As human beings, our body faces modifications and variations all thetime due to fluctuations in both our external and internal environments.Therefore, there is a constant need for adaptation to these changes in order tokeep cells alive and the entirety of our body effective. A set of structuresreferred to as G proteins play and essential role to help the body adapt to thefluctuations mentioned. G-proteins are a family of membrane proteins, either monomeric orheterotrimeric, which are bound to the inner surface of the cell membrane. Theycan be described as a bridge that links the membrane receptor and the cellulareffector as they act as signal transducers which communicate signals fromvarious hormones, neurotransmitters, chemokines, and autocrine and paracrinefactors1to 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.
Heterotrimeric G-proteins are made up of three (-tri-) different(hetero-) subunits as their name suggests: the alpha (Ga), thelargest which contains the site allowing GTP to be converted to GDP to enableto renewal of the G-protein cycle, the beta (G?), and gamma (G?) subunits, eachwith a different amino acid composition2,and thus a different structure. When GDP binds the alpha subunit, this subunitremains bound to the beta and gamma subunits, forming an inactive turmericprotein3.When an agonist binds GPCRs, it causes a conformational change thatis transmitted to the G-protein, activating this last one by replacing GDP (ADPequivalent) with GTP (ATP equivalent).
The release of the GDP molecule causes thealpha subunit to dissociates from the beta-gamma dimer complex and become’active’. It is activated to mediate signal transduction through variousenzymes such as phospholipase C and adenylyl cyclase. The ?? dimer complex isnot fixed to the membrane and can migrate about the cell membrane, away fromthe a subunit, while still remaining on the cytoplasmic side of this lastone because of its hydrophobic nature. This process only stops with thehydrolysis 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 removedfrom the GCPR4.As we know of today, many different kinds of heterotrimericG-proteins exist, with around 20 known types of Ga units.Despite their differences, they all act as biomedical switches that influenceion channels or the rate of production of second messengers. They are proteinsthat, through a series of events called signalling cascade, control theconcentrations of second messengers inside cells.
These 20 types fall into 4families of G proteins: the Gi, the GS, the Gqand the G12/13 families5which make up the majority of G proteins found in the mammalian cell. Eachinitiate a unique downstream signalling pathway as the combinations of thethree subunits making up the heterotrimer are different. In this essay, we willfocus only on the first three categories, being Gs, GI,and Gq.Alfred G.
Gilman and his co-workers used biochemical and genetictechniques to identify the first G-protein after the discovery of a linkbetween the hormone receptor and the amplifier by Martin Rodbell and hiscollaborators6. Thefirst G-protein to be identified was the Gs which was found toactivate and stimulate the production of adenylyl cyclase molecules. Itcatalyses 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 wasdiscovered and was found to inhibit the actions of the Gs protein,thus reducing the production of adenylyl cyclase. Inside the cell, the cAMPbinds to other proteins such as ion channels to alter the cell activity. The Gqprotein is slightly different to the two others in that it is involved in theinositol system rather than the cAMP system. As mentioned before, cAMP binds to protein kinase A.
Protein kinaseA is a heterotetramer composed of two types of subunits: catalytic andregulatory whose activity depends upon the concentration of cAMP. Indeed, whenthe concentration of cAMP is high, cAMP binds to active sites on the proteinkinase, provoking a conformational change which allows the protein kinase A torelease free catalytic subunits that can catalyse the phosphorylation ofthreonine and serine residues on target proteins. On the other hand, whenconcentrations of cAMP are low, the protein kinase is inactive as cAMP can’tbind to it and therefore remains bound to a regulatory subunit dimer, unable torelease free catalytic subunits. This signalling sequence is eventuallyterminated by the action of phosphodiesterase, an enzyme which converts cAMPinto AMP.In human exercise, the essentiality of the Gs protein isclearly illustrated. During the fed state, when glucose is abundant, skeletalmuscles work to convert this molecule into large polysaccharide molecules tostore energy for when it will be required.
During exercise, the body yearns forATP therefore this glycogen is broken back down to glucose which will then gothrough glycolysis to fulfil the muscle’s craving for ATP and then give rise tomuscle contraction. Indeed, during exercise, the sympathetic nervous system isactivated and chemical signals such as epinephrine secreted by the adrenalmedulla increase in the body’s blood circulation, thus increasing metaboliclevels. Increased levels of epinephrine in the system cause ?-adrenergicreceptors, a specific type of adrenergic receptor on the muscle membrane linkedto Gs proteins, to activate. Upon the activation of these receptors,the GTP-binding protein dissociates, resulting in the activation of adenylylcyclase which then leads to higher concentrations of cAMP. cAMP activatesprotein kinase A which goes on to activate glycogen phosphorylase, an enzymethat facilitates the biological response of the breakdown of glycogen intoglucose that release ATP required for muscle contraction. It then makes itclear that the activation of the Gs protein, more precisely theproduction of second messenger, is important in allowing humans to have theability to increase their mobility. Having seen that second messengers are key to human mobility, it isimportant that they are constantly regulated to ensure the muscles respond onlywhen asked to.
In opposition to Gs proteins, Gi proteinsare here to inhibit the production of adenylyl cyclase, causing the intracellularconcentration of cAMP to fall. This effect is notable when acetylcholine bindsto the GCPR muscarinic M2 AChR as once bound, the associated Gprotein is activated and the ?? complex isseparated from the a subunit, making it free to open or interact with potassium channelsof the heart. This is a mechanism used by the parasympathetic nervous system toslow down heart rate as it causes potassium ions to flow out of the cells andtherefore cells become less excitable. We can affirm that Gq proteins are different from the twoother types, Gs and Gi as they mainly use the inositolphosphate system as opposed to the cAMP system. We can nevertheless seesimilarities between the different types.
Indeed, similarly to Gsproteins, Gq proteins are important in the body’s response to danger.Gqa1 receptors once bound tocatecholamines induce constriction in blood vessels of the skin. Gqproteins have been found to regulate the plasma-membrane-bound enzymes phospholipaseC-? (PLC?)7.These enzymes are most commonly activated by GPCRs and heterotrimericG-proteins either by the release of ?-subunits of the Gq family orby the ?? dimers from activated Gi family members. For example, acetylcholinebinds to GPCRs present on the pancreas inducing amylase secretion through the Gqpathway, while vasopressin targets GPCRs in the liver which ultimately resultsin glycogen breakdown. With the hydrolyzation of the phosphodiester bond of thephosphatidylinositol 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 differentsignalling pathways where they act as secondary messengers to achieve differenteffects8.
Indeed, IP3 is a water-soluble molecule able to diffusethrough 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 concentrationwhich leads to a set of different physiological responses such as hormonesecretion or the contraction of smooth and cardiac muscle. DAG on the otherhand is generated by the hydrolysis of phosphatidyl inositol is a hydrophobicmolecule and is retained in the membrane when IP3 is produced. Like many othermembrane lipids, DAG is able to diffuse in the plane of the membrane. In doingso, it progresses to activate the enzyme protein kinase C (PKC). PKCs functionsimilarly to PKAs, but phosphorylate hydroxyl groups on targeted proteins suchas serine and threonine.
They are able to generate various physiologicalresponses, such as increasing the rate of DNA transcription or receptoractivation. 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. Theyindeed play an important role as intermediate between membrane receptoractivation and intracellular response which will eventually lead to aphysiological response. These G-proteins allow us to avoid and survive dangersin everyday life and control even smaller ionic processes in the body, such asthe regulation of Ca2+ ions.
1 Neves, SusanaR., 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 theG-protein.” Function of the G-protein. N.p.
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6 “The Discovery of G Proteins”, https://www.nobelprize.org/nobel_prizes/medicine/laureates/1994/illpres/disc-gprot.
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