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2- extracellular signalling molecules (16 Oct) (2- Protein/peptide signals…
2- extracellular signalling molecules (16 Oct)
1- types of signalling molecules
hydrophilic
float around in blood
proteins, peptides ,
have the vast majority of signalling molec.
hydrophobic
produced from cholestrol
does NOT dissolve in blood
our steroids
gasses
NO, CO, SH2(solphate)
smal amino asid or nucleoside derivatives eq. thyroid hormones (behave differently becau. they are small)
they get different type of :
Synthesis/storage/transport/Receptor-type(switched off by different mechanism/location/degradation
2- Protein/peptide signals
vast majority of signalling molecules: proteins or pieces of proteins: peptides
communication betw. cells in blood- get activated
inflammatory response
how proteins synthesized:
switch on a gene
get transcript
translated into a protein
exocytosis
signalling molec. get stored in vesicles
some signals get along and hit the cells
vesicles get vomited in the extraceluular fluid by exocytosis
hydrophilic
float around in blood , or in extra cellular fluid
we do Not have transport issues by proteins as signalling molecules
very rapid acting
way of switching off the molecule
1- they sometimes get endocytosed
2- destroy these pro. by having enzymes that chop them off in little pieces
protease enzymes
chop off each of signaalling molecules
liberate the free amino acid
to use
3- Hydrophobic signals -steroids
name steroid hormones
cortisol,
regulate blood sugar
half life in 3.5 days
aldosterone,
regulate blood salts
testosterone
progesterone
oestrogen
require transport proteins
bind them to transport proteins
to get them into our blood stream
Not float in blood
transpo. pro. job. carry stroid hormones in our blood
much longer lived
produce cholestor in our cells
modify it betw. endoplasmic reticulum and mitocondrian
diffuses out through plasma membrane
gets picked up by carrier protein
degrade : get it out of the body
dont have enzymes to mop it up
transport these enzymes back to the liver
group of enzymes : Cytochrome P450 oxidase :star:
enzymes will break little bits of this hormone
which disables them a bit
excrete them out of body
pump them in the bile
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4- type of receptor that signalling
molec is bind to is impo.
most of signalling molecules have
multiple different receptore
steroids only have one receptor
protein type of signalling molecules
have lots of different
receptor types
acetylcholin ACh
have vastly different effects
depending on what sort
of receptor it binds to
binds to a rec. on
skeletal muscle cell
causing contraction
binds to 2 different types of
maskerinic receptors :question:
present on heart
when acetyl cholin binds to that
receptor causes the
opposite of contraction
slows down the heart beat
binds to mascerinic
receptors on salivary cells
causes secretion of salava and amylase is the other enzyme
present in the salava
and the effect it has is impo.
not just the signalling molec.
5- receptors
cell surface receptors
present on the outside of the cell
bind to a hydrophilic molecule on the outside of the cell
transduce that signal inside of the cell
signalling molec. can NOT enter the cell
big protein complexes that are far too big
to get across plasma membrane
all of these types of receptors
have to be at the plasma membrane
and have a bit that sticks out of the cell
that binds to our chemical messenger
have a bit inside the cell
activates second messenger
3 classes
1-ionotropic receptors: ion channel coupled receptor :star:
changing how ions are distributed across plasma memb.
important for functioning of
nervous system and muscles
normally closed
pic. Na+ channel
keeps Na on one side of plasma memb.
signalling molecule: acetyle choline binds to receptor
the ion chennel opens
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fast
2- enzyme coupled receptor : metabotropic receptors :star: changing the metabolism inside the cell
direct enzyme activation
receptor binds to chemical messenger on the outside of the cell
inside of the cell we have an enzyme:
active part of an enzyme
normally inactive
when signalling molec binds to the receptor: the enzymes inside become activep
enzymes catalyse change inside the cell: change in cell behaviour
eg. RTKs= receptor tyrosine kinase
slower
3- G protein coupled receptor: metabotropic receptors
changing the metabolism inside the cell- indirect
the same as enzyme coupled receptors
except the enzymes and the receptor
are 2 different separate entities
rece. binds to a sig. molec. on the outside of the cell
changes the shape of the recept.
receptor binds to sth called a G protein
G protein activates an enzym
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intracellular receptors
steroid type of hormone
or really small hormones
like thyroid hormones
can diffuse across plasma membrane
steroids are lipid based
they have no problem entering A CELL
bind to receptors that are
present inside the cell
can be present in the nucleus or cytoplasm
all act by changing
TRANSCRIPTION
part of the receptor is a transcription factor
they are produced
in inactive form
when they get bound by
specific signaling molecule
they get activated
usually they bind to dna and switch on
or off all of the target genes
that changes the behaviour of the cell
2 different classes of (intracellular) nuclear receptors
class 1: sit in the cytoplasm when inactive
TF= transcription factor
produced in the cytoplasm
gets activated by translocation
when activated enter the nucleus
the way they get activated
hormone molecule diffuses
across plasma membrane
binds to receptor complex
after bindig: receptor complex
get trans-located into the nucleus
once in the nucleus
it is still active
binds to DNA and swithches on or off transcription of target cells
class 2: does the same thing as class 1 except the receptors are always present in the nucleus
produced in the nucleus
get activated by binding to hormone (chemical messenger)
when they are inactive : present in the nucleus
bound to some sort of repressor complexp
when our hormon molec. diffuses into the cell
enters the nucleus
binds to the complex
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6-metabotropic cell surface receptors
act by second messengers
when we activate signalling system inside the cell
we can do that by phosphorylation
of different molecules
we have a lot of enzymes that are
produced in their off state
when we add a phosphate
changes the activity of the enzyme
enzyme becomes active
so signal going from outside of the
cell to the inside of the cell
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one of the most common
when using phosphate to activate the signal
Receptor tyrosine kinase : RTKs :star:
receptor: sth that picks up signalling molec. on the outside of the cell
kinase: phorphorylate proteins
tyrosine: where the kinase chooses to act is on the tyrosine residue of the protein
the kinase is completely inactive
when they are not bound by signaling molecules
by binding sig. molec. we activate kinase
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G proteins
how G protein couple receptors work
they bind to Guanosin triphosphate=Gprotein
when they bind to GTP they are activated
GPCR has guanosine exchange factor (GEF) activity
binding to GDP
they are repressed
binding to different forms of guanosine
dictates whether switched on or off
use an enzyme to remove GDP
and GTP binds and swithes on our signal
how G protein couple receptors work
binding to the receptor causes removal of GDP
and attachment of GTP
means switching on the signal
by activating the G protein inside the cell
Deactivated by GTPase-activating proteins (GAPs)
GPCRs
GPCRs do the same thing as RTKs but have 1 extra step
we have 2 things present:
1- inactive. receptors
2- inactive G proteins
when the sig.molec. binds to the receptor
G protein translocate into the receptor and bind to it
repressor molec. = GDP release from the G protein
this allows GTP to bind
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7-Receptor activation causes
signalling complexes to form
how G protein couple receptor work
we can have all signalling mole. loose inside the cell
after the receptor become activated they all will bind to the receptor
assembling signal complexes
we have an inactive receptor
also we have signalling components very nearby
what holds these together is lipid raft
it is a big globe of cholesterol that stops these things from moving away
when we activate our receptor
all of the signalling molecules are very close by
we get a big complex that formed
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scaffold protein
all second messengers are either bound to a receptor =
called scaffold protein
scafold protein keeps all of Gpro. or enzymes very close to the receptor
RTKs and GPCRs activate many signalling pathways
NO MEMORISATION NEEDED
mishmash of signalling cascade that can occur
RTKs
phosphrylate enzymes
the pathway downstream of this activates lots of other second messengers
they all gain up on either:
transcription factors for
transcription regulations
other enzymes that are involved in cell methabolism
requires huge amount of integration to make cells function
GPCR
activates G protein
8- 2nd messengers
they enable certain functions to occur in any signalling schematic
often our cells will be exposed to very low number
of signalling molec.
so if you want big effects on cells from small
signals
you need to have amplifications of that signal
that is what second messenger allow
1 signalling molecule binding to 1 receptor
activates a kinase
that can phosphorylate thousands
of signalling molecules inside the cell
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you can also get spread of the signals not only local signalling event
in something such as nerves such as a meter long
signalling event at one end of the exon
and it will be spread to the other side of the axon
get spreading of the signal
integeration of lots of different signalling mechanisms
for example for PKC= protein Kinase C
2 different types os signalling mechanism
1- from G protein coupled receptor
2- from receptor tyrosine kinase
are both ending up in the same effector protein
we can get integration and modulation of lots
of signalling mechanisms
before we actually get the effect
EXAM:remember the common ones for the exam
the common molecules that we use inside cells down stream of these receptors
Second messengers
cyclic AMP= cyclic adonesin monophosphate
cyclic GMP: ' guanosin "
1,2- diacyl glycerol = DAG
IP3= Inositol 1,4,5 triphosphate = phospholipid
Ions= the most impo. signalling ion in terms of all cells signalling events is Ca 2+
Ca2+ kicks off a lot of cell signalling events that change how cells function
eg. protein kinase A PKA
it enters the nucleus and activates the transcription factors inside the nucleus`
lots of ways to activate protein kinase A
normally PKA is in its inactive form
G molecules binding to protein couple receptor
GPCR the associate and activate G proteins
G proteins then activate Cyclic AMP in cell signalling
cAMP will activate PKA
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eg. phospholipid signaling
in IP3 signalling : we have one of our signal transduction secondary messengers is tethered to the plasma memb.
when IP3 signalling is switched off these secondary messengers are actually held at the plasma membrane
to activate them we have to release them in the plasma membrane
so that they can diffuse through the cell and perform some sort of function
thethering to the plasma membrane is regulated by GPCR : G pro. coupled receptor
when we get a signal binding to a receptor it activates our G protein
G protein activates sth called phospholipase
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