Signal transduction in Epithelia I
When signalling molecules are sent out into the bloodstream,
most cells will have contact with this signalling molecule. But
only cells with the correct receptor can respond to this signal
(ligand). So when ligand binds to receptor, this causes an
activation of a effector which often is a enzyme. This enzyme
will produce second messenger (Note ligand is the first
messenger) which is a small chemical that goes off activing
more effector which is a enzyme that can go through a serious
of cascade pathways and eventually causing a cellular
response. Different cellular response could be present for the
same ligand depending on the cell.
Ligands can be water or lipid soluble, water solubles such as peptide hormones
cannot penetrate the plasma membrane so they bind to their receptor outside the
membrane, usually an integral membrane protein. Lipid soluble such as steroid and
thyroid hormones can diffuse through the plasma membrane so they bind their
receptor in the cytoplasm of cell.Also a negative feedback is present some way
along the pathway where it will act to decreae the signal and turn off the cellular
Lipid soluble ligands
aldosterone is a lipid soluble ligand that
enters the plasma membrane and binding
onto cytosol mineralocorticoid receptor.
Once this ligand and receptor complex is
formed, this complex then translocates into
the nucleus and acts as a transcription factor
with other components and activating
transcription of mRNA.Aexample is SGK
gene is activated, SGK is serine &
glucocodicoid regulated kinase.
SGK then will make more Na channels thus giving it a influx of Na ions.
Different ligand receptor complex will bind to different regions of DNA thus
expressing a different gene. Depending on what proteins are made, this will lead to
different cellular response.
RNApolmerase will help with transcription making a mRNAwhich then will go
through translation making protein, could be signalling molecule or enzyme etc. Aldosterone
Aldosterone are targetting the kidney collecting duct cells where signal transduction
will occur. It is a steroid hormone of the ineralocorticoid family produced by the
outer section of adrenal cortex called zona glomerulosa.
In a response to low blood pressure, kidney releases angiotensinogen which goes
through a serious of cacscade pathways in the blood and eventually turning into
angiotensin II.Angiotensin II can cause blood vlessels to constrict and driving
blood pressure up.
Angiotensin II and low blood pressure can also directly activate the release of
aldosterone from the adrenal cortex.Aldosterone travels in the blood via a carrier
protein to the kidney.Aldosterone then binds to the mineralocorticoid receptor
inside principal cells of the collecting duct of kidney and forms a transcription
This transcription factor complex then migrates into the nucleus where it will bind
to promoter DNAupstream of specific gene. The group of genes that aldosterone
promotes and binds to are called aldosterone-inducible genes on the DNA such as
the SGK kinase gene.
This gene then translates into aldosterone-induced proteins (AIPs) such as the SGK
kinase protein.AIPs then act to increase the number of epithelial sodium channels
at plasma membrane of collecting duct of kidney. This will increase Na re-
absorption via increasing Na channel (ENaC) on apical membrane. This then also
allow water to follow the Na. So Na and water re-enter the blood and increase in
blood volume and blood pressure increases.
This pathway takes about 1 hour to take effect and is a slow effect. There is a
negative feedback control, as you re-absorb more sodium and water back in to the
blood, this will cause a increase a blood pressure so “low blood pressure” stimuli is
lost and aldosterone release ceases.
signalling molecules that are water soluble cannot pass the bilayer of the phosphate
lipids, this means that their receptor must be found on the membrane. They can be
grouped into G protein coupled receptors (GPRC), enzyme-linked receptors and ion
channel linked receptors or ligand gated ion channels.
So a ligand bind to a transmembrane receptor forming a receptor-ligand complex.
conformational changes will then activate a closly related GTP protein which will
dissociate from the receptor and binding to effector such as enzyme or ion channel
(adenylyl cyclise). This then generate a second messenger (cAMP) which activates
a second effector such as kinases (PKA), leading to cellular response. So to switch off this cellular response, receptor can become inactivated called
desensitisation via phosphorylation. The receptor and the ligand can be taken up by
cells called downregulation via endocytosis. We can inactivate the G protein and
also negative feedback exists.
G protein have a active state where it can go and
act on the effector and also a inactive state. So
during activation, where GDP is released and
substituted for a GTP and G protein complex is
now activated.After awhile GTP will
hydrolysised, loosing a phosphate group and
becoming GDP again and inactivating it.
So associated with the GPCR, there will be a
inactive G protein closely associated with it. The
G protein is made up of 3 subunits of alpha, beta
and gamma. There are many different types of G
protien. In the absence of ligand the G protein is bound to receptor with alpha
subunit binding to GDP. When ligand binds to receptor this will cause alpha subunit
to bind to a GTP and dissociate from the beta and gamma subunits and it is now
activated. Then activated alpha subunit then will bind and activates its effector
(enzyme) while beta and gamma subunit may regulate ion channels directly. adenylyl cyclase, while another inhibitory G protien with
alpha-i subunit which will inhibit the effector of adenylyl
Epinephrine (adrenaline) or anti-diuretic
hormone (ADH) can activate the GPCR with
alpha-s subunit. This will in turn activate the
adenylyl cyclase effector which convertsATP
into cAMP (cyclicAMP). cAMP is a
secondary messenger and it acts on protein kinaseAand
activating it. PKAis made up of 2 catalytic subunit and 2
regulatory subunit, on binding of cAMP, the catalytic
subunits can be released and activated. Kinse can add
phosphate group onto substrates thus activating it, so PKA
activates a substrate by adding a additional phosphate group