OUTCOME 1: MOLECULAR MECHANISMS OF CELL SIGNALLING
GENERAL PRINCIPLES
Cells need to be able to respond to a wide range of biological signals including
hormones, odorants, growth factors, light, neurotransmitters…etc. Whatever
format this original signal takes, it is always extracellular; whilst the effect it elicits
is intracellular ie the signal has to be transduced across the membrane into the
cell. As you’ll see the responses generated by cells may seem very diverse but
the processes of detecting the extracellular signal (reception), and transducing it
into an intracellular effect are actually highly conserved.
Here we’ll focus on some of the best understood pathways with the aim of
understanding the themes they share as opposed to the precise detail involved.
This approach has been selected for a number of reasons:
(1)
signalling entails a myriad of stages: too many to remember them all
accurately
(2)
a number of pathways are not fully elucidated ie some components are
still being identified so details are constantly changing
(3)
some signalling molecules work by means which are not understood ie
no real detail of pathways are yet available.
With this in mind the other key points to highlight are that signal transducing
systems share a number of common features:
(1)
A high degree of specificity
This is due to the complementary interaction between the signalling
molecule and the receptor which detects it. This binding of a small ligand
by a receptor protein requires the same non-covalent interactions that
occur between enzymes/substrates and between antibodies/antigens.
These interactions include hydrogen bonds, Van der Waals forces,
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hydrophobic interactions and ionic bonds and require that the ligand binds
to a specific area on the receptor known as the binding site (cf active site
in enzymes).
A second factor contributing to specificity is the fact that not all cells
possess receptors for a given hormone. Hence, whilst insulin might affect
liver cells (hepatocytes), muscle cells (myocytes) and fat cells
(adipocytes), it won’t have an effect on epithelial cells. Also, even in cells
where a signal may bind to a receptor it’s not always the case that the
intracellular target of the signal will be present. For example, although
adrenaline binds to red blood cells (erythrocytes) it doesn’t alter glycogen
metabolism as it does in hepatocytes. Both cell types possess receptors
for this hormone but in erythrocytes the adrenaline-sensitive glycogen
metabolising enzyme is absent.
(2)
A high degree of sensitivity
The high affinity of receptors for the signalling molecules is the primary
factor underlying this level of specificity. Receptor proteins can bind
ligands at a level of picomolar concentrations (10-12 moles per litre). This
equates to a dissociation constant (Kd) in the region of 10-10M or smaller.
Another factor influencing sensitivity is the co-operative nature of ligand
binding. Here, binding of a small amount of ligand introduces
structural/conformational changes in the receptor which make it easier for
subsequent ligands to bind (cf oxygen binding to haemoglobin). As a
result of this co-operation, small changes in ligand concentration can
cause large changes in activity of the receptor ie the receptor appears
highly sensitive to subtle fluctuations in ligand concentration.
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The final factor contributing to sensitivity is the “cascade” nature of
signalling pathways. This effect sees a small amount of ligand having a
dramatic effect on a cell. The underlying mechanism is that receptor
occupancy triggers a series of reactions in which enzymes (often kinases)
activate enzymes. As each enzyme can activate many molecules of a
second enzyme the effect is amplified at each stage, with the result that a
single hormone molecule may alter the activity of tens of thousands of
protein molecules within a cell. This amplification, of several orders of
magnitude, can occur within milliseconds of the original receptor being
occupied by ligand.
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In summary then:
Signal interacts with
specific receptor.
Activated receptor
causes changes in
activity of a protein
within cell
(usually requires
few intermediate steps).
Cell undergoes change
in metabolic activity.
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RECEPTION
TRANSDUCTION
EFFECT
7
AMPLIFICATION VIA THE CASCADE EFFECT
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RECEPTORS
As already discussed, receptors are proteins (mainly glycoproteins) responsible
for the recognition and binding of specific molecules such as the hormone insulin.
They are generally found spanning the cell membrane (integral proteins)
although, as we’ll see later, some receptors are also found inside the cell
(intracellular proteins).
Cell-surface receptor
The extracellular face of the receptor is where high affinity binding of ligands
occurs. As stated earlier this requires the ligand to be a specific ‘shape ‘to bind to
the receptor and the interaction between the two is fully reversible, relying on
non-covalent bonding. Different cell types have different distributions of
receptors, so whilst ligands such as adrenaline may circulate in the blood, only
those cells with “adrenergic” receptors will respond.
Once a ligand binds to the receptor it induces a conformational change in the
protein which in turn leads to changes within the target cell. How these changes
occur forms the bulk of this outcome so let’s begin by considering the different
types of receptors.
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Categories of receptors
There are three main categories of receptors: G-protein coupled receptors; ionchannel receptors and tyrosine kinase receptors.

G-protein coupled receptors
This is the largest category of receptor, with many different cellular responses
resulting from activation of G-protein coupled receptors (GPCR). For example,
glycogen breakdown, secretion from mast cells, and pacemaker activity are all
influenced by G-protein coupled receptors.
Often described as serpentine receptors, the extracellular domain of this protein
is responsible for ligand binding, whilst a loop on the cytosolic side is responsible
for activating a G-protein (guanosine nucleotide binding protein; you will learn
more about G proteins later).
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G-proteins are located on the cytoplasmic face of the membrane and behave like
molecular switches as they are capable of being turned on and off. This
switching results from their intrinsic GTPase activity ie they have the ability to
hydrolyse GTP.
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Binding of a ligand to a GPCR activates the G-protein to swap or exchange GDP
for GTP (as shown in the previous diagram and on page 13). When the
triphosphate nucleotide (GTP) is bound, the G-protein is said to be active or
“switched on”. The active G-protein then dissociates from the receptor and
activates an effector such as an enzyme or ion channel. Having done this job,
the G-protein is then “switched off” by hydrolysing the GTP back to GDP,
releasing inorganic phosphate in the process.
GTP
GDP + Pi
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Examples of some of the hormones that work through such a GPCR are:
adrenaline, prostaglandin E1 and vasopressin.
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
Ion-channel receptors
These receptors span the cell membrane and act as pores to allow the passage
of ions such as Na+, K+, Cl-, and Ca2+. In general, an ion channel is selective for
the type of ion it allows through ie positive or negative ions but not both. Allowing
ions to move from one side of a membrane to the other causes a change in the
distribution of charge. In this way the receptor can influence change within the
cell.
Ion-channel receptors are found in excitable cells such as neurones and muscle
cells (myocytes). Here we focus on ligand-gated ion channels, with voltage gated
ion channels being discussed in Outcome 2. One of the best understood ligandgated ion channels is the nicotinic acetylcholine receptor. This protein is found at
nerve synapses and opens in response to the neurotransmitter acetylcholine or
in response to nicotine. The responsiveness of the protein to the presence of
such ligands gives this class of receptor their name: ligand-gated ion channels.
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Once the ligand has bound to the receptor, the ion channel changes
conformation, allowing the pore in the membrane to open and passage of ions
across the lipid bilayer to occur. When the ligand dissociates from the receptor
the channel will close up again, so blocking any further ion movement.
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
Tyrosine Kinase receptors
As the name implies, this category of receptor has intrinsic tyrosine kinase
activity. Here, activation of the receptor leads to autophosphorylation of certain
tyrosine residues (it phosphorylates itself) which further activates the receptor to
carry out its effect within the target cell.
The best characterised example of a TK receptor is the insulin receptor
This receptor is composed of two alpha subunits located on the extracellular side
of the membrane and two beta subunits that span the membrane. Insulin binds
to the alpha subunits and causes a conformational change. This results in
autophosphorylation of tyrosine residues in the carboxy terminus of the beta
subunits. Autophosphorylation causes enhanced activity of the tyrosine kinase
domain, which then phosphorylates other target proteins that mediate insulin’s
intracellular effects.
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Receptor desensitisation
The sensitivity of ligand/receptor interactions can be altered through a process
known as desensitisation. If the concentration of a ligand is persistently high, the
cell can adapt by activating a feedback mechanism that switches off the signal.
This feedback mechanism, termed desensitisation, can involve either switching
off the receptor itself or removing the receptor from the cell surface.
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Intracellular receptors
So far we have looked at signalling through cell surface receptors. Steroid
hormones however cause changes in cell activity through intracellular receptors.
Steroid hormones are lipophilic and can easily pass through the cell lipid bilayer.
These hormones regulate cell activity by binding to, and interacting with DNA.
The result is that DNA transcription and ultimately protein translation is affected.
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G PROTEINS
Previously we discussed guanosine-nucleotide binding proteins (G-proteins) only
in general terms. In this section you’ll see that this is actually a family of proteins,
the majority of which are heterotrimeric (made up of three different parts), and
involved in a myriad of cellular signalling pathways.
Heterotrimeric G-proteins are composed of three distinct subunits termed alpha
(), beta (), and gamma (). This protein complex is found associated with its
serpentine receptor in the membrane when the receptor is inactive (see diagram)
NB: we will discuss effectors in more detail later.
The diagram shows that the alpha subunit has GDP bound. In this state the
receptor/G-protein complex is inactive.
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Once a ligand binds to the receptor the conformational change that ensues
activates the G-protein complex, with the end result being that GDP is replaced
by GTP on the alpha subunit.
You should also notice that once the  subunit had GTP bound, it dissociates
from the  complex, which itself remains as a dimer. The  subunit stays
attached to the membrane but now interacts with the effector rather than with the
receptor. This interaction is only temporary, as the G-protein is “switched off” by
the GTPase activity of the  subunit. GTP is hydrolysed back to GDP and the 
subunit re-associates with the  dimer. The GPCR complex is thereby returned
to a resting state that can be reactivated by another ligand binding event.
G-proteins therefore function to transduce extracellular signals across the
membrane leading to changes within the cell. The changes that occur within the
target cell depend on the cell type and the GPCR in question; G-proteins regulate
the activity of a range of effector systems largely due to the existence of a
number of different subtypes of the  subunit.
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Main groups of  subunits
subunit
Effect
*Gs
Activates the enzyme adenylyl cyclase
*Gi
Inhibits the enzyme adenylyl cyclase
*Gq
Stimulates the enzyme phospholipase C
Golf
Involved in olfaction (smell)
Gt
Transduces visual signals in retina
G12/13
Regulates the cytoskeleton
* we will look at the specific effects of these subunits in the section on effectors.
Monomeric G-proteins
Composed of only a singe subunit, these G-proteins have similarities with the 
subunits of heterotrimeric G-proteins. This similarity is in their ability to exchange
GDP for GTP to become active, and then to hydrolyse the GTP to switch
themselves “off”.
In contrast to the G subunit however they are not directly associated with a
receptor. In fact, they are generally several steps away from an activated
tyrosine kinase receptor. Here receptor occupancy leads to the activation of a
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variety of adaptor proteins which ultimately lead to activation of the monomeric
G-protein. This family of G-proteins includes members such as ras, rho and rab,
with ras probably being the best understood.
This ability of ras to switch between an “off” and an “on” state is important in the
development of some human cancers. The enzyme cascades activated by ras
include those responsible for cell growth and proliferation. Thirty percent of
human cancers are linked to mutations in ras that prevent it from being switched
“off”; therefore these enzyme cascades are continually activated.
In summary, the G-protein superfamily is a major player in the process used to
convey information across the cell membrane. These proteins are able to
function over and over again as they are only ever activated transiently due to
their ability to hydrolyse GTP, and they are involved in cellular activities such as
gene expression, differentiation and growth. As a result, this group of proteins
are partly responsible for facilitating cells in adapting to their environment.
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EFFECTORS
Once a ligand has bound to its specific receptor, changes within the cell are
brought about by the interaction with an effector. So far, we have looked at the
different categories of receptor and in this section we’ll look at the effectors
employed in signal transduction pathways.
Cyclases

Adenylyl cyclase
This effector is an enzyme that’s part of the cell membrane; an integral protein.
The active site of adenylyl cyclase is located on the cytosolic side of the
membrane and it’s here that it catalyses the formation of cAMP (cyclic AMP) from
ATP (adenosine triphosphate). cAMP is known as a second messenger and it
acts to facilitate further changes within the cell (see later).
The activity of adenylyl cyclase itself is regulated by the  subunits of G-protein
complexes. In the previous section we mentioned 2 subtypes of  subunit which
affected adenylyl cyclase: Gs (stimulatory) and Gi(inhibitory).
As an example of Gs interaction with adenylyl cyclase, consider the ligand
adrenaline. This hormone binds to -adrenergic receptors in the cell membrane
leading to a conformational change which in turn activates the Gs protein
complex.
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As we’ve seen before this activation involves the replacement of GDP with GTP
on the alpha subunit (and the dissociation of ). With GTP bound, the active
Gs subunit moves towards the adenylyl cyclase effector and stimulates the
production of cAMP. Gs remain attached to the membrane throughout this
event.
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Due to its intrinsic GTPase activity the stimulation of adenylyl cyclase by Gsis
self-limiting. Gs-GTP hydrolyses back to G s-GDP.
In this format the alpha subunit can re-associate with , and the G-protein
heterotrimer is ready to undergo another activation cycle.
Interestingly, the  complex associated with the -adrenergic receptor has a role
in desensitisation. While Gs is in the process of stimulating adenylyl cyclase, the
 complex recruits other proteins to the membrane which bind to the
-adrenergic receptor and signal its internalisation. By internalising the receptor
in this way it is unable to bind any more ligand.
Finally, the bacterial toxin produced by the microbe responsible for cholera
prevents the GTPase activity of Gs. As a result Gs is constantly active and
cAMP is continually produced by adenylyl cyclase. Consequently, many of the
physiological responses to cholera toxin are due to this increased cAMP level.
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Adenylyl cyclase activity can also be affected by another subtype of G ; that is
Gi (inhibitory). As the name suggests, if a receptor is coupled to a G-protein
complex containing a Gi subunit then adenylyl cyclase activity is inhibited, so
cAMP will not be formed. Receptors such as the opiate receptors in brain, 1adrenergic receptors in platelets, and adenosine receptors in the heart are all
coupled to Gi.
Interestingly some cells/tissues possess both inhibitory and stimulatory
receptors. For example, cardiac tissue has both -adrenergic receptors (coupled
to Gs) and also adenosine receptors (coupled to Gi).
Because cardiac muscle has input from these two receptor classes, it is possible
to modulate the force of contraction through receptors and signal transduction
systems to rapidly meet the organism’s needs.
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
Guanylyl cyclase
Guanylyl cyclase is an effector that exists in two forms. It is an enzyme that
catalyses the production of the second messenger cyclic GMP (cGMP). The
precise role of this molecule will be described later but, as with cAMP, it acts to
facilitate changes within the target cell.
Guanosine 3’, 5’-cyclic
Guanosine triphosphate (GTP)
monophosphate (cGMP)
The two forms of guanylyl cyclase are discussed below:
(a)
Soluble guanylyl cyclase: an intracellular enzyme that is activated
by nitric oxide. This enzyme is found in smooth muscle tissue,
particularly in blood vessels. Here, activation of guanylyl cyclase
and the resultant production of cGMP, results in vasodilation
(widening of the blood vessels) and increased blood flow.
(b)
Membrane bound guanylyl cyclase
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Extracellular ligands that bind to receptors such as this are ANF
(atrial natruiretic factor) and guanylin. These ligands activate
cGMP formation and their receptors are found in renal ducts and in
intestinal tissue respectively.
Phospholipases
This family of enzymes all hydrolyse ester bonds in phospholipids (membrane
lipids) and are effectors in signal transduction pathways.

Phospholipase A2
A cytosolic enzyme, PLA2 is activated following the opening of calcium ion
channels. Once activated, the enzyme hydrolyses phospholipids such as
phosphatidylinositol, in the cell membrane to produce arachadonic acid. This
molecule can then mediate changes within the target cell.

Phospholipase C
A membrane bound effector, PLC is activated by occupancy of -adrenergic
receptors via Gq as depicted in the following diagram:
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Kinases
This family of enzymes regulate the activity of other proteins (primarily other
enzymes) by phosphorylating them. This addition of a phosphate residue to the
serine or threonine side chains usually results in a functional change in the target
protein. The kinases regulate many cellular pathways as illustrated below:

Protein Kinase A.
PKA is activated by cAMP and regulates proteins
involved in glycogen, sugar and lipid metabolism.

Protein Kinase C.
PKC is activated by calcium and DAG (see page 33).
This is a membrane bound enzyme which
phosphorylates target proteins involved in, amongst
other things, cellular proliferation and the cell cycle.

Ca2+/CaM Kinase. Regulated by calcium ions and a small protein known
as calmodulin, this kinase is involved in muscle
contraction and neurotransmitter secretion.
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SECOND MESSENGERS
Probably the best characterised second messenger molecule is cyclic AMP
(adenosine 3’,5’ cyclic monophosphate or cAMP).
This molecule is formed from the ubiquitous ATP by the action of adenylyl
cyclase as discussed earlier.
ATP
cAMP + PPi
[Hydrolysis of pyrophosphate (PPi) to inorganic phosphate (Pi) drives this
endergonic reaction]
cAMP is a very stable molecule and is used as a second messenger for many
hormones including adrenaline, glucagon, TSH, and vasopressin. The first
messenger (hormone) never actually enters the cell; rather its biological effects
are mediated inside the cell by cAMP. The cyclic nucleotide influences many
cellular processes, including platelet aggregation and glycogen metabolism, by
activating the protein kinase known as Protein Kinase A (PKA). PKA-mediated
phosphorylation of target proteins causes the range of biological effects.
In a similar manner, cGMP plays a critical role in the functioning of a number of
signalling molecules. It is synthesised in a reaction catalysed by guanylyl
cyclase (see earlier).
GTP
cGMP + PPi
cGMP = guanosine 3’,5’ cyclic monophosphate
This effector can be stimulated by receptor occupancy in some tissues (eg ANF
in the kidney, leading to altered ion transport) or directly by nitric oxide in other
tissues (eg in heart muscle this cause relaxation). cGMP is therefore a second
messenger which carries different messages in different tissues, most of its
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actions being mediated through a protein kinase known as PKG (protein kinase
G) which phosphorylates target proteins.
Other than cyclic nucleotides, phospholipid-derived molecules are the next major
class of second messenger. Hormones which use this type of second
messenger include angiotensin, adrenaline (2-subytpe of receptors) and
oxytocin.
The best understood second messengers in this category are inositol 1,4,5
trisphosphate (IP3) and diacylglycerol (DAG). These molecules are produced in
equimolar amounts by the hydrolysis of the membrane lipid phosphatidylinositol
4,5 bisphosphate (PIP2)
PI-4,5-P2
IP3 + DAG
IP3 is a water-soluble molecule so can diffuse from the membrane where it is
produced to the endoplasmic reticulum where specific IP3-receptors exist on the
membrane. IP3-occupancy of these receptors leads to release of calcium ions
from the ER by opening Ca2+-channels in the membrane. Ca2+ can act as a
second messenger in its own right (see later) but here it helps trigger the
activation of yet another protein kinase, PKC, which phosphorylates cellular
proteins leading to the biological effect of the original hormone. [Technically Ca2+
in this role would be a ‘third’ messenger!!]
The DAG molecule produced along with IP3 also acts as a second messenger; it
activates protein kinase C in conjunction with IP3.
Ca2+ ions, because they can activate Ca2+-dependent enzymes and trigger
intracellular responses are technically second messenger ‘molecules’. Calcium
is used as a second messenger in processes such as muscle contraction and
exocytosis. Normally calcium ions are sequestered within cells but can be
released (via ion channels) to cause abrupt changes in the intracellular calcium
concentration which can be used for signalling purposes. These changes in ion
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concentrations are detected by a small (17kD) protein known as calmodulin.
Ca2+ binding causes a conformational change in calmodulin resulting in the
protein becoming active ie it can interact with and modulate the activity of a
number of target proteins, one of the most important being the Ca2+/calmodulindependent protein kinase (CaM kinase). Yet again then a second messenger
leads to activation of a kinase whose phosphorylation of target proteins leads to
a biological change within the cell.
TERMINATION OF SIGNALS
Signal transduction exerts a change in the target cell but whatever the nature of
the signal the transduction event itself is terminated quite rapidly. Termination of
signal can involve: removal of hormone from the receptor; hydrolysis of GTP by
the G-protein (GDP-bound alpha subunits being inactive); degradation of the
second messenger molecule or reuptake of the second messenger molecule.
In the first example, hormone-receptor interactions utilise non-covalent bonds so
the binding is fully reversible. Hormones constantly associate with and
dissociate from receptors as the whole situation is a dynamic equilibrium:
H+R
HR
Degradation of the hormone molecule (or excretion from the body) means the
stimulus is eventually removed.
At the G protein stage the activation of the G protein is self-limiting due to the
inherent GTPase activity of this molecule.
At the level of the second messenger, Ca2+ can be taken up via ion channels to
be stored within the ER or the sacroplasmic reticulum ie reuptake of second
messenger terminates the signal. Alternatively, in the case of cAMP, cGMP,
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DAG and IP3, enzyme-catalysed hydrolysis is required to degrade the second
messenger.
IP3 is rapidly hydrolysed by phosphatase enzymes to remove the 5-phosphate
residue. This occurs within a few seconds and terminates IP3’s role as a second
messenger ie it is very short lived. Successive dephosphorylations by other
phosphatase covert the molecule back to inositol.
DAG can be hydrolysed to glycerol and free fatty acids or it can actually be
phosphorylated to yield phosphatidic acid.
[Note; degradation of phosphoinositol molecules yields an number of
intermediates which either have, or may yet be proven to have, signalling roles of
their own. For example, free fatty acids from DAG hydrolysis can include
arachadonic acid (C20) which is a signalling molecule in its own right and also
acts as the precursor for a series of hormones including prostaglandins.]
cAMP and cGMP are hydrolysed by enzymes known as phosphodiesterases. A
whole family of these enzymes exist in different cellular locations and with
different specificities. However, they all share the characteristic that they
catalyse the hydrolysis of the phosphoester bond to degrade cAMP (or cGMP) to
5’AMP (or 5’GMP)
5’AMP + H+
cAMP
H20
The 5’ monophosphate nucleotide is not active as a second messenger.
Summary of termination routes:
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A.
Stop production/release of ligand.
B.
Modify/remove receptor to prevent further binding.
C.
Turn ‘off’ the G-protein ie utilise the GTPase activity.
D.
Remove the second messenger eg reuptake or degradation.
E.
Reverse the modification of the target proteins eg dephosphorylate using
phosphatase enzymes.
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Taking these termination routes into account, how long does a hormone actually
‘work’ for? In terms of the duration of hormone action, it is believed to range from
about 20 minutes to several hours, depending on the hormone.
In cases where phosphorylations were mediated by CaM kinase, PKA, PKG,
insulin-receptor tyrosine kinase..etc dephosphorylation will terminate the effect of
the hormone. In each case this will be mediated by a phosphatase enzyme
which will cleave the phosphate moiety from the respective amino acid side
chains.
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Overall then it should be clear that by varying signalling components it is possible
to introduce diversity whilst sticking to a fairly common theme:
A.
Different potency of ligands at same receptor (discussed further in
Outcome 3).
B.
Different subtypes of receptors mediate different pathways.
C.
Different G proteins activate different effectors.
D.
Different isoforms of enzymes/ion channels mediate different pathways.
E.
Variation in downstream signalling components defines the cellular
response.
F.
Response depends on cell type.
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