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This essay describes the complex
pathway performed by the heterotrimeric G proteins which are very important in
our body. This is because it allows signal cascade and amplification. G
proteins are very important to regulate an incredible range of bodily
functions, ranging from sensation all the way to growth and to hormonal
responses.

 

Cells in the body will respond to the
chemical signals by initiating an appropriate physiological response. This
process is called transduction. There are four different ways in which
activation of a receptor can change the activity of a cell. First, opening of
an ion channel which allows membrane potential modulation. Second, activation
of membrane-bound enzyme which carries out a metabolic reaction. Third, activation
of a G protein-linked receptor which modulates an ion channel or alter the
intracellular concentration of a specific chemical called a second messenger.
Lastly, action on intracellular receptor to modulate the transcription of
specific genes. In this essay, we will be focusing on G-proteins.

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For G-proteins to work its magic, they
require a sidekick to function. Just like how batman requires robin to fight
crime. Which in this case is the G protein coupled receptors known as GPCRs. These
are the largest group of membrane receptors found in eukaryotes. It acts like
an inbox for your emails, receiving various messages from all around the body
in the form of different types of signals. Such as light energy, peptides,
lipids, sugars, and proteins. Many eukaryotes rely on GPCRs to receive
information from their environment. For example, a simple type of eukaryote
called yeast have GPCRs that sense glucose and mating factors that are present
in their environment.

 

GPCRs consist of a single strand of
polypeptide that is folded into a globular shape and embedded in a cell’s
plasma membrane. It contains 7 transmembrane alpha helices, hence having seven
segments of this molecule that spans the entire width of the membrane. Therefore,
GPCRs are known as seven-transmembrane receptors or even heptahelical receptor.

 

The intervening portions loop both
inside and outside the cell, the extracellular loops will form part of the site
where specific signaling molecules known as agonist will bind to, just like a
lock and key. When an extracellular agonist is bound, the GPCR will transmit
the signal from the agonist to the G-protein which lies intracellularly. Hence
this relays the signal to the cells.

 

The origin behind the name of G-protein
is simple, it is because they are specialized proteins with the ability to bind
to nucleotides guanosine triphosphate (GTP) and guanosine diphosphate (GDP). G-proteins
that are associated with GPCRs are all heterotrimeric, which means that they
have three different subunits. Which are an alpha subunit, a beta subunit and a
gamma subunit. The beta and gamma subunits are linked tightly together and
won’t separate. The alpha and gamma subunits both have lipid anchors which
allows them to be attached to the plasma membrane.

 

However monomeric G-proteins also
exist, but these G-proteins are not associated with GPCRs. They exist as small
proteins with a single subunit. They belong to the Ras superfamily of small
GTPases, they are like the alpha subunit found in the heterotrimers. However,
they can also bind to GTP and GDP just like the heterotrimers, and they are
involved in signal transduction.

 

The activation and inactivation of the
G-protein depends solely on whether the alpha subunit is bound to GTP or GDP.
If it binds to the GTP it is active, if it binds to the GDP it is inactive. So,
during the absence of a signal, the GDP will be attached to the alpha subunit,
and the entire G protein-GDP complex will bind to a nearby GPCR. In GDP-bound
conformation, GDP molecule is unable to leave the alpha subunit due to the
inhibition by the beta-gamma dimer, which stabilizes an inactive conformation
of the heterotrimeric G-protein.

 

To look in more detail, the alpha
subunit consists of two conserved domains, which are the GTP-ase domain and the
helical domain. GTP-ase domain is the area where hydrolysis of the GTP occurs and
provides the binding surface for the beta-gamma dimer, GPCR and the effector
proteins.

 

When a signaling molecule binds with
the GPCR, it will be activated. This means a change in conformation of the GPCR
will occur, which leads to the activation of the G-protein. The G-protein is
activated only when the GDP molecule is released from the alpha subunit and is
replaced by GTP molecule. This causes the G-protein to undergo conformational
changes, hence as a result the G protein will dissociate into two parts.

 

First part is the GTP-bound alpha
subunit, and the second part is the beta-gamma dimer. Both parts will remain
anchored to the plasma membrane, but they are no longer bound to the GPCR, this
allows the two complexes to diffuse laterally to interact with other membrane
proteins in the cell. G proteins will remain active as long as their alpha
subunits remain bound to the GTP.

 

Thus, both the alpha subunit and the
beta-gamma dimer activates different downstream effectors leading to different
physiological response. Targets for activated G proteins include various
enzymes that produce second messengers and ion channels that allow specific
ions to act as second messengers. Activation of one GPCR can activate more than
one G-protein, which leads to a signal cascade. Causing more enzymes to be
activated. G proteins basically work like a switch, which gets turned on and
off by signal-receptor interactions on the cell’s surface.

 

However, when the GTP is hydrolysed
back to GDP, the alpha subunit will become inactive once more and bind back
together with the beta-gamma dimer to form back the inactive heterotrimers.
Furthermore, the G-protein will re-associate with the inactive GPCR. Heterotrimeric
G proteins belong to a superfamily of regulator GTP hydrolyses that are divided
into main three classes based on the sequence of similarity of the alpha
subunit. Consist of Gs, Gi and Gq.

 

Gs, the “s” represents stimulatory,
this is a type of excitatory G-protein. This type stimulates the adenylyl
cyclase to produce cAMP. Gs is associated with the receptors for many hormones
such as adrenaline, glucagon, luteinizing hormone, parathyroid hormone,
adrenocorticotropic hormone. In humans, the cAMP is involved in responses that
are related to the sensory input, hormones and nerve transmissions.

 

Only one molecule of hormone or other
chemical mediator is required to activate the membrane receptor which in turn
activates more than one Gs. But each Gs can only activate one adenylyl cyclase,
but upon activation of a single adenylyl cyclase, it can produce many molecules
of cAMP from ATP. Hence this allows a cell to amplify the initial signal many
times. The signal is terminated by conversion of cAMP to AMP by enzymes known
as phosphodiesterase. Activity of adenylyl cyclase and phosphodiesterase determines
the intracellular concentration of cyclic AMP.

 

One example of this mechanism is the action
of epinephrine on skeletal muscle. Skeletal muscle stores glucose as glycogen
which is a large polysaccharide. During exercise, ATP is required to fuel
muscle contraction. ATP is obtained from the breakdown of glycogen to glucose.
This change in metabolism is triggered by the hormone epinephrine that is
secreted into the blood from the adrenal medulla.

 

Increased levels of circulating
epinephrine activate a kind of adrenergic receptor on the muscle membrane
called a beta-adrenergic receptor or beta-adrenoceptor. These receptors are
linked to Gs, and when the alpha subunit of Gs dissociates it activates adenylyl
cyclase. The activation of adenylyl cyclase leads to an increase in the
intracellular concentration of cAMP.

 

Eventually, cAMP activates another
enzyme called protein kinase A which will activate another enzyme called
glycogen phosphorylase which breaks glycogen down to glucose. Each individual step
progressively amplifies the initial signal and lead to the rapid production of
glucose.

However, the Gs is not all great and
dandy, it is also the target of the toxin release by Vibrio cholerae, which is
a type of bacterium that causes cholera. This bacterium can be commonly found
in tropical countries, because the vector is a female Anopheles mosquito. One
of the symptoms of this disease is that it causes diarrhea which leads to
dehydration of the body, in severe cases it might even cause death.

Once the cholera toxin that is released
enters the cytosol it will activate the Gs through an ADP-ribosylation reaction
that locks the G protein in its GTP-bound form, which causes it to remain in
the active state. Hence this causes continuous high levels of cAMP to be
produced, which results in a great loss of salts from the cells of the
intestinal epithelium. Water will follow by osmosis, hence this causes the
diarrhea.

 

Besides that, there are the Gi, the “i”
represents inhibitory. During activation the G protein inhibits adenylyl
cyclase, which results in the lowering of the level of cAMP in the cell. For
example, Gi will be switched on by the receptor for somatostatin, which are
secreted by the delta cells located in the islets of Langerhans. The
inactivation of the adenylyl cyclase will in turn activate protein kinase A
(PKA). Which leads to activation of cAMP responsive element-binding protein
(CREB), this molecule modulates gene transcription.

 

Activated Gi can have various effects
on the cells, such as activating the mitogen-activated protein kinase (MAPK)
and phosphatidylinositol 3-kinase (PI3K) pathways. This causes phosphorylation
of extracellular signal-regulated kinases (ERKs) and protein kinase B (PKB).
Hence, the activated PKB will phosphorylate and inhibit the action of glycogen
synthase kinase 3 beta, which is a major kinase in the brain.

 

Besides that, Gi can cause activation
of enzyme phospholipase A2 which induces the release of arachidonic acid (AA)
as well as inhibition of sodium-hydrogen ion exchanger in the plasma membrane.
The activation of Gi can also lower the intracellular levels of calcium ions due
to calcium channel closure. Furthermore, Gi protein causes the opening of
potassium ion channels via their beta-gamma dimer. Hence some of the effects
are smooth muscle contraction and depression of neuronal activity.

 

This pathway plays a role in modulating
calcium signaling and regulating the size of the releasable secretory pool,
rate of exocytosis and endocytosis. This is how somatostatin inhibits the
release of gastrin by the G cells of the gastric mucosa. Besides that,
Bordetella pertussis toxin (PTX), discovered as the islet-activating protein,
mediates the ADP ribosylation of Gi proteins.

 

Moving on, there is the Gq, this
activates the phospholipase C (PLC) which will generate the second messengers.
This membrane associated enzyme catalyzes the synthesis of inositol
triphosphate (IP3) and diacylglycerol (DAG) from the membrane lipid phosphatidyl
inositol. IP3 will bind to IP3 receptors, which are calcium channels in the
endoplasmic reticulum (ER).

Activation of these channels results in
the release of calcium ions from intracellular store sites, this causes the
concentration of calcium to increase, hence resulting intracellular change of
activity. Many cellular responses depend on this pathway. For example, enzymes
secretion by the pancreatic acinar cells and smooth muscle contraction.

 

Another role of IP3 receptors are that
there are involved in fertilization and is essential for determination of
dorso-ventral axis formation in a fetus. Besides that, Gq are normally found
with GPCR for vasopressin, thyroid-stimulating hormone (TSH) and angiotensin. This
pathway is also found in thrombin receptors in platelets to promote blood
clotting.

 

The diacylglycerol (DAG) that is
generated by hydrolysis of phosphatidyl inositol is a hydrophobic molecule. Hence
it is retained in the membrane when IP3 is formed. Due to it being hydrophobic,
it is able to diffuse in the phospholipid bilayer where it is able to interact
and activate another enzyme called protein kinase C. This enzyme activates
other enzymes and thereby regulates various cellular responses, such as DNA
transcription. Diacylglycerol (DAG) can also be metabolized to form arachidonic
acid.

 

In conclusion, G proteins plays a huge
role in cell signaling, which enables the body to grow and develop normally.
And provide correct reactions towards various environmental cues and develop
certain tolerance against any stressful conditions. Thus, it ensures the
survival of the organism.

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