activated IRS-1
guanine nucleotide exchange factor (GEF) - changes any guanine associated with the target
Ras
G protein, enzyme
what activates the same cascade as insulin?
EGF
what does insulin count as?
growth factor because activates CDKs
PI-3K
what does it cause when activated?
phosphoinositide 3-kinase
phosphorylates phosphotidylinositol 4,5 bisphosphate (PIP2) to produce phosphotidylinositol 3,4,5 triphosphate (PIP3) which recruits PIP3-dependent protein kinase (PDK1) which activates protein kinase B (PKB also called Akt)
second messenger
small metabolically unique molecule, not a protein, whose conc can change rapidly, relay signals from receptors to target molecules in cytoplasm or nucleus
growth factor
phosphorylation of IRS-1 amplifies signal and recruits and activates Ras so MAPK cascade, gene expression changes
glucose regulator
phosphorylation of IRS-1 amplifies signal, conversion of membrane lipids and amplification via lipid dependent kinase, activation of PKB
upregulates glucose entry into cells and glycogen production
why are there 2 pathways involved in IR signalling?
there’s no point in growing if there is no food supply
PTEN
PIPs-specific phosphatase
removes phosphate at position 3 of PIP3 to convert to PIP2
so shuts off signalling through PKB
PKB
converts excess glucose to glycogen
transport of GLUT4 glucose transporter to membrane
Lipostat theory 1953
evidence?
adipose tissue decreases - feedback stimulates feeding behaviour (hunger) and reduced fatty acid oxidation (store it)
LEPTIN released by adipose, binds to receptor in hypothalamus and tells brain you’re full
Leptin discovery
Lep obese mice
display physiological behaviour of starvation, diabetes, won’t stop eating
injection of leptin gene corrects obesity
anorexigenic
appetite-reducing neurones in hypothalamus
alpha-MSH
alpha-melanocute stimulating hormone
modulates nervous transmission
suppression of apetite, stimulate sympathetic NS
JAK
soluble Janus kinase
cytosolic non-receptor tyrosine kinases, transduce cytokine-mediated signals via JAK-STAT pathway
2 phosphate transferring domains - 1 kinase, 1 negatively regulates kinase activity of 1st
(Janus - god with 2 faces)
STAT
signal transducer and activator of transcription
activated by activated receptor
NLS
nuclear localisation signals
where does leptin signal other than the brain?
liver and muscle cells making them more sensitive to insulin
signals through IRS-2
EPO
signalling?
erytropoietin
hormone that under hypoxic (low O2) conditions, secreted to increase production of RBCs
used to cheat in sport
via JAK-STAT pathway using STATs
GPCR structure
G-protein coupled receptor same basic structure extracellular domains E1 to E4 transmembrane domains H1-H7 cytosolic domains C1-C3 and C4 tail
multiple heterotrimeric G-proteins
Gs - stimulates adenylate cyclase
Gi - inhibits adenylate cyclase
etc.
thinking errors
type 1 - believing a false (it’s false but you think true)
type 2 - rejecting a truth (it’s true but you think false)
physiological response promotes type 1 error e.g. run if there’s a noise that might be a lion
cortisol
increases blood sugar through gluconeogenesis
suppresses immune system
cAMP
2nd messenger
signalling molecule
activates variety of proteins
response depends on which target proteins are in cell
activates protein kinase A (PKA) which targets proteins (transcription factors, ion channels, enzymes)
complex epinephrine signalling
Epinephrine binds:
① a β-adrenergic GPCR receptor coupled to a Gs heterotrimeric G protein:
Gαs is activated and stimulates adenylate cyclase
Gβs subunits inhibit adenylate cyclase
② an α-adrenergic GPCR receptor coupled to a Gi heterotrimeric G protein:
Gαi is activated and inhibits adenylate cyclase
Gβγi subunits activate a MAPK kinase cascade
3 ways to turn off adrenaline response
loss of ligand regenerates receptor
alpha turns itself off
adenylate cyclase converts G-alpha to inactive form
glucagon and adrenaline link
glucagon stimulates glycogen breakdown, which is the same response as adrenaline but long term slow response unlike adrenaline which is fast
CTx
cholera toxin
binds to cell surface ganglioside lipid GM1 on intestinal epithelial cells
endocytosis, goes to Golgi into ER
PDI protein breaks disulphide bond that holds toxin subunits together, A1 subunit bound to BiP, dislocates but refolds when enter cytosol of cell
CTxA modifies G-alpha-s ON permanently so adenylate cyclase always on, rise in cAMP, interfere with CFTR - diarrhoea
light reception
passes through neural layer through rods and cone cells
signal in discs of photoreceptive membrane in outer segment of retine
light receptor structure
inner and outer segments - primary cilium
rod cells - non-colour vision and depth at low light intensity
cone cells - colour, high light intensity
rod cells
outer segment has discs not connected to plasma membrane
disc is closed sac of membrane with photosensitive rhodopsin
rhodopsin
specialised GPCR
made of opsin linked to 11-cis-retinal (prosthetic group which receives light)
covalently attached to nitrogen in side chain of specific lysine residue of TM domain 7
mammalian rhodopsin
500nm peak absorbance
rod cell respond to single photon
5 responses lead to register of flash of light
3 mechanisms that make rods insensitive to high light
prolonged cGMP-gated channel closure
phosphorylation of opsin reduces transducin activation
arrestin binding to phosphorylated opsin stops transducin activation
our colour vision
we are typically trichromats
414-426nm blue
530-532 nm green
560-563nm red
organism that can see the most colours
Mantis shrimp - Neogonodactylus oestedii
16 pigments
sildenafil citrate
structure similar to cGMP so inhibits cGMP PDE so cause blue-tinged vision, can’t tell blue and green apart
also targets PDE-5 in corpus cavernosum (erectile tissue)
nitric oxide
activates guanylate cyclase inside cell by binding to haem group
converts from GTP to cGMP - alters activity of target proteins
angina treatment today
glycrol trinitrate (nitroglycerine NG) cause dilation of blood vessels
high blood pressure and NO
autonomous nerves in vessel wall respond to high blood pressure and release ACh which binds to receptors on plasma membrane of endothelial cells - increases endothelial cell calcium - 2nd messenger - activates nitric oxide synthase (arginine to citrulline and nitric oxide)
nitric oxide synthase isoforms and functions
NOS1, nNOS, neuronal isoform - development of nervous system, protection against cardiac arrhythmia ,peristalsis and sexual arousal
NOS2, iNOs, inducible isoform - produces large amounts of NO as a defence mechanism by macrophages, cause of septic shock
NOS3, eNOS, endothelial isoform - controls vascular tone, insulin secretion, regulates angiogenesis, role in embryonic heart development and morphogenesis of coronary arteries and cardiac valves
bNOS, bacterial NOS - protects against oxidative damage, immune attack
amyl nitrate
vasodilator
vapourises to generate NO
dilates vascular smooth muscle
lowered blood pressure
cyclic nucleotides
2ndary messengers
control physiological processes like smooth muscle contractility
phosphodiesterases (PDEs)
superfamily of metallophosphydrolases that cleave 3’,5’-cyclic phosphate moiety of cAMP/cGMP to produce 5’ nucleotide
PDE5
increases blood pressure
target for succeful drug sildenafil citrate
4 types of oestrogen receptors
E1 - menopause
E2 - reproductive years
E3 - pregnancy
E4 - pregnancy
tamoxifen
hormone treatment for breast cancer
signaliing via ERs is inhibited
