Gs, The different isoforms of G-proteins mentioned above,

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Last updated: June 14, 2019

Gs, Gi and Gq are present in a familyof proteins called heterotrimeric G-proteins. These proteins are formed by acomplex of three different parts: alpha, beta and gamma subunits. Additionally,they are named ‘G’ proteins as they bind to purine nucleotides of guaninecalled guanine triphosphate (GTP) and guanine diphosphate (GDP). G-proteins areconsidered a class of membrane-bound proteins that regulate protein function,leading to control over the concentration of second messengers through asignalling cascade.

There are four different isoforms that G-proteins can bedivided into: Gs, Gi, Gq and G12/13; however, this essay willexplore the signalling pathways downstream of Gs, Gi and Gq. The signallingpathways involve G-protein coupled receptors (GPCRs) and secondary signallingcascades which regulate the function of specific proteins. Understanding of thefunction of these pathways begins with the roles of the various subunits.

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 The heterotrimeric G-proteins allcontain the three parts, with alpha being the largest and most active subunit.They are specialised proteins with the ability to bind guanine nucleotides. Thealpha subunit is considered the most active as it is the binding site of GTPand GDP which regulate the secondary cascade but the beta-gamma complex canmediate the same amount of functions. The GTP or GDP is often consideredanother subunit of the G protein as it regulates the function of the proteinwith its target. G proteins are very diverse as some can stimulate activity attheir target proteins and others inhibit it. The G protein is associated to theplasma membrane at the alpha and gamma subunit by lipid anchors. The beta-gammasubunits always remain as a heterodimer but can regulate function as a complexas well as modulating the alpha subunit.

Each subunit is a protein composed ofdifferent amino acids therefore they have different structures.  Generally, G-proteins function can bedescribed through the interaction of the different subunits with the targetproteins. As G-proteins are linked with the inner surface of the plasmamembrane, they interact with various intracellular proteins such as kinases,channels and GPCRs.

They perform a signalling cascade by acting as signaltransducers to communicate between extracellular hormones and neurotransmittersand their intracellular targets. The GPCRs are the link between theextracellular ligand, and the G-protein which will regulate intracellularfunction. The different isoforms of G-proteins mentioned above, have differenteffects on the proteins they regulate which leads to differences inconcentrations of the second messengers. GPCRs form receptors from manydifferent functions in the body, including adrenergic amines, acetylcholine andvisual receptors to name a few.  Approximately 865 genes in the humanbody code for GPCRs as they are so common and variable but only found ineukaryotes. Humans have over 1000 known GPCRs and each one has a specificfunction. They are activated by agonist ligands that cause a conformationalchange which is transmitted through the seven cytoplasmic, transmembrane loopsof the receptor.

The seven transmembrane alpha helices give it an uniqueappearance, specific to its function and secondary cascade. The conformationalchange leads to activation of the alpha site of the G-protein through bindingof GTP in replacement of GDP. The G proteins transduce signals from many GPCRsto the effector proteins such as ion channels and enzymes. Following this,changes in intracellular production, secretion or reduction of secondarymessengers occurs through regulation.GPCRs function under a lock and keymechanism with one or a few specific protein molecules. When the complementaryprotein ligand fits into the GPCR, it will result in a conformational change ofthe GPCR which triggers a complex secondary cascade, resulting in specific cellfunctions. As the conformational change occurs, the alpha subunit of the Gprotein exchanges the GDP for GTP.

As GTP is bound to the alpha subunit, itwill dissociate from the beta-gamma complex and bind to its target protein toregulate it. The alpha subunit and beta-gamma dimer can both interact andregulate the function of specific target proteins. Once activated, the targetprotein can relay signals via second messengers. This process between the GPCRand the G protein in the membrane can occur continuously while thecomplimentary ligand is bound to the GPCR site. The last process tore-establish the resting state is achieved through the hydrolysis of GTP toGDP. As GDP is now bound to the alpha subunit, it re-associates with thebeta-gamma dimer and the ligand detaches from the GPCR. The regulation of theprocess back to the normal state, has many methods in the body.

The main way isthrough the RGS (regulation of G protein signalling) protein.Water soluble hormones are an exampleof ligands that can bind to transmembrane proteins such as GPCRs. They arehydrophilic, and therefore cannot diffuse through the lipid bilayer. Atechnique for their action is binding to protruding integral transmembraneproteins in the plasma membrane. The hormone binding to the receptor is a firstmessenger action, which leads to secondary messenger activation. The bindingleads to G-protein molecules being activated which leads to a secondary cascadeof events.

An example of this binding is the G protein activation in skeletalmuscle. The action of epinephrine (adrenaline) on skeletal muscle highlightsthe role of G-proteins in the regulation of cyclic AMP (cAMP). As skeletalmuscle stores glucose as glycogen, when exercising, ATP is used in musclecontraction to convert the glycogen back to glucose. This process is initiatedby epinephrine secreted into the bloodstream from the adrenal medulla.

Increased epinephrine results in activation of the beta adrenoreceptor on themuscle membrane. This receptor is linked to G-proteins, as it stimulates thedissociation of the alpha subunit from the beta-gamma dimer and activatesadenyly cyclase. The next step is the increase in cAMP which leads to a furtherchain of enzyme activation which will eventually lead to the breakdown ofglycogen in glucose. Gs and Gi proteins have oppositefunctions on the concentration of cyclic AMP (cAMP). Receptors using Gs proteinclass are beta 1, beta 2, dopamine 1, histamine 2 and vasopressin 2. When thesereceptors are stimulated, it causes the Gs protein to activate adenlyl cyclasewhich converts ATP into cAMP. cAMP activates protein kinase A which increasesintracellular levels of calcium in the heart, leading to heart musclecontraction, smooth muscle relaxation and glycogenolysis. On the other hand,receptors using Gi class are M2, alpha 2 and dopamine 2.

When these receptorsare stimulated, the Gi protein will inhibit adenyly cyclase which leads to adecrease in cAMP and therefore a decrease in protein kinase A. The Gi proteinfunction example is when somatostatin inhibits the release of gastrin by Gcells in the gastric mucosa. This is the main signalling cascade throughactivation of these G proteins. The cAMP formed due to receptor activationbinds to other proteins such as enzymes and ion channels to regulate theirfunction. The change in concentration of this molecule regulates the functionof other proteins through the Gs and Gi proteins. Furthermore, once the adenylycylase is activated, it can produce many molecules of cAMP, so the cell canamplify the initial signal many times.

Only one cAMP molecule is needed toactivate another protein in the cell but the signal can be terminated throughthe conversion of cAMP to AMP by phosphodiesterases. The final form of G proteins discussedare Gq proteins. Receptors using G protein class Gq are H1, alpha 1, V1, M1 andM3. This is an important second messenger cascade starting at phospholipids inthe inner lining of the plasma membrane. The phospholipid commonly described isphosphatidyl inositol 4,5-bisphosphate. When the acetylcholine acts as thebinding ligand, muscarinic G protein receptors activate an enzyme calledphospholipase C, the plasma membrane cleaves the phospholipid into PIP2. ThePIP2 then splits by hydrolysis into two molecules: diacylglycerol (DAG) andinositol 1,4,5-triphosphate (IP3). Both products act asintracellular mediators and initiate a secondary messenger cascade.

IP3 is awater-soluble molecule that binds to an IP3 receptor to mobilise calcium fromthe store in the endoplasmic reticulum to be released intracellularly. Theincrease in calcium leads to activation of calcium depend events such as smoothmuscle contraction and enzyme secretion by pancreatic acinar cells. DAG is ahydrophobic molecule that is therefore retained in the membrane.

It can diffusein the plane of the membrane to stimulate activation of protein kinase C.Protein kinase C activation leads to phosphorylation of target proteins andregulation of various physiological responses. This is the secondary messengercascade for the Gq protein. Certain G proteins can be permanentlyactivated by bacterial toxins.

The change to the protein occurs throughcovalent modification of the alpha subunit of the G proteins or throughmutations in the generation process of cyclic AMP. An example of this is choleratoxin in intestinal epithelial cells. It is a deadly toxin produced by cholerabacteria. It modifies the G proteins in intestinal epithelial cells so theybecome permanently activated. This leads to a huge increase in theintracellular cAMP concentration. A secondary process of cAMP in these cells isto stimulate active transport of Cl- ions out into the lumen of the intestines.Due to a build up of Cl- ions in the lumen, water flows out of the cells viaosmosis and Na+ ions also follow the Cl- ions as they are attracted to thenegative charge build up in the lumen.

Cholera toxin effectively results insodium and chloride ions and water being excessively ejected into the faeces.The treatment for this involves a replacement of the lost fluids through oralrehydration therapy or intravenously and antibiotic therapy with tetracycline.Although these G-proteins are permanently activated, there are methods oftreatment to stop their effect and remove the initial binding ligand.In conclusion, the heterotrimericG-proteins can be divided into three forms: Gs, Gi and Gq. They each have adistinct signalling pathway which occurs due to the change in the subunits:alpha, beta and gamma.

The alpha subunit dissociation due to a change from GDPto GTP results in a secondary cascade of events which regulate theintracellular concentrations of various molecules. Gs and Gi affect cAMPconcentrations and Gq affects DAG and IP3. The G proteins are linked to GPCRswhich are activated when a ligand binds to their initial extracellular bindingsite via a lock and key mechanism. These receptors are unique as they haveseven transmembrane alpha helices. Finally, certain G proteins can be activatedin a permanent state due to bacterial toxins.

This occurs as the binding to theGPCR is constant which stimulates the activation of the G protein and thefollowing secondary cascade of events of the different G proteins.

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