As human beings, our body faces modifications and variations all the
time due to fluctuations in both our external and internal environments.
Therefore, there is a constant need for adaptation to these changes in order to
keep cells alive and the entirety of our body effective. A set of structures
referred to as G proteins play and essential role to help the body adapt to the
fluctuations mentioned.

G-proteins are a family of membrane proteins, either monomeric or
heterotrimeric, which are bound to the inner surface of the cell membrane. They
can be described as a bridge that links the membrane receptor and the cellular
effector as they act as signal transducers which communicate signals from
various hormones, neurotransmitters, chemokines, and autocrine and paracrine
factors1
to the cell through secondary messengers, such as cyclic AMP or IP3.
The indeed interact with multiple cellular proteins, including ion channels,
their corresponding G-protein coupled receptors -also known as GCPRs-,
arrestins, and kinases.

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Heterotrimeric G-proteins are made up of three (-tri-) different
(hetero-) subunits as their name suggests: the alpha (Ga), the
largest which contains the site allowing GTP to be converted to GDP to enable
to renewal of the G-protein cycle, the beta (G?), and gamma (G?) subunits, each
with a different amino acid composition2,
and thus a different structure. When GDP binds the alpha subunit, this subunit
remains bound to the beta and gamma subunits, forming an inactive turmeric
protein3.

When an agonist binds GPCRs, it causes a conformational change that
is transmitted to the G-protein, activating this last one by replacing GDP (ADP
equivalent) with GTP (ATP equivalent). The release of the GDP molecule causes the
alpha subunit to dissociates from the beta-gamma dimer complex and become
‘active’. It is activated to mediate signal transduction through various
enzymes such as phospholipase C and adenylyl cyclase. The ?? dimer complex is
not fixed to the membrane and can migrate about the cell membrane, away from
the a subunit, while still remaining on the cytoplasmic side of this last
one because of its hydrophobic nature. This process only stops with the
hydrolysis of GTP to GDP, causing the alpha subunit and the ?? dimer to re-assemble and go back to its trimeric configuration,
which is ‘inactive’. This happens once the ligand or signal molecule is removed
from the GCPR4.

As we know of today, many different kinds of heterotrimeric
G-proteins exist, with around 20 known types of Ga units.
Despite their differences, they all act as biomedical switches that influence
ion channels or the rate of production of second messengers. They are proteins
that, through a series of events called signalling cascade, control the
concentrations of second messengers inside cells. These 20 types fall into 4
families of G proteins: the Gi, the GS, the Gq
and the G12/13 families5
which make up the majority of G proteins found in the mammalian cell. Each
initiate a unique downstream signalling pathway as the combinations of the
three subunits making up the heterotrimer are different. In this essay, we will
focus only on the first three categories, being Gs, G­I,
and Gq.

Alfred G. Gilman and his co-workers used biochemical and genetic
techniques to identify the first G-protein after the discovery of a link
between the hormone receptor and the amplifier by Martin Rodbell and his
collaborators6. The
first G-protein to be identified was the Gs which was found to
activate and stimulate the production of adenylyl cyclase molecules. It
catalyses the conversion of ATP into cyclic AMP (cAMP), a second messenger. Then,
cAMP binds protein kinase A.

Not long after this discovery, the Gi protein was
discovered and was found to inhibit the actions of the Gs protein,
thus reducing the production of adenylyl cyclase. Inside the cell, the cAMP
binds to other proteins such as ion channels to alter the cell activity. The Gq
protein is slightly different to the two others in that it is involved in the
inositol system rather than the cAMP system.

As mentioned before, cAMP binds to protein kinase A. Protein kinase
A is a heterotetramer composed of two types of subunits: catalytic and
regulatory whose activity depends upon the concentration of cAMP. Indeed, when
the concentration of cAMP is high, cAMP binds to active sites on the protein
kinase, provoking a conformational change which allows the protein kinase A to
release free catalytic subunits that can catalyse the phosphorylation of
threonine and serine residues on target proteins. On the other hand, when
concentrations of cAMP are low, the protein kinase is inactive as cAMP can’t
bind to it and therefore remains bound to a regulatory subunit dimer, unable to
release free catalytic subunits. This signalling sequence is eventually
terminated by the action of phosphodiesterase, an enzyme which converts cAMP
into AMP.

In human exercise, the essentiality of the Gs protein is
clearly illustrated. During the fed state, when glucose is abundant, skeletal
muscles work to convert this molecule into large polysaccharide molecules to
store energy for when it will be required. During exercise, the body yearns for
ATP therefore this glycogen is broken back down to glucose which will then go
through glycolysis to fulfil the muscle’s craving for ATP and then give rise to
muscle contraction. Indeed, during exercise, the sympathetic nervous system is
activated and chemical signals such as epinephrine secreted by the adrenal
medulla increase in the body’s blood circulation, thus increasing metabolic
levels. Increased levels of epinephrine in the system cause ?-adrenergic
receptors, a specific type of adrenergic receptor on the muscle membrane linked
to Gs proteins, to activate. Upon the activation of these receptors,
the GTP-binding protein dissociates, resulting in the activation of adenylyl
cyclase which then leads to higher concentrations of cAMP. cAMP activates
protein kinase A which goes on to activate glycogen phosphorylase, an enzyme
that facilitates the biological response of the breakdown of glycogen into
glucose that release ATP required for muscle contraction. It then makes it
clear that the activation of the Gs protein, more precisely the
production of second messenger, is important in allowing humans to have the
ability to increase their mobility.

Having seen that second messengers are key to human mobility, it is
important that they are constantly regulated to ensure the muscles respond only
when asked to. In opposition to Gs proteins, Gi proteins
are here to inhibit the production of adenylyl cyclase, causing the intracellular
concentration of cAMP to fall. This effect is notable when acetylcholine binds
to the GCPR muscarinic M2 AChR as once bound, the associated G
protein is activated and the ?? complex is
separated from the a subunit, making it free to open or interact with potassium channels
of the heart. This is a mechanism used by the parasympathetic nervous system to
slow down heart rate as it causes potassium ions to flow out of the cells and
therefore cells become less excitable.

We can affirm that Gq proteins are different from the two
other types, Gs and Gi as they mainly use the inositol
phosphate system as opposed to the cAMP system. We can nevertheless see
similarities between the different types. Indeed, similarly to Gs
proteins, Gq proteins are important in the body’s response to danger.
Gqa1 receptors once bound to
catecholamines induce constriction in blood vessels of the skin. Gq
proteins have been found to regulate the plasma-membrane-bound enzymes phospholipase
C-? (PLC?)7.
These enzymes are most commonly activated by GPCRs and heterotrimeric
G-proteins either by the release of ?-subunits of the Gq family or
by the ?? dimers from activated Gi family members. For example, acetylcholine
binds to GPCRs present on the pancreas inducing amylase secretion through the Gq
pathway, while vasopressin targets GPCRs in the liver which ultimately results
in glycogen breakdown. With the hydrolyzation of the phosphodiester bond of the
phosphatidylinositol 4,5-bisphosphate (PIP2) plasma membrane lipid,
the second messengers diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3)
are generated. They function as intracellular mediators and both have different
signalling pathways where they act as secondary messengers to achieve different
effects8.

Indeed, IP3 is a water-soluble molecule able to diffuse
through the cytoplasm and bind to its specific receptor to mobilize Ca2+
from the store within the endoplasmic reticulum9.
It initiates an efflux of Ca2+ ions, increasing its concentration
which leads to a set of different physiological responses such as hormone
secretion or the contraction of smooth and cardiac muscle. DAG on the other
hand is generated by the hydrolysis of phosphatidyl inositol is a hydrophobic
molecule and is retained in the membrane when IP3 is produced. Like many other
membrane lipids, DAG is able to diffuse in the plane of the membrane. In doing
so, it progresses to activate the enzyme protein kinase C (PKC). PKCs function
similarly to PKAs, but phosphorylate hydroxyl groups on targeted proteins such
as serine and threonine. They are able to generate various physiological
responses, such as increasing the rate of DNA transcription or receptor
activation.

 

Throughout this essay, we have seen that G-proteins, in our case Gs,
Gi and Gq proteins, are crucial in the many processes of the human system. They
indeed play an important role as intermediate between membrane receptor
activation and intracellular response which will eventually lead to a
physiological response. These G-proteins allow us to avoid and survive dangers
in everyday life and control even smaller ionic processes in the body, such as
the regulation of Ca2+ ions.

             

 

 

 

 

1 Neves, Susana
R., Prahlad T. Ram, and Ravi Iyengar. “G protein pathways.” Science 296.5573 (2002): 1636-1639.

2Pocock, G., Richards, C.,
& Richards, D. (2013). Human Physiology. OUP Oxford.

3 “Function of the
G-protein.” Function of the G-protein. N.p., n.d. Web. 05 Jan. 2017. .

4 Alberts, B.,
Johnson, A., Lewis, J., Raff, M., Roberts, K., & Walter, P. (2002).
Molecular biology of the cell. New York: Garland Science.

5 Neves, Susana R., Prahlad T. Ram, and Ravi Iyengar. “G
protein pathways.” Science 296.5573 (2002): 1636-1639.

6 “The Discovery of G Proteins”, https://www.nobelprize.org/nobel_prizes/medicine/laureates/1994/illpres/disc-gprot.html

7 Alberts, Bruce
et al. Molecular Biology of the Cell. 6th ed., New York, Garland
Science, 2014.

8 Alberts, Bruce
et al. Molecular Biology of the Cell. 6th ed., New York, Garland Science,
2014.

9 Pocock,
G., Richards, C., & Richards, D. (2013). Human Physiology. OUP Oxford.

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