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Lecture 22

BIOB11H3 Lecture Notes - Lecture 22: Pancreatic Juice, Signal Transduction, Autocrine Signalling


Department
Biological Sciences
Course Code
BIOB11H3
Professor
Dan Riggs
Lecture
22

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Lecture 22
Cellular Communication
Autocrine secretes some kind of signal but the cell also has receptor that recognizes
the signal it just sent
o A way for cell to regulates its own cell
Paracrine cell makes signal and cells that have receptors in its environment recognizes
this
Endocrine some cell or tissue that produces a signalling molecule and that hormone is
delivered to the blood stream where it can go and reach distant targets
15-2
o we have some type of signalling cell producing a signalling molecule like a
hormone
o this hormone is a first messenger takes the message to somewhere else
o Response of 2nd cell must have a receptor to receive the signal
o Depending on the cell type you can activate one of two pathway s
Effector and without effector
o Then many steps and depending on the pathway or the signal we can have
different results
Hormones produced in endocrine glands
o Delivered to circulatory systems
Berthold role of testis in male sexual development
Castrated roosters and observed that they displayed abnormal social behaviour and did
not develop secondary sex characteristics
When he transplanted the testis back they began to behave normally
o The transplanted testis had re-established a connection to the circulatory system
Some type of signalling molecule is produced by the testis which dictate
male sexual development
Bayliss and Starling
Injected acid to the small intestine to mimic signalling molecules this makes the animal
think it had a meal and there is secretion of pancreatic juice
Are nerve connections responsible for signaling?
o Severe the connection between the nerve and the pancreas
Pancreatic juice was produced so that means that the nerves are not the
carrier of that signal
o Put a clamp on the blood vessels
There is no secretion of pancreatic juice
There is some chemical message released by intestine and it is carried to
pancreas by circulatory system
Hormone was the term for these chemical messengers
Signal transduction pathways
STPS rely on changes in the phosphorylation of regulators
o Kinases phosphorylate, phosphatases take off phosphate group
Some targets are active when phophostyalted and others the opposite

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Provides the means to quickly regulate protein activity
Kinases
o Kinase 1 is now active that kinase looks for a target and it activates 2, and 2
activates 3 and 3 activates 4 and 4 was a transcription factor which conducts
changes in transcription
o What controls this?
G proteins
o Typically, membrane bound
o Transduce signal from receptor to effector
o Situated at plasma membranes to interact with receptor and effectors
o Ligand comes along and activates receptor which leads to the activation of the g
protein
Most g proteins are heterodimers
A and y subunits are linked to membrane bound lipids (post translational
modification) and this positions them at the plasma membrane where
they interact with receptor and effects
A sub unit is the active form
It will bind to GDP or GTP and only active in the GTP form
Most Ga subunits have GTPase activity, have activity that cleaves
GTP to make them inactive
o Effectors produce secondary messengers which are a way to amplify the signal
Modulation of G protein activity
Alpha becomes active
Ga activity depends on bound GTP
o Modulation of activity will centre on whether something is GTP or GDP bound
GDI’s
o Inactive G protein is in GDP bound form
o When GDI binds it keeps the inactive protein from releasing GDP and binding
GTP
o Keeps it inactive
o Signalling to downstream effects is interrupted
GEFs
o Allows the g protein to exchange GDP for GTP and this switches it on
GAPs
o Gtpase activating proteins, GAPS activate gtpase activity which hydrolyzes GTP
to GDP inactivating the g protein
o The concentration of the GAP protein is related to the duration of the signal
G protein signaling pathway
Blue box is the plasma membrane happening at the surface
Alpha has gdp so it is in it’s inactive form
At some time some ligand (ex.hormone) that interacts with the receptor this induces a
conformational change in the receptor that allows it to interact with the G protein
o Can only bind to G once it changes conformation

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This results in GDP being lost and gtp now binds to the alpha subunit
This activated receptor changes its structure and loses its affinity for beta and gamma
and alpha structure has changed and now it has affinity for the effector
o This effector is AC which is an enzyme that takes ATP and converts it into cyclic
ATP and this serves as a second messenger and this is where amplification takes
place
o Take a small amount of signal and amplifying that signal to produce the molecule
cAMP
Now GTP is cleaved and it is in the GDP form it’s conformation changes losing affinity for
AC and gains affinity for y and b and is in its inactive state
The receptor may still be being stimulated by whatever ligand binded to it
o We now need to turn off the receptor, the receptor gets phosphorylated by GRK
(a kinase)
o This is where the G protein would normally interact to stop the G protein from
associating with it, stopping further signalling
o Arrestin binds to the phosphates, the receptor will then become desensitized
and no G protein are activated
Arrestin mediated internalization of GPCRs
o Arrestin has affinity for both the receptor but also for the protein AP2 (clatherin
coated vesicle)
o Receptor has now interacted with this clatherin coated AP2 and endocytosis
takes place and now the receptor that was on the PM has now been brought into
the cell through an endosome
o Three possible fates:
Can build active signalling pathways on the endosomes, associates with
ERK
Could either become a lysosome or fuses with one and it is destroyed
(now cell is truly desensitized)
Desensitizing the cell to the signal and then return it to the cell
membrane through an endosome
G protein Coupled Receptors
o There are over 200 g protein coupled receptors in humans
o Over 1/3 of all prescription drugs act in G protein mediated signalling pathways
act as ligands that bind to receptors
mimics the binding of the signalling molecule
o Two pathways:
This could stimulate the receptor to up regulate your body
Or could inactivate the receptor to slow down the signalling of the ligand
pathway
o A mutation in the G protein receptor and that leads to a signalling problem
o Something could be wrong with the G protein itself (defective)
o G protein alpha subunits are coded by a gene family and some of them when
they are active are stimulatory promote signalling
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