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Describe the signalling pathways downstream of the heterotrimeric G proteins Gs, Gi and Gq

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 an 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 factors[1] to the cell through secondary messengers, such as a 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.

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 composition[2], 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 protein[3].

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 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 GCPR[4].

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 signaling 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 families[5] which make up the majority of G proteins found in the mammalian cell. Each initiate a unique downstream signaling 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 collaborators[6]. The first G-protein to be identified as the Gs which was found to activate and stimulate the production of adenylyl cyclase molecules. It catalyzes the conversion of ATP into the 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 catalyze 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 signaling sequence is eventually terminated by the action of phosphodiesterase, an enzyme which converts cAMP into AMP.

In the 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 fulfill 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 the 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 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 a-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 messenger’s diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) is generated. They function as intracellular mediators and both have different signaling pathways where they act as secondary messengers to achieve different effects[8].

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 reticulum[9]. 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 the smooth and cardiac muscle. DAG, on the other hand, is generated by the hydrolysis of phosphatidylinositol 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 an 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.

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