G protein coupled receptors and their Signaling Mechanism

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G Protein Coupled Receptors and their Signaling Mechanisms


G Protein Coupled Receptors

G Protein Coupled ReceptorsFaraza JavedMphil PharmacologyG Protein-Coupled ReceptorsG protein-coupled receptors(GPCRs), also known asseven-transmembrane domain receptors,7TM receptors,serpentine receptor, andG protein-linked receptors(GPLR), constitute a largeproteinfamily ofreceptorsthat sense moleculesoutside thecelland activate insidesignal transductionpathways and ultimately, cellular responses. They are called seven-transmembrane receptors because they pass through the cell membrane seven times.Theligandsthat bind and activate these receptors include: Light sensitive compoundsHormones andNeurotransmittersThat vary in size from small molecules topeptidesto largeproteins.Families of GPCR3 Families:A Rhodopsin familyB - Secretin/Glucagon receptor family eg. Peptide hormones.C - Metabotropic Glutamate familyeg. GABAB , Glutamate.

Rhodopsin Receptor FamilyRLRare afamilyofproteins comprise ofG protein-coupled receptors and are extremely sensitive to light. Itactivates the G proteintransducin(Gt) to activate thevisual phototransductionpathway.Mutation of the rhodopsin gene is a major contributor to various retinopathies.Remaining receptors areligandedby knownEndogenouscompounds.

Examples include receptor (FXR) farnesoid X receptor, which is activated bybile acid,liver X receptor(LXR), andperoxisome proliferator-activated receptor(PPAR).Secretin Receptor FamilyThe secretin-receptor family of GPCRs includeVasoactive intestinal peptide receptorsand receptors forsecretin,calcitoninand parathyroid hormone/parathyroid hormone-related peptides.These receptors activateadenylyl cyclaseand thephosphatidyl-inositol-calcium pathway.Metabotropic Glutamate FamilyThe metabotropic glutamate receptors (mGluRs) are family C GPCR that participate in the modulation of synaptic transmission and neuronal excitability throughout the central nervous system.They have been subdivided into three groups, based on intracellular signalling mechanisms.Group I mGlu receptors (coupled to PLC and intracellular calcium signalling).

Group IIGroup III receptors are negatively coupled to adenylyl cyclase.

These receptors are generally widely distributed throughout the mammalian brain with high levels in the cerebellum and thalamus. Structure of G ProteinG proteins, also known asguanine nucleotide-binding proteins,involved in transmitting signals and function as molecular switches. Their activity is regulated by factors that control their ability to bind to and hydrolyzeguanosine triphosphate(GTP) toguanosine diphosphate(GDP). When they bind GTP, they are 'on', and, when they bind GDP, they are 'off '.

G protein complexes are Made up ofalpha(),beta() and gamma()subunits.

Beta and gamma subunits can form a stable dimeric complex referred to as thebeta-gamma complex.

G proteins located within the cell are activated byGPCRs that span the cell membrane. Inside the cell, on the plasma membrane, G Protein binds GDP when inactive and GTP when active. When the GPCRs binds to a signal molecule, the receptor is activated and changes shape, thereby allowing it to bind to an inactive G Protein. When this occurs, GTP displaces GDP which activates the G Protein. The newly activated G Protein then migrates along the cell membrane until it binds to adenylyl cyclase which convert ATP to cAMP that leads to the next step in the pathway and generates a cellular response. After transduction, G Protein functions as a GTPase and hydrolyzes the bound GTP which causes a phosphate group to fall off. This regenerates GDP and inactivates the G Protein and the cycle repeats.

G Protein Mediated PathwaysSecondary messenger Systems Involved In Signal Transduction:Adenylate cyclase cAMP mediated pathway Phospholipase mediated pathway

cAMP Mediated Pathway

ThecAMP-dependent pathway, also known as theadenylyl cyclasepathway, is aG protein-coupled receptor triggeredsignaling cascade used incell communication.When a GPCR is activated by its extracellular ligand, a conformational change is induced in the receptor that is transmitted to an attached intracellularheterotrimeric G proteincomplex.TheGsalpha subunitof the stimulated G protein complex exchanges GDPforGTPand is released from the complex.

In a cAMP-dependent pathway, the activated Gsalpha subunit binds to and activates an enzyme calledadenylyl cyclase, which, in turn, catalyzes the conversion ofATPinto (cAMP).Gs cAMP Dependent Pathway Increases in concentration of thesecond messengercAMP may lead to the activation of an enzyme calledprotein kinase A(PKA).

The PKA enzyme is also known as cAMP-dependent enzyme because it gets activated only if cAMP is present. Many different cell responses are mediated by cAMP. These include increase in heart rate, cortisol secretion, and breakdown of glycogen and fat.GTPGDP GDPGTP ATP cAMPCell responseATProtein kinaseADPPInactive proteinActive proteinhormoneAdenylate cyclase Signaling SystemACRSInhibitorRiThis pathway can:Activate enzymesandRegulate gene expression

If cAMP-dependent pathway is not controlled, it can ultimately lead to hyper-proliferation, which may contribute to the development and/or progression ofcancer.

Alterations in number, structure or function of receptors will lead to disorder in cellular signal transduction.Up-regulation/hypersensitivity Down-regulation/desensitization Receptor Gene Mutation

HyperthyroidismHyperthyroidism, often calledoveractive thyroid, is a condition in which thethyroid gland producesand secretes excessive amounts of the thyroid hormones T3 and/or T4.Grave diseaseis the most common cause of hyperthyroidism.Mechanism: Thethyrotropin receptor(TSH receptor) responds tothyroid-stimulating hormone and stimulates the production ofthyroxine(T4) andtriiodothyronine(T3). The TSH receptor is a member of theG protein-coupled receptorand is coupled to theGsprotein. Mutation in TSHR gene (chromosome 14q31) lead to the hyperactivation of cAMP pathway results in hyperactivation of gland and make progress towards the development of tumor.Treatment:Antithyroid Medicine including Propylthiouracil, Methimazole and Carbimazole.Radioactive Iodine Cholera Toxin

Cholerais an infection of thesmall intestinecaused by thebacteriumVibrio cholerae.Mechanism:When cholera toxin is released from the bacteria in the infected intestine, it binds to the intestinal cells known as enterocytes. Toxin enters, where it activates the G protein Gsthrough an ADP-ribosylation reaction that acts to lock the G protein in its GTP-bound form, thereby continually stimulating adenylate cyclase to produce cAMP.Increased Gsactivation leads to increasedadenylate cyclase activity, which increases the intracellular concentration of cAMP to more than 100-fold over normal and over-activates cytosolicPKA. These active PKA then phosphorylate the cystic fibrosis transmembrane conductance regulator(CFTR) chloride channel proteins, which leads to ATP-mediated efflux ofchloride ionsand leads to secretion ofH2O,Na+,K+, andHCO3-into theintestinal lumen.In addition, the entry of Na+and consequently the entry of water into enterocytes are diminished. The combined effects result in rapid fluid loss from the intestine, leading to severedehydration.

G-protein modificationcholera lumen of intestine GsCTACcAMP Cl-H2ONa+CT--Cholera toxin Gs ribosylationTreatment:Rehydration. The goal is to replace lost fluids and electrolytes using a simple rehydration solution, oral rehydration salts (ORS). Intravenous fluids.Antibiotics.Zinc supplements.

Gi cAMP Dependent Pathway

Gimainly inhibits thecAMP dependent pathwayby inhibiting adenylate cyclase activity, decreasing the production ofcAMPfrom ATP, which, in turn, results in decreased activity ofcAMP-dependent protein kinase. Therefore, the ultimate effect of Giis the opposite ofcAMP-dependent protein kinase.When Gi receptors get activated, they release activatedG-protein- subunits from inactiveheterotrimeric G proteincomplexes. Gdimeric protein interacts with GIRK channels to open them so that they become permeable to potassium ions, resulting in hyperpolarization of the cell. These receptors are primarily found on heart as well as in brain.Atrial fibrillation(abnormal heart rhythm) is associated with shorter action potential duration and believed to be affected by the G protein-gated K+channel, IK,Ach. The IK,AChchannel, when activated by G proteins, allows the flow of K+across the plasma membrane and out of the cell. This current hyperpolarizes the cell, thus terminating the action potential. In chronic atrial fibrillation there is an increase in this inwardly rectifying current because of constantly activated IK,AChchannels.Increase in the current results in shorter action potential duration experienced in chronic atrial fibrillation and leads to the subsequent fibrillating of the cardiac muscle.Blocking IK,AChchannel activity could be a therapeutic target in atrial fibrillation and is an area under study.

Opioids are prescribed to treat chronic pain in different diseases, GIRK channels are activated by certain GPC opioid receptors, which leads to the inhibition of nociceptive transmission, thus functioning in pain relief.Studies have shown that G proteins directly activate GIRKs which were found to participate in propagation of morphine-induced analgesia in inflamed spines of mice.Research pertaining to chronic pain management continues to be performed in this field.GPC ReceptorsG ProteinReceptorsSignaling Pathway GSBeta adrenergic receptors, glucagon, histamine, serotonin

Increase Adenylyl cyclase CAMPExcitatory effectsGiAlpha2 adrenergic receptors, mAchR, opioid, serotonin

Decrease Adenylyl cyclase CAMP Cardiac K+ channel open- decrease heart rate


mAchR, serotoni


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