15G Protein-coupled Receptor

8/9/2019 15G Protein-coupled Receptor

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G protein-coupled receptor

The seven-transmembrane -helix structure of a G protein

coupled receptor

G proteincoupled receptors(GPCRs), also known asseven-transmembrane domain receptors,7TM recep-tors,heptahelical receptors,serpentine receptor, andG proteinlinked receptors(GPLR), constitute a largeproteinfamily ofreceptorsthat sensemoleculesoutsidethecelland activate insidesignal transductionpathwaysand, ultimately, cellular responses. They are called seven-transmembrane receptors because they pass through thecell membrane seven times.

G proteincoupled receptors are found only ineukaryotes, including yeast, choanoflagellates,[2]

and animals. The ligands that bind and activate thesereceptors include light-sensitive compounds, odors,pheromones, hormones, and neurotransmitters, andvary in size from small molecules to peptidesto largeproteins. G proteincoupled receptors are involved inmany diseases, and are also the target of approximately40% of all modern medicinal drugs.[3][4] The 2012Nobel Prize in Chemistrywas awarded toBrian KobilkaandRobert Lefkowitz for their work that was crucialfor understanding how G proteincoupled receptorsfunction..[5] There have been at least seven otherNobelPrizesawarded for some aspect of G proteinmediatedsignaling.

There are two principal signal transduction pathways in-volving the G proteincoupled receptors:

thecAMPsignal pathway and

thephosphatidylinositolsignal pathway.[6]

When a ligand binds to the GPCR it causes a conforma-tional change in the GPCR, which allows it to act as a

guanine nucleotide exchange factor(GEF). The GPCRcan then activate an associatedG proteinby exchangingits boundGDPfor aGTP. The G proteins subunit, to-gether with the bound GTP, can then dissociate from the and subunits to further affect intracellular signalingproteins or target functional proteins directly dependingonthesubunittype(G,G/,G/,G/).[7]:1160

1 Classification

Classification Scheme of GPCRs. Class A (Rhodopsin-like),

Class B (Secretin-like),Class C (Glutamate Receptor-like), Oth-

ers (Adhesion (33), Frizzled (11), Taste type-2 (25), unclassified

(23)).[8]

The exact size of the GPCRsuperfamilyis unknown, butnearly 800 differenthuman genes(or 4% of the en-tireprotein-coding genome) have been predicted fromgenome sequence analysis.[8] Although numerous classifi-cation schemes have been proposed, the superfamily wasclassically divided into three main classes (A, B, and C)

with no detectable sharedsequence homologybetweenclasses.

The largest class by far is class A, which accounts fornearly 85% of the GPCR genes. Of class A GPCRs,over half of these arepredicted to encode olfactory recep-tors, while theremaining receptors are liganded by knownendogenous compoundsor are classified asorphan recep-tors. Despite the lack of sequence homology betweenclasses, all GPCRs have a commonstructureand mech-anism ofsignal transduction. The very large rhodopsinA group has been further subdivided into 19 subgroups(A1-A19).[9]

More recently, an alternative classification systemcalled GRAFS (Glutamate, Rhodopsin, Adhesion,Frizzled/Taste2, Secretin) has been proposed.[8]

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https://en.wikipedia.org/wiki/Secretin_receptorhttps://en.wikipedia.org/wiki/Taste_receptorhttps://en.wikipedia.org/wiki/Frizzledhttps://en.wikipedia.org/wiki/Adhesion-GPCRshttps://en.wikipedia.org/wiki/Rhodopsinhttps://en.wikipedia.org/wiki/Metabotropic_glutamate_receptorhttps://en.wikipedia.org/wiki/Rhodopsin-like_receptors#Classeshttps://en.wikipedia.org/wiki/Signal_transductionhttps://en.wikipedia.org/wiki/Protein_tertiary_structurehttps://en.wikipedia.org/wiki/Orphan_receptorhttps://en.wikipedia.org/wiki/Orphan_receptorhttps://en.wikipedia.org/wiki/Chemical_compoundhttps://en.wikipedia.org/wiki/Endogenoushttps://en.wikipedia.org/wiki/Ligand_(biochemistry)https://en.wikipedia.org/wiki/Olfactory_receptorshttps://en.wikipedia.org/wiki/Olfactory_receptorshttps://en.wikipedia.org/wiki/Sequence_homologyhttps://en.wikipedia.org/wiki/Sequence_analysishttps://en.wikipedia.org/wiki/Genomehttps://en.wikipedia.org/wiki/Protein_biosynthesishttps://en.wikipedia.org/wiki/Geneshttps://en.wikipedia.org/wiki/Humanhttps://en.wikipedia.org/wiki/Superfamily_(molecular_biology)https://en.wikipedia.org/wiki/G12/G13_alpha_subunitshttps://en.wikipedia.org/wiki/G%CE%B1qhttps://en.wikipedia.org/wiki/G%CE%B1ihttps://en.wikipedia.org/wiki/G%CE%B1shttps://en.wikipedia.org/wiki/Guanosine_triphosphatehttps://en.wikipedia.org/wiki/Guanosine_diphosphatehttps://en.wikipedia.org/wiki/G_proteinhttps://en.wikipedia.org/wiki/Guanine_nucleotide_exchange_factorhttps://en.wikipedia.org/wiki/Phosphatidylinositolhttps://en.wikipedia.org/wiki/Cyclic_adenosine_monophosphatehttps://en.wikipedia.org/wiki/G_proteinhttps://en.wikipedia.org/wiki/Nobel_Prizehttps://en.wikipedia.org/wiki/Nobel_Prizehttps://en.wikipedia.org/wiki/Robert_Lefkowitzhttps://en.wikipedia.org/wiki/Brian_Kobilkahttps://en.wikipedia.org/wiki/Nobel_Prize_in_Chemistryhttps://en.wikipedia.org/wiki/Proteinhttps://en.wikipedia.org/wiki/Peptidehttps://en.wikipedia.org/wiki/Neurotransmitterhttps://en.wikipedia.org/wiki/Hormonehttps://en.wikipedia.org/wiki/Pheromonehttps://en.wikipedia.org/wiki/Odorhttps://en.wikipedia.org/wiki/Ligand_(biochemistry)https://en.wikipedia.org/wiki/Choanoflagellatehttps://en.wikipedia.org/wiki/Yeasthttps://en.wikipedia.org/wiki/Eukaryotehttps://en.wikipedia.org/wiki/Signal_transductionhttps://en.wikipedia.org/wiki/Cell_(biology)https://en.wikipedia.org/wiki/Moleculehttps://en.wikipedia.org/wiki/Membrane_receptorhttps://en.wikipedia.org/wiki/Protein


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2 3 RECEPTOR STRUCTURE

By this system, GPCRs can be grouped into 6classes based on sequence homology and functionalsimilarity:[10][11][12][13]

Class A (or 1) (Rhodopsin-like)

Class B (or 2) (Secretin receptor family) ClassC (or3)(Metabotropic glutamate/pheromone)

ClassD(or4)(Fungal mating pheromone receptors)

Class E (or 5) (Cyclic AMP receptors)

Class F (or 6) (Frizzled/Smoothened)

The human genome encodes thousands of G protein-coupled receptors,[14] about 350 of which detect hor-mones, growth factors, and other endogenous ligands.Approximately 150 of the GPCRs found in the humangenome have unknown functions.

Some web-servers[15] and bioinformatics predictionmethods[16][17] have been used for predicting the classifi-cation of GPCRs according to their amino acid sequencealone, by means of thepseudo amino acid compositionapproach.

2 Physiological roles

GPCRs are involved in a wide variety of physiologicalprocesses. Some examples of their physiological roles in-

clude:

1. The visual sense: Theopsinsuse a photoisomeriza-tion reaction to translate electromagnetic radiationinto cellular signals. Rhodopsin, for example, usesthe conversion of 11-cis-retinal to all-trans-retinalfor this purpose

2. The gustatory sense (taste): GPCRs in taste cellsmediate release ofgustducinin response to bitter-and sweet-tasting substances.

3. The sense of smell: Receptors of the olfactoryepitheliumbind odorants (olfactory receptors) andpheromones (vomeronasal receptors)

4. Behavioral and mood regulation: Receptorsin the mammalian brain bind several differentneurotransmitters , includingserotonin, dopamine,GABA, andglutamate

5. Regulation of immune system activity andinflammation: Chemokine receptors bind ligandsthat mediate intercellular communication betweencells of the immune system; receptors such ashistamine receptors bind inflammatory mediatorsand engage target cell types in the inflammatory

response. GPCRs are also involved in immune-modulation and directly involved in suppression ofTLR-induced immune responses from T cells.[18]

6. Autonomic nervous system transmission: Both thesympathetic andparasympatheticnervous systemsare regulated by GPCR pathways, responsible forcontrol of many automatic functions of the bodysuch as blood pressure, heart rate, and digestive pro-cesses

7. Cell density sensing: A novel GPCR role in regulat-ing cell density sensing.

8. Homeostasis modulation (e.g., water balance).[19]

9. Involved in growth andmetastasisof some types oftumors.[20]

3 Receptor structure

GPCRs are integral membrane proteins that possess

seven membrane-spanning domains or transmembranehelices.[21][22] The extracellular parts of the receptor canbeglycosylated. These extracellular loops also containtwo highly conserved cysteine residues that form disulfidebondsto stabilize the receptor structure. Some seven-transmembrane helix proteins (channelrhodopsin)thatre-semble GPCRs may contain ion channels, within theirprotein.

Similar to GPCRs, the adiponectin receptors 1and 2 (ADIPOR1 and ADIPOR2) also possess 7transmembrane domains. However, ADIPOR1 andADIPOR2 are orientated oppositely to GPCRs in the

membrane (i.e., extracellularN-terminus, cytoplasmicC-terminus) and do not associate withG proteins.[23]

Early structural models for GPCRs were based on theirweak analogy to bacteriorhodopsin, for which a struc-ture had been determined by both electron diffraction(PDB 2BRD, 1AT9)[24][25] and X ray-based crystal-lography (1AP9).[26] In 2000, the first crystal struc-ture of a mammalian GPCR, that of bovinerhodopsin(1F88), was solved.[27] While the main feature, theseven-transmembrane helices, is conserved, the relative orien-tation of the helices differ significantly from that of bac-teriorhodopsin. In 2007, the first structure of a human

GPCR was solved (2R4R,2R4S).[28] This was followedimmediately by a higher resolution structure of the samereceptor (2RH1).[29][30] Thishuman2-adrenergic recep-torGPCR structure, proved highly similar to the bovinerhodopsin in terms of therelative orientation of theseven-transmembrane helices. However, the conformation ofthe second extracellular loop is entirely different betweenthe two structures. Since this loop constitutes the lidthat covers the top of the ligand binding site, this con-formational difference highlights the difficulties in con-structinghomology modelsof other GPCRs based onlyon the rhodopsin structure.

The structures of activated and/or agonist-bound GPCRshave also been determined.[31][32][33][34] These structuresindicate how ligand binding at the extracellular side of a
https://en.wikipedia.org/wiki/Homology_modelinghttps://en.wikipedia.org/wiki/Beta-2_adrenergic_receptorhttps://en.wikipedia.org/wiki/Beta-2_adrenergic_receptorhttp://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=2RH1http://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=2R4Shttp://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=2R4Rhttp://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=1F88https://en.wikipedia.org/wiki/Rhodopsinhttp://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=1AP9https://en.wikipedia.org/wiki/X-ray_crystallographyhttps://en.wikipedia.org/wiki/X-ray_crystallographyhttp://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=1AT9http://www.rcsb.org/pdb/explore/explore.do?structureId=2BRDhttps://en.wikipedia.org/wiki/Protein_Data_Bankhttps://en.wikipedia.org/wiki/Bacteriorhodopsinhttps://en.wikipedia.org/wiki/G_proteinhttps://en.wikipedia.org/wiki/C-terminushttps://en.wikipedia.org/wiki/N-terminushttps://en.wikipedia.org/wiki/Transmembrane_domainhttps://en.wikipedia.org/wiki/ADIPOR2https://en.wikipedia.org/wiki/ADIPOR1https://en.wikipedia.org/wiki/Channelrhodopsinhttps://en.wikipedia.org/wiki/Disulfide_bondhttps://en.wikipedia.org/wiki/Disulfide_bondhttps://en.wikipedia.org/wiki/Cysteinehttps://en.wikipedia.org/wiki/Glycosylationhttps://en.wikipedia.org/wiki/Transmembrane_helixhttps://en.wikipedia.org/wiki/Transmembrane_helixhttps://en.wikipedia.org/wiki/Integral_membrane_proteinhttps://en.wikipedia.org/wiki/Tumorhttps://en.wikipedia.org/wiki/Metastasishttps://en.wikipedia.org/wiki/Parasympathetic_nervous_systemhttps://en.wikipedia.org/wiki/Sympathetic_nervous_systemhttps://en.wikipedia.org/wiki/Inflammationhttps://en.wikipedia.org/wiki/Inflammationhttps://en.wikipedia.org/wiki/Inflammatory_mediatorshttps://en.wikipedia.org/wiki/Histamine_receptorshttps://en.wikipedia.org/wiki/Chemokinehttps://en.wikipedia.org/wiki/Inflammationhttps://en.wikipedia.org/wiki/Immune_systemhttps://en.wikipedia.org/wiki/Glutamatehttps://en.wikipedia.org/wiki/Gamma-aminobutyric_acidhttps://en.wikipedia.org/wiki/Dopaminehttps://en.wikipedia.org/wiki/Serotoninhttps://en.wikipedia.org/wiki/Neurotransmitterhttps://en.wikipedia.org/wiki/Brainhttps://en.wikipedia.org/wiki/Mammalhttps://en.wikipedia.org/wiki/Olfactory_epitheliumhttps://en.wikipedia.org/wiki/Olfactory_epitheliumhttps://en.wikipedia.org/wiki/Gustducinhttps://en.wikipedia.org/wiki/Rhodopsinhttps://en.wikipedia.org/wiki/Electromagnetic_radiationhttps://en.wikipedia.org/wiki/Opsinhttps://en.wikipedia.org/wiki/Pseudo_amino_acid_compositionhttps://en.wikipedia.org/wiki/Smoothenedhttps://en.wikipedia.org/wiki/Frizzledhttps://en.wikipedia.org/wiki/Cyclic_AMP_receptorshttps://en.wikipedia.org/wiki/Fungal_mating_pheromone_receptorshttps://en.wikipedia.org/wiki/Metabotropic_glutamate_receptorhttps://en.wikipedia.org/wiki/Class_C_GPCRhttps://en.wikipedia.org/wiki/Secretin_receptor_familyhttps://en.wikipedia.org/wiki/Rhodopsin-like_receptors


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3

receptor leads to conformational changes in the cytoplas-mic side of the receptor. The biggest change is an out-ward movement of the cytoplasmic part of the 5th and6th transmembrane helix (TM5 and TM6). The struc-ture of activated beta-2 adrenergic receptor in complexwith G confirmed that the G binds to a cavity created

by this movement.[35]

4 Structure-function relationships

Two-dimensional schematic of a generic GPCR set in a LipidRaft. Click the image for higher resolution to see details regarding

the locations of important structures.

In terms of structure, GPCRs are characterized by an ex-tracellular N-terminus, followed by seven transmembrane(7-TM)-helices(TM-1 to TM-7) connected by threeintracellular (IL-1 to IL-3) and three extracellular loops(EL-1 to EL-3), and finally an intracellular C-terminus.The GPCR arranges itself into a tertiary structure re-sembling a barrel, with the seven transmembrane helicesforming a cavity within the plasma membrane that servesa ligand-binding domain that is often covered by EL-2. Ligands may also bind elsewhere, however, as is thecase for bulkier ligands (e.g.,proteinsor largepeptides),which instead interact with the extracellular loops, or, asillustrated by the class Cmetabotropic glutamate recep-tors(mGluRs), the N-terminal tail. The class C GPCRsare distinguished by their large N-terminal tail, whichalso contains a ligand-binding domain. Upon glutamate-binding to an mGluR, the N-terminal tail undergoes aconformational change that leads to its interaction withthe residues of the extracellular loops and TM domains.The eventual effect of all three types ofagonist-inducedactivation is a change in the relative orientations of the

TM helices (likened to a twisting motion) leading to awider intracellular surface and revelation of residues ofthe intracellular helices and TM domains crucial to signal

transduction function (i.e., G-protein coupling). Inverseagonistsandantagonistsmay also bind to a number ofdifferent sites, but the eventual effect must be preventionof this TM helix reorientation.

The structure of the N- and C-terminal tails of GPCRs

may also serve important functions beyond ligand-binding. For example, The C-terminus of M3muscarinicreceptors is sufficient, and the six-amino-acid polyba-sic (KKKRRK) domain in the C-terminus is necessaryfor its preassembly with G proteins.[36] In particular,the C-terminus often containsserine(Ser) orthreonine(Thr) residues that, when phosphorylated, increase theaffinityof the intracellular surface for the binding ofscaffolding proteins called -arrestins(-arr).[37] Oncebound, -arrestins bothstericallyprevent G-protein cou-pling and may recruit other proteins, leading to the cre-ation of signaling complexes involved in extracellular-signal regulated kinase (ERK) pathway activation or re-

ceptorendocytosis(internalization). As the phosphory-lation of these Ser and Thr residues often occurs as a re-sult of GPCR activation, the -arr-mediated G-protein-decoupling and internalization of GPCRs are importantmechanisms ofdesensitization.[38]

A final common structural theme among GPCRs ispalmitoylation of one or more sites of the C-terminaltail or the intracellular loops. Palmitoylation is the co-valent modification ofcysteine(Cys) residues via addi-tion of hydrophobicacyl groups, and has the effect oftargeting the receptor tocholesterol- andsphingolipid-rich microdomains of the plasma membrane calledlipid

rafts. As many of the downstream transducer and ef-fector molecules of GPCRs (including those involved innegative feedbackpathways) are also targeted to lipidrafts, this has the effect of facilitating rapid receptor sig-naling.

GPCRs respond to extracellular signals mediated bya huge diversity of agonists, ranging from proteins tobiogenic aminestoprotons, but all transduce this signalvia a mechanism of G-protein coupling. This is madepossible by aguanine-nucleotide exchange factor (GEF)domain primarily formed by a combination of IL-2 andIL-3 along with adjacent residues of the associated TM

helices.

5 Mechanism

The G protein-coupled receptor is activated by an exter-nal signal in the form of a ligand or other signal media-tor. This creates a conformational change in the receptor,causing activation of aG protein. Further effect depends

on the type of G protein. G proteins are subsequently in-activated by GTPase activating proteins, known asRGSproteins.
https://en.wikipedia.org/wiki/Regulator_of_G_protein_signallinghttps://en.wikipedia.org/wiki/Regulator_of_G_protein_signallinghttps://en.wikipedia.org/wiki/G_proteinhttps://en.wikipedia.org/wiki/Guanine_nucleotide_exchange_factorhttps://en.wikipedia.org/wiki/Guaninehttps://en.wikipedia.org/wiki/Protonshttps://en.wikipedia.org/wiki/Biogenic_amineshttps://en.wikipedia.org/wiki/Negative_feedbackhttps://en.wikipedia.org/wiki/Lipid_rafthttps://en.wikipedia.org/wiki/Lipid_rafthttps://en.wikipedia.org/wiki/Sphingolipidhttps://en.wikipedia.org/wiki/Cholesterolhttps://en.wikipedia.org/wiki/Acylhttps://en.wikipedia.org/wiki/Cysteinehttps://en.wikipedia.org/wiki/Palmitoylationhttps://en.wikipedia.org/wiki/Desensitization_(medicine)https://en.wikipedia.org/wiki/Endocytosishttps://en.wikipedia.org/wiki/Extracellular_signal-regulated_kinaseshttps://en.wikipedia.org/wiki/Stericallyhttps://en.wikipedia.org/wiki/Arrestinhttps://en.wikipedia.org/wiki/Affinity_(pharmacology)https://en.wikipedia.org/wiki/Phosphorylationhttps://en.wikipedia.org/wiki/Threoninehttps://en.wikipedia.org/wiki/Serinehttps://en.wikipedia.org/wiki/Receptor_antagonisthttps://en.wikipedia.org/wiki/Inverse_agonistshttps://en.wikipedia.org/wiki/Inverse_agonistshttps://en.wikipedia.org/wiki/Agonisthttps://en.wikipedia.org/wiki/Metabotropic_glutamate_receptorshttps://en.wikipedia.org/wiki/Metabotropic_glutamate_receptorshttps://en.wikipedia.org/wiki/Peptidehttps://en.wikipedia.org/wiki/Proteinhttps://en.wikipedia.org/wiki/Ligand_(biochemistry)https://en.wikipedia.org/wiki/Protein_tertiary_structurehttps://en.wikipedia.org/wiki/C-terminushttps://en.wikipedia.org/wiki/Alpha_helixhttps://en.wikipedia.org/wiki/Transmembrane_domainhttps://en.wikipedia.org/wiki/N-terminus


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4 5 MECHANISM

Cartoon depicting the basic concept of GPCR ConformationalActivation. Ligand binding disrupts an ionic lock between the

E/DRY motif of TM-3 and acidic residues of TM-6. As a re-

sult, the GPCR reorganizes to allow activation of G-alpha pro-

teins. The side perspective is a view from above and to the side

of the GPCR as it is set in the plasma membrane (the membrane

lipids have been omitted for clarity). The intracellular perspec-

tive shows the view looking up at the plasma membrane from

inside the cell.[39]

5.1 Ligand binding

GPCRs include: receptors for sensory signal media-tors (e.g., light and olfactory stimulatory molecules);adenosine, bombesin, bradykinin, endothelin, -aminobutyric acid (GABA), hepatocyte growth factor(HGF),melanocortins,neuropeptide Y,opioidpeptides,opsins,somatostatin,GH,tachykinins, members of thevasoactive intestinal peptide family, and vasopressin;biogenic amines (e.g., dopamine, epinephrine,norepinephrine, histamine, glutamate (metabotropiceffect),glucagon,acetylcholine(muscarinic effect), and

serotonin);chemokines;lipidmediators ofinflammation(e.g., prostaglandins, prostanoids, platelet-activatingfactor, and leukotrienes); and peptide hormones (e.g.,calcitonin, C5a anaphylatoxin, follicle-stimulating hor-mone (FSH), gonadotropin-releasing hormone (GnRH),neurokinin, thyrotropin-releasing hormone (TRH),cannabinoids, and oxytocin). GPCRs that act as re-ceptors for stimuli that have not yet been identified areknown asorphan receptors.

However, in other types of receptors that have been stud-ied, wherein ligands bind externally to the membrane,the ligandsof GPCRs typically bind within the trans-

membrane domain. However,protease-activated recep-torsare activated by cleavage of part of their extracellulardomain.[40]

5.2 Conformational change

Crystal structure of activated beta-2 adrenergic receptor in com-

plex with Gs(PDBentry3SN6). The receptor is colored red, G

green, G cyan, and G yellow. The C-terminus of G is located

in a cavity created by an outward movement of the cytoplasmic

parts of TM5 and 6.

The transduction of the signal through the membraneby the receptor is not completely understood. It isknown that in the inactive state, the GPCR is bound toaheterotrimeric G proteincomplex. Binding of an ago-nist to the GPCR results in aconformationchange in thereceptor that is transmitted to the bound G subunit ofthe heterotrimeric G protein. The activated G subunitexchangesGTPin place ofGDPwhich in turn triggersthe dissociation of G subunit from the G dimer andfrom the receptor. The dissociated G and G subunitsinteract with other intracellular proteins to continue the

signal transduction cascade while the freed GPCR is ableto rebind to another heterotrimeric G protein to form anew complex that is ready to initiate another round ofsignal transduction.[41]

It is believed that a receptor molecule exists in a con-formational equilibrium between active and inactive bio-physical states.[42] The binding of ligands to the recep-tor may shift the equilibrium toward the active receptorstates.[43] Three types of ligands exist: Agonists are lig-ands that shift the equilibrium in favour of active states;inverse agonistsare ligands that shift the equilibrium infavour of inactive states; and neutral antagonists are lig-

ands that do not affect the equilibrium. It is notyet knownhow exactly the active and inactive states differ from eachother.
https://en.wikipedia.org/wiki/Inverse_agonisthttps://en.wikipedia.org/wiki/Guanosine_diphosphatehttps://en.wikipedia.org/wiki/Guanosine_triphosphatehttps://en.wikipedia.org/wiki/Protein_structurehttps://en.wikipedia.org/wiki/Heterotrimeric_G_proteinhttps://en.wikipedia.org/wiki/Signal_transductionhttp://www.rcsb.org/pdb/cgi/explore.cgi?pdbId=3SN6https://en.wikipedia.org/wiki/Protein_Data_Bankhttps://en.wikipedia.org/wiki/Protease-activated_receptorhttps://en.wikipedia.org/wiki/Protease-activated_receptorhttps://en.wikipedia.org/wiki/Ligand_(biochemistry)https://en.wikipedia.org/wiki/Orphan_receptorhttps://en.wikipedia.org/wiki/Oxytocinhttps://en.wikipedia.org/wiki/Cannabinoidhttps://en.wikipedia.org/wiki/Thyrotropin-releasing_hormonehttps://en.wikipedia.org/wiki/Neurokininhttps://en.wikipedia.org/wiki/Gonadotropin-releasing_hormonehttps://en.wikipedia.org/wiki/Follicle-stimulating_hormonehttps://en.wikipedia.org/wiki/Anaphylatoxinhttps://en.wikipedia.org/wiki/Calcitoninhttps://en.wikipedia.org/wiki/Leukotrieneshttps://en.wikipedia.org/wiki/Platelet-activating_factorhttps://en.wikipedia.org/wiki/Platelet-activating_factorhttps://en.wikipedia.org/wiki/Prostanoidhttps://en.wikipedia.org/wiki/Prostaglandinshttps://en.wikipedia.org/wiki/Inflammationhttps://en.wikipedia.org/wiki/Lipidhttps://en.wikipedia.org/wiki/Chemokineshttps://en.wikipedia.org/wiki/Serotoninhttps://en.wikipedia.org/wiki/Muscarinichttps://en.wikipedia.org/wiki/Acetylcholinehttps://en.wikipedia.org/wiki/Glucagonhttps://en.wikipedia.org/wiki/Metabotropichttps://en.wikipedia.org/wiki/Glutamatehttps://en.wikipedia.org/wiki/Histaminehttps://en.wikipedia.org/wiki/Norepinephrinehttps://en.wikipedia.org/wiki/Epinephrinehttps://en.wikipedia.org/wiki/Dopaminehttps://en.wikipedia.org/wiki/Biogenic_aminehttps://en.wikipedia.org/wiki/Vasopressinhttps://en.wikipedia.org/wiki/Vasoactive_intestinal_peptidehttps://en.wikipedia.org/wiki/Tachykininshttps://en.wikipedia.org/wiki/Growth_hormonehttps://en.wikipedia.org/wiki/Somatostatinhttps://en.wikipedia.org/wiki/Opsinhttps://en.wikipedia.org/wiki/Opioidhttps://en.wikipedia.org/wiki/Neuropeptide_Yhttps://en.wikipedia.org/wiki/Melanocortinhttps://en.wikipedia.org/wiki/Hepatocyte_growth_factorhttps://en.wikipedia.org/wiki/Gamma-aminobutyric_acidhttps://en.wikipedia.org/wiki/Endothelinhttps://en.wikipedia.org/wiki/Bradykininhttps://en.wikipedia.org/wiki/Bombesinhttps://en.wikipedia.org/wiki/Adenosinehttps://en.wikipedia.org/wiki/Olfactory


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5.4 Crosstalk 5

5.3 G-protein activation/deactivation cycle

Cartoon depicting the Heterotrimeric G-protein activa-tion/deactivation cycle in the context of GPCR signaling

See also:G protein

When the receptor is inactive, theGEFdomain may bebound to an also inactive -subunit of a heterotrimericG-protein. These G-proteins are atrimerof , , and subunits (known as G, G, and G, respectively) thatis rendered inactive when reversibly bound toGuanosinediphosphate (GDP) (or, alternatively, no guanine nu-cleotide) but active when bound toGuanosine triphos-phate(GTP). Upon receptor activation, the GEF domain,in turn,allostericallyactivates the G-protein by facilitat-ing the exchange of a molecule of GDP for GTP at theG-proteins -subunit. The cell maintains a 10:1 ratio ofcytosolic GTP:GDP so exchange for GTP is ensured. Atthis point, the subunits of the G-protein dissociate fromthe receptor, as well as each other, to yield a G-GTPmonomerand a tightly interactingG dimer, which arenow free to modulate the activity of other intracellularproteins. The extent to which they maydiffuse, how-ever, is limited due to thepalmitoylationof G and thepresence of an isoprenoid moiety that has been covalently

added to the C-termini of G.Because G also has slowGTPGDP hydrolysiscapa-bility, the inactive form of the -subunit (G-GDP) iseventually regenerated, thus allowing reassociation witha G dimer to form the resting G-protein, which canagain bind to a GPCR and await activation. The rateof GTP hydrolysis is often accelerated due to the ac-tions of another family of allosteric modulating proteinscalledRegulators of G-protein Signaling, or RGS pro-teins, which are a type ofGTPase-Activating Protein, orGAP. In fact, many of the primaryeffectorproteins (e.g.,adenylate cyclases) that become activated/inactivated

upon interaction with G-GTP also have GAP activity.Thus, even at this early stage in the process, GPCR-initiated signaling has the capacity for self-termination.

5.4 Crosstalk

Proposed downstream interactions between integrin signaling

and GPCRs. Integrins are shown elevating Ca2+ and phosphory-

lating FAK, which is weakening GPCR signaling.

GPCRs downstream signals have been shown to possi-bly interact withintegrinsignals, such asFAK.[44] Inte-grin signaling will phosphorylate FAK, which can thendecrease GPCR Gs activity.

6 GPCR signaling

If a receptor in an active state encounters aG protein, itmay activate it. Some evidence suggests that receptorsand G proteins are actually pre-coupled.[36] For example,binding of G proteins to receptors affects the receptorsaffinity for ligands. Activated G proteins are bound toGTP.

Further signal transduction depends on the type of G pro-tein. The enzymeadenylate cyclaseis an example of a

cellular protein that can be regulated by a G protein, inthis case the G proteinG. Adenylate cyclase activity isactivated when it binds to a subunit of the activated Gprotein. Activation of adenylate cyclase ends when the Gprotein returns to theGDP-bound state.

Adenylate cyclases (of which 9 membrane-bound and onecytosolic forms are known in humans) may also be acti-vated or inhibited in other ways (e.g., Ca2+/Calmodulinbinding), which can modify the activity of these enzymesin an additive or synergistic fashion along with the G pro-teins.

The signaling pathways activated through a GPCR are

limited by theprimary sequenceandtertiary structureofthe GPCR itself but ultimately determined by the par-ticularconformationstabilized by a particularligand, as
https://en.wikipedia.org/wiki/Ligand_(biochemistry)https://en.wikipedia.org/wiki/Protein_conformationhttps://en.wikipedia.org/wiki/Tertiary_structurehttps://en.wikipedia.org/wiki/Protein_primary_structurehttps://en.wikipedia.org/wiki/Calmodulinhttps://en.wikipedia.org/wiki/Guanosine_diphosphatehttps://en.wikipedia.org/wiki/Gs_alpha_subunithttps://en.wikipedia.org/wiki/Adenylate_cyclasehttps://en.wikipedia.org/wiki/Guanosine_triphosphatehttps://en.wikipedia.org/wiki/G_proteinhttps://en.wikipedia.org/wiki/PTK2https://en.wikipedia.org/wiki/Integrinhttps://en.wikipedia.org/wiki/Integrinhttps://en.wikipedia.org/wiki/Adenylate_cyclasehttps://en.wikipedia.org/wiki/Effector_(biology)https://en.wikipedia.org/wiki/GTPase_activating_proteinhttps://en.wikipedia.org/wiki/Regulator_of_G_protein_signallinghttps://en.wikipedia.org/wiki/GTP-asehttps://en.wikipedia.org/wiki/Covalent_bondhttps://en.wikipedia.org/wiki/Isoprenoidhttps://en.wikipedia.org/wiki/Palmitoylationhttps://en.wikipedia.org/wiki/Diffusehttps://en.wikipedia.org/wiki/Beta-gamma_complexhttps://en.wikipedia.org/wiki/Monomerhttps://en.wikipedia.org/wiki/Allostericallyhttps://en.wikipedia.org/wiki/Guanosine_triphosphatehttps://en.wikipedia.org/wiki/Guanosine_triphosphatehttps://en.wikipedia.org/wiki/Guanosine_diphosphatehttps://en.wikipedia.org/wiki/Guanosine_diphosphatehttps://en.wikipedia.org/wiki/Protein_trimerhttps://en.wikipedia.org/wiki/Heterotrimeric_G-proteinhttps://en.wikipedia.org/wiki/Heterotrimeric_G-proteinhttps://en.wikipedia.org/wiki/Guanine_nucleotide_exchange_factorhttps://en.wikipedia.org/wiki/G_protein


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6 6 GPCR SIGNALING

G-protein-coupled receptor mechanism

well as the availability of transducermolecules. Cur-rently, GPCRs areconsidered to utilize two primary typesof transducers: G-proteinsand -arrestins. Because -arrs have highaffinityonly to thephosphorylatedformof most GPCRs (see above or below), the majority ofsignaling is ultimately dependent upon G-protein activa-tion. However, the possibility for interaction does allowfor G-protein-independent signaling to occur.

6.1 G-protein-dependent signaling

There are three main G-protein-mediated signaling path-ways, mediated by foursub-classesof G-proteins distin-guished from each other bysequence homology (G,G/,G/, andG/). Each sub-class of G-protein

consists of multiple proteins, each the product of multi-plegenesand/orsplice variationsthat may imbue themwith differences ranging from subtle to distinct with re-

gard to signaling properties, but in general they appearreasonably grouped into four classes. Because the signaltransducing properties of the various possible combi-nations do not appear to radically differ from one another,these classes are defined according to the isoform of their-subunit.[7]:1163

While most GPCRs are capable of activating more thanone G-subtype, they also show a preference for onesubtype over another. When the subtype activated de-pends on the ligand that is bound to the GPCR, thisis called functional selectivity (also known as agonist-directed trafficking, or conformation-specific agonism).However, the binding of any single particular agonist mayalso initiate activation of multiple different G-proteins,as it may be capable of stabilizing more than one con-formation of the GPCRs GEF domain, even over thecourse of a single interaction. In addition, a conforma-tion that preferably activates oneisoformof G may ac-

tivate another if the preferred is less available. Further-more, feedbackpathways may result in receptor modi-fications(e.g., phosphorylation) that alter the G-proteinpreference. Regardless of these various nuances, theGPCRs preferred coupling partner is usually defined ac-cording to the G-protein most obviously activated bytheendogenousligand under mostphysiologicaland/orexperimentalconditions.

6.1.1 G signaling

1. The effector of both the G and G/ pathways

is the cyclic-adenosine monophosphate (cAMP)-generating enzymeadenylate cyclase, or AC. Whilethere are ten different AC gene products in mam-mals, each with subtle differences intissuedistribu-tion and/or function, allcatalyzethe conversion ofcytosolic adenosine triphosphate(ATP) to cAMP,and all are directly stimulated by G-proteins of theG class. In contrast, however, interaction with Gsubunits of the G/ type inhibits AC from gener-ating cAMP. Thus, a GPCR coupled to G coun-teracts the actions of a GPCR coupled to G/, andvice versa. The level of cytosolic cAMP may then

determine the activity of various ion channels as wellas members of theser/thr-specific protein kinase A(PKA) family. Thus cAMP is considered asecondmessengerand PKA a secondaryeffector.

2. The effector of the G/ pathway isphospholipaseC- (PLC), which catalyzes the cleavageof membrane-bound phosphatidylinositol 4,5-biphosphate (PIP2) into the second messen-gers inositol (1,4,5) trisphosphate (IP3) anddiacylglycerol(DAG). IP3 acts on IP3 receptorsfound in the membrane of theendoplasmic reticu-lum(ER) to elicitCa2+ release from the ER, while

DAG diffuses along the plasma membranewhereit may activate any membrane localized forms ofa second ser/thr kinase called protein kinase C
https://en.wikipedia.org/wiki/Protein_kinase_Chttps://en.wikipedia.org/wiki/Plasma_membranehttps://en.wikipedia.org/wiki/Ca2+https://en.wikipedia.org/wiki/Endoplasmic_reticulumhttps://en.wikipedia.org/wiki/Endoplasmic_reticulumhttps://en.wikipedia.org/wiki/Inositol_trisphosphate_receptorhttps://en.wikipedia.org/wiki/Diglyceridehttps://en.wikipedia.org/wiki/Inositol_trisphosphatehttps://en.wikipedia.org/wiki/Phosphatidylinositol_4,5-bisphosphatehttps://en.wikipedia.org/wiki/Phosphatidylinositol_4,5-bisphosphatehttps://en.wikipedia.org/wiki/Phospholipase_Chttps://en.wikipedia.org/wiki/Phospholipase_Chttps://en.wikipedia.org/wiki/Effector_(biology)https://en.wikipedia.org/wiki/Second_messenger_systemhttps://en.wikipedia.org/wiki/Second_messenger_systemhttps://en.wikipedia.org/wiki/Protein_kinase_Ahttps://en.wikipedia.org/wiki/Serine/threonine-specific_protein_kinasehttps://en.wikipedia.org/wiki/Cyclic_nucleotide-gated_ion_channelhttps://en.wikipedia.org/wiki/Adenosine_triphosphatehttps://en.wikipedia.org/wiki/Cytosolichttps://en.wikipedia.org/wiki/Catalyzehttps://en.wikipedia.org/wiki/Tissue_(biology)https://en.wikipedia.org/wiki/Adenylyl_cyclasehttps://en.wikipedia.org/wiki/Cyclic_amphttps://en.wikipedia.org/wiki/Experimentalhttps://en.wikipedia.org/wiki/Physiologicalhttps://en.wikipedia.org/wiki/Endogenoushttps://en.wikipedia.org/wiki/Post-translational_modificationhttps://en.wikipedia.org/wiki/Post-translational_modificationhttps://en.wikipedia.org/wiki/Feedbackhttps://en.wikipedia.org/wiki/Isoformhttps://en.wikipedia.org/wiki/Guanine_nucleotide_exchange_factorhttps://en.wikipedia.org/wiki/Agonisthttps://en.wikipedia.org/wiki/Functional_selectivityhttps://en.wikipedia.org/wiki/Beta-gamma_complexhttps://en.wikipedia.org/wiki/Beta-gamma_complexhttps://en.wikipedia.org/wiki/Splice_varianthttps://en.wikipedia.org/wiki/Geneshttps://en.wikipedia.org/wiki/G12/G13_alpha_subunitshttps://en.wikipedia.org/wiki/G%CE%B1qhttps://en.wikipedia.org/wiki/G%CE%B1ihttps://en.wikipedia.org/wiki/G%CE%B1shttps://en.wikipedia.org/wiki/Sequence_homologyhttps://en.wikipedia.org/wiki/Class_(biology)https://en.wikipedia.org/wiki/Phosphorylatedhttps://en.wikipedia.org/wiki/Affinity_(pharmacology)https://en.wikipedia.org/wiki/Arrestinhttps://en.wikipedia.org/wiki/G-proteinshttps://en.wikipedia.org/wiki/Transducer


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7

(PKC). Since many isoforms of PKC are also acti-vated by increases in intracellular Ca2+, both thesepathways can also converge on each other to signalthrough the same secondary effector. Elevatedintracellular Ca2+ also binds andallostericallyacti-vates proteins calledcalmodulins, which in turn go

on to bind and allosterically activate enzymes suchasCa2+/calmodulin-dependent kinases(CAMKs).

3. The effectors of the G/ pathway are threeRhoGEFs (p115-RhoGEF, PDZ-RhoGEF, andLARG), which, when bound to G/ allostericallyactivate the cytosolic small GTPase, Rho. Oncebound to GTP, Rho can then go on to activate vari-ous proteins responsible forcytoskeletonregulationsuchas Rho-kinase(ROCK). Most GPCRs that cou-ple to G/ also couple to other sub-classes, oftenG/.

6.1.2 G signaling

The above descriptions ignore the effects of Gsignalling, which can also be important, in particular inthe case of activated G/-coupled GPCRs. The pri-mary effectors of G are various ion channels, suchasG-protein-regulated inwardly rectifying K+ channels(GIRKs),P/Q- andN-type voltage-gated Ca2+ channels,as well as some isoforms of AC and PLC, along withsome phosphoinositide-3-kinase(PI3K) isoforms.

6.2 G-protein-independent signaling

Although they are classically thought of workingonly together, GPCRs may signal through G-protein-independent mechanisms, and heterotrimeric G-proteinsmay play functional roles independent of GPCRs.GPCRs may signal independently through many proteinsalready mentioned for their roles in G-protein-dependentsignaling such as -arrs, GRKs,and Srcs. In addition, fur-ther scaffolding proteins involved insubcellular localiza-tionof GPCRs (e.g.,PDZ-domain-containing proteins)may also act as signal transducers. Most often the effec-tor is a member of theMAPKfamily.

6.2.1 Examples

In the late 1990s, evidence began accumulating to suggestthat some GPCRs are able to signal without G proteins.TheERK2mitogen-activated protein kinase, a key sig-nal transduction mediator downstream of receptor acti-vation in many pathways, has been shown to be activatedin response to cAMP-mediated receptor activation in theslime moldD. discoideumdespite the absence of the as-

sociated G protein - and -subunits.[45]

In mammalian cells, the much-studied 2-adrenoceptorhas been demonstrated to activate the ERK2 pathway af-

ter arrestin-mediated uncoupling of G-protein-mediatedsignaling. Therefore, it seems likely that some mecha-nisms previously believed related purely to receptor de-sensitisation are actually examples of receptors switch-ing their signaling pathway, rather than simply beingswitched off.

In kidney cells, the bradykinin receptor B2 has beenshown to interact directly with a protein tyrosine phos-phatase. The presence of a tyrosine-phosphorylatedITIM(immunoreceptor tyrosine-based inhibitory motif)sequence in the B2 receptor is necessary to mediate thisinteraction and subsequently the antiproliferative effectof bradykinin.[46]

6.2.2 GPCR-independent signaling by het-

erotrimeric G-proteins

Although it is a relatively immature area of research, itappears that heterotrimeric G-proteins may also take partin non-GPCR signaling. There is evidence for roles assignal transducers in nearly all other types of receptor-mediated signaling, including integrins, receptor tyro-sine kinases(RTKs),cytokine receptors(JAK/STATs),as well as modulation of various other accessory pro-teins such asGEFs,Guanine-nucleotide Dissociation In-hibitors (GDIs) andprotein phosphatases. There mayeven be specific proteins of these classes whose pri-mary function is as part of GPCR-independent pathways,

termedActivators of G-protein Signalling(AGS). Boththe ubiquity of these interactions and the importance ofG vs. G subunits to these processes are still unclear.

7 Details of cAMP and PIP2 path-

ways

Activation effects of cAMP on protein kinase A

There are two principal signal transduction pathways in-volving theG protein-linked receptors: thecAMPsignalpathway and thephosphatidylinositolsignal pathway.[6]
https://en.wikipedia.org/wiki/Phosphatidylinositolhttps://en.wikipedia.org/wiki/Cyclic_adenosine_monophosphatehttps://en.wikipedia.org/wiki/G_protein-coupled_receptorshttps://en.wikipedia.org/wiki/Activators_of_G-protein_Signallinghttps://en.wikipedia.org/wiki/Protein_phosphataseshttps://en.wikipedia.org/wiki/Guanosine_nucleotide_dissociation_inhibitorshttps://en.wikipedia.org/wiki/Guanosine_nucleotide_dissociation_inhibitorshttps://en.wikipedia.org/wiki/Guanine_nucleotide_exchange_factorhttps://en.wikipedia.org/wiki/JAK-STAT_signaling_pathwayhttps://en.wikipedia.org/wiki/Cytokine_receptorshttps://en.wikipedia.org/wiki/Receptor_tyrosine_kinaseshttps://en.wikipedia.org/wiki/Receptor_tyrosine_kinaseshttps://en.wikipedia.org/wiki/Integrinshttps://en.wikipedia.org/wiki/Immunoreceptor_tyrosine-based_inhibitory_motifhttps://en.wikipedia.org/wiki/Bradykinin_receptor_B2https://en.wikipedia.org/wiki/Dictyostelium_discoideumhttps://en.wikipedia.org/wiki/Slime_moldhttps://en.wikipedia.org/wiki/MAPK1https://en.wikipedia.org/wiki/MAPKhttps://en.wikipedia.org/wiki/PDZ_(biology)https://en.wikipedia.org/wiki/Subcellular_localizationhttps://en.wikipedia.org/wiki/Subcellular_localizationhttps://en.wikipedia.org/wiki/Src_(gene)https://en.wikipedia.org/wiki/G_protein-coupled_receptor_kinasehttps://en.wikipedia.org/wiki/Arrestinhttps://en.wikipedia.org/wiki/PI3Khttps://en.wikipedia.org/wiki/Voltage-dependent_calcium_channelhttps://en.wikipedia.org/wiki/N-type_calcium_channelhttps://en.wikipedia.org/wiki/Q-type_calcium_channelhttps://en.wikipedia.org/wiki/P-type_calcium_channelhttps://en.wikipedia.org/wiki/G_protein-coupled_inwardly-rectifying_potassium_channelhttps://en.wikipedia.org/wiki/Beta-gamma_complexhttps://en.wikipedia.org/wiki/Rho-associated_protein_kinasehttps://en.wikipedia.org/wiki/Cytoskeletonhttps://en.wikipedia.org/wiki/Rho_family_of_GTPaseshttps://en.wikipedia.org/wiki/Small_GTPasehttps://en.wikipedia.org/wiki/LARGhttps://en.wikipedia.org/wiki/PDZ-RhoGEFhttps://en.wikipedia.org/wiki/P115-RhoGEFhttps://en.wikipedia.org/wiki/RhoGEF_domainhttps://en.wikipedia.org/wiki/Ca2+/calmodulin-dependent_protein_kinasehttps://en.wikipedia.org/wiki/Calmodulinhttps://en.wikipedia.org/wiki/Allosterically


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8 8 RECEPTOR REGULATION

The effect of Rs and Gs in cAMP signal pathway

The effect of Ri and Gi in cAMP signal pathway

7.1 cAMP signal pathway

Main article:cAMP-dependent pathway

The cAMP signal transduction contains 5 main char-acters: stimulative hormone receptor (Rs) or in-hibitory hormone receptor (Ri); stimulative regulativeG-protein (Gs) or inhibitory regulative G-protein (Gi);adenylyl cyclase; protein kinase A (PKA); and cAMPphosphodiesterase.

Stimulative hormone receptor (Rs) is a receptor that canbind with stimulative signal molecules, while inhibitoryhormone receptor (Ri) is a receptor that can bind withinhibitory signal molecules.

Stimulative regulative G-protein is a G-protein linkedto stimulative hormone receptor (Rs), and its subunitupon activation could stimulate the activity of an enzymeor other intracellular metabolism. On the contrary, in-hibitory regulative G-protein is linked to an inhibitoryhormone receptor, and its subunit upon activation couldinhibit the activity of an enzyme or other intracellularmetabolism.

Adenylyl cyclase is a 12-transmembrane glycoprotein thatcatalyzes ATP to form cAMP with the help of cofactorMg2+ or Mn2+. The cAMP produced is a second messen-

ger in cellular metabolism and is an allosteric activator ofprotein kinase A.

Protein kinase A is an important enzyme in cellmetabolism due to its ability to regulate cell metabolismby phosphorylating specific committed enzymes in the

metabolic pathway. It can also regulate specific gene ex-pression, cellular secretion, and membrane permeability.The protein enzyme contains two catalytic subunits andtwo regulatory subunits. When there is no cAMP,thecomplex is inactive. When cAMP binds to the regulatorysubunits, their conformation is altered, causing the disso-ciation of the regulatory subunits, which activates proteinkinase A and allows further biological effects.

These signals then can be terminated by cAMP phospho-diesterase, which is an enzyme that degrades cAMP to5'-AMP and inactivates protein kinase A.

7.2 Phosphatidylinositol signal pathway

Main article:IP3/DAG pathway

In thephosphatidylinositolsignal pathway, the extracel-lular signal molecule binds with the G-protein receptor(G) on the cell surface and activates phospholipase C,which is located on theplasma membrane. Thelipasehydrolyzesphosphatidylinositol 4,5-bisphosphate (PIP2)into two second messengers:inositol 1,4,5-trisphosphate(IP3)anddiacylglycerol (DAG). IP3 binds with theIP3

receptor in the membrane of the smooth endoplasmicreticulum and mitochondria to open Ca2+ channels. DAGhelps activateprotein kinase C (PKC), which phosphory-lates many other proteins, changing their catalytic activi-ties, leading to cellular responses.

The effects of Ca2+ are also remarkable: it cooper-ates with DAG in activating PKC and can activate theCaM kinasepathway, in which calcium-modulated pro-teincalmodulin(CaM) binds Ca2+, undergoes a changein conformation, and activates CaM kinase II, which hasunique ability to increase its binding affinity to CaM byautophosphorylation, making CaM unavailable for the

activation of other enzymes. The kinase then phosphory-lates target enzymes, regulating their activities. The twosignal pathways are connected together by Ca2+-CaM,which is also a regulatory subunit of adenylyl cyclase andphosphodiesterase in the cAMP signal pathway.

8 Receptor regulation

GPCRs become desensitized when exposed to their lig-and for a prolonged period of time. There are two recog-nized forms of desensitization: 1)homologous desensi-

tization, in which the activated GPCR is downregulated;and2) heterologous desensitization, wherein the activatedGPCR causes downregulation of a different GPCR. The
https://en.wikipedia.org/wiki/Heterologous_desensitizationhttps://en.wikipedia.org/wiki/Homologous_desensitizationhttps://en.wikipedia.org/wiki/Homologous_desensitizationhttps://en.wikipedia.org/wiki/Calmodulinhttps://en.wikipedia.org/wiki/Ca2+/calmodulin-dependent_protein_kinasehttps://en.wikipedia.org/wiki/Protein_Kinase_Chttps://en.wikipedia.org/wiki/IP3_receptorhttps://en.wikipedia.org/wiki/IP3_receptorhttps://en.wikipedia.org/wiki/Diacylglycerolhttps://en.wikipedia.org/wiki/Inositol_trisphosphatehttps://en.wikipedia.org/wiki/Inositol_trisphosphatehttps://en.wikipedia.org/wiki/Phosphatidylinositol_4,5-bisphosphatehttps://en.wikipedia.org/wiki/Lipasehttps://en.wikipedia.org/wiki/Cell_membranehttps://en.wikipedia.org/wiki/Phospholipase_Chttps://en.wikipedia.org/wiki/Phosphatidylinositolhttps://en.wikipedia.org/wiki/IP3/DAG_pathwayhttps://en.wikipedia.org/wiki/Phosphodiesterasehttps://en.wikipedia.org/wiki/Protein_Kinase_Ahttps://en.wikipedia.org/wiki/Adenylyl_cyclasehttps://en.wikipedia.org/wiki/Hormone_receptorhttps://en.wikipedia.org/wiki/Hormonehttps://en.wikipedia.org/wiki/CAMP-dependent_pathway


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8.3 Mechanisms of GPCR signal termination 9

key reaction of this downregulation is thephosphorylationof the intracellular (orcytoplasmic) receptor domain byprotein kinases.

8.1 Phosphorylation by cAMP-dependent

protein kinases

Cyclic AMP-dependent protein kinases (protein kinaseA) are activated by the signal chain coming from the Gprotein (that was activated by the receptor) viaadenylatecyclaseandcyclic AMP(cAMP). In a feedback mech-anism, these activated kinases phosphorylate the recep-tor. The longer the receptor remains active the more ki-nases are activated and the more receptors are phospho-rylated. In 2-adrenoceptors, this phosphorylation resultsin the switching of the coupling from the G class of G-protein to theGclass.[47] cAMP-dependent PKA medi-

ated phosphorylation can cause heterologous desensitisa-tion in receptors other than those activated.[48]

8.2 Phosphorylation by GRKs

TheG protein-coupled receptor kinases(GRKs) are pro-tein kinases that phosphorylate only active GPCRs. G-protein-coupled receptor kinases (GRKs) are key modu-lators of G-protein-coupled receptor (GPCR) signaling.They constitute a family of seven mammalian serine-threonine protein kinases that phosphorylate agonist-bound receptor. GRKs-mediated receptor phosphory-lation rapidly initiates profound impairment of receptorsignaling and desensitization. Activity of GRKs and sub-cellular targeting is tightly regulated by interaction withreceptor domains, G protein subunits, lipids, anchoringproteins and calcium-sensitive proteins.[49]

Phosphorylation of the receptor can have two conse-quences:

1. Translocation: The receptor is, along with the partof the membrane it is embedded in, brought tothe inside of the cell, where it is dephosphorylated

within the acidic vesicular environment[50]

and thenbrought back. This mechanism is used to regu-late long-term exposure, for example, to a hormone,by allowing resensitisation to follow desensitisa-tion. Alternatively, the receptor may undergo lyso-zomal degradation, or remain internalised, where itis thought to participate in the initiation of signallingevents, the nature of which depending on the inter-nalised vesicles subcellular localisation.[48]

2. Arrestin linking: The phosphorylated receptor canbe linked to arrestinmolecules that prevent it frombinding (and activating) G proteins, in effect switch-

ing it off for a short period of time. This mecha-nism is used, for example, withrhodopsininretinacells to compensate for exposure to bright light.

In many cases, arrestins binding to the receptoris a prerequisite for translocation. For example,beta-arrestin bound to 2-adrenoreceptors acts as anadaptor for binding with clathrin, and with the beta-subunit of AP2 (clathrin adaptor molecules); thus,the arrestin here acts as a scaffold assembling the

components needed for clathrin-mediated endocy-tosis of 2-adrenoreceptors. [51][52]

8.3 Mechanisms of GPCR signal termina-

tion

As mentioned above, G-proteins may terminate their ownactivation due to their intrinsic GTPGDP hydrolysiscapability. However, this reaction proceeds at a slowrate(.02 times/sec) and, thus, it would take around 50 sec-onds for any single G-protein to deactivate if other fac-

tors did not come into play. Indeed, there are around30isoformsofRGS proteinsthat, when bound to Gthrough theirGAP domain, accelerate the hydrolysis rateto 30 times/sec. This 1500-fold increase in rate al-lows for the cell to respond to external signals with highspeed, as well as spatialresolutiondue to limited amountofsecond messengerthat can be generated and limiteddistance a G-protein can diffuse in .03 seconds. For themost part, theRGS proteinsarepromiscuous in their abil-ity to activate G-proteins, while which RGS is involved ina given signaling pathway seems more determined by thetissue and GPCRinvolved than anythingelse. In addition,RGS proteins have the additional function of increasingthe rate of GTP-GDP exchange at GPCRs, (i.e., as a sortof co-GEF) further contributing to the time resolution ofGPCR signaling.

In addition, the GPCR may bedesensitizeditself. Thiscan occur as:

1. a direct result of ligand occupation, wherein thechange in conformation allows recruitment ofGPCR-Regulating Kinases(GRKs), which go on tophosphorylate variousserine/threonineresidues ofIL-3 and theC-terminal tail. Upon GRK phos-

phorylation, the GPCRs affinity for -arrestin(-arrestin-1/2 in most tissues) is increased, at whichpoint -arrestin may bind and act to bothstericallyhinder G-protein coupling as well as initiate theprocess ofreceptor internalizationthroughclathrin-mediated endocytosis. Because only the ligandedre-ceptor is desensitized by this mechanism, it is calledhomologous desensitization

2. the affinity for -arrestin may be increased in aligand occupation and GRK-independent mannerthrough phosphorylation of different ser/thr sites(but also of IL-3 and the C-terminal tail) by PKC

and PKA. These phosphorylations are often suffi-cient to impair G-protein coupling on their own aswell.
https://en.wikipedia.org/wiki/Homologous_desensitizationhttps://en.wikipedia.org/wiki/Clathrin-mediated_endocytosishttps://en.wikipedia.org/wiki/Clathrin-mediated_endocytosishttps://en.wikipedia.org/wiki/Receptor-mediated_endocytosishttps://en.wikipedia.org/wiki/Stericallyhttps://en.wikipedia.org/wiki/Arrestinhttps://en.wikipedia.org/wiki/C-terminalhttps://en.wikipedia.org/wiki/Threoninehttps://en.wikipedia.org/wiki/Serinehttps://en.wikipedia.org/wiki/Phosphorylationhttps://en.wikipedia.org/wiki/G_protein-coupled_receptor_kinasehttps://en.wikipedia.org/wiki/Protein_conformationhttps://en.wikipedia.org/wiki/Receptor_theoryhttps://en.wikipedia.org/wiki/Homologous_desensitizationhttps://en.wikipedia.org/wiki/Promiscuoushttps://en.wikipedia.org/wiki/Second_messengerhttps://en.wikipedia.org/wiki/Angular_resolutionhttps://en.wikipedia.org/wiki/GTPase_activating_proteinhttps://en.wikipedia.org/wiki/Regulator_of_G_protein_signallinghttps://en.wikipedia.org/wiki/Protein_isoformhttps://en.wikipedia.org/wiki/Rate_constanthttps://en.wikipedia.org/wiki/GTPasehttps://en.wikipedia.org/wiki/Retinahttps://en.wikipedia.org/wiki/Rhodopsinhttps://en.wikipedia.org/wiki/Arrestinhttps://en.wikipedia.org/wiki/G_protein-coupled_receptor_kinaseshttps://en.wikipedia.org/wiki/Gi_alpha_subunithttps://en.wikipedia.org/wiki/Beta-2_adrenergic_receptorhttps://en.wikipedia.org/wiki/Cyclic_AMPhttps://en.wikipedia.org/wiki/Adenylate_cyclasehttps://en.wikipedia.org/wiki/Adenylate_cyclasehttps://en.wikipedia.org/wiki/Protein_kinase_Ahttps://en.wikipedia.org/wiki/Protein_kinase_Ahttps://en.wikipedia.org/wiki/Protein_kinasehttps://en.wikipedia.org/wiki/Cytoplasmhttps://en.wikipedia.org/wiki/Phosphorylation


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10 11 DICTYOSTELIUM DISCOIDEUM

3. PKC/PKA may, instead, phosphorylate GRKs,which can also lead to GPCR phosphorylation and-arrestin binding in an occupation-independentmanner. These latter two mechanisms allow for de-sensitization of one GPCR due to the activities ofothers, orheterologous desensitization. GRKs may

also have GAP domains and so may contribute to in-activation through non-kinasemechanisms as well.A combination of these mechanisms may also occur.

Once -arrestin is bound to a GPCR, it undergoes a con-formational change allowing it to serve as a scaffoldingprotein for an adaptor complex termedAP-2, which inturn recruits another protein calledclathrin. If enoughreceptors in the local area recruit clathrin in this man-ner, they aggregate and themembranebuds inwardly as aresult of interactions between the molecules of clathrin,in a process called opsonization. Once the pit has been

pinched off, theplasma membranedue to the actions oftwo other proteins calledamphiphysinanddynamin, itis now anendocytic vesicle. At this point, the adaptermolecules and clathrin havedissociated, and the recep-tor is eithertraffickedback to the plasma membrane ortargeted tolysosomesfordegradation.

At any point in this process, the -arrestins may also re-cruit other proteinssuch as thenon-receptor tyrosinekinase(nRTK),c-SRCwhich may activateERK1/2, orothermitogen-activated protein kinase(MAPK) signal-ing through, for example, phosphorylation of the smallGTP-ase,Ras, or recruit the proteins of theERK cas-

cade directly (i.e., Raf-1, MEK, ERK-1/2) at whichpoint signaling is initiated due to their close proximityto one another. Another target of c-SRC are the dynaminmolecules involved in endocytosis. Dynamins polymerizearound the neck of an incoming vesicle, and their phos-phorylation by c-SRC provides the energy necessary forthe conformational change allowing the final pinchingoff from the membrane.

8.4 GPCR cellular regulation

Receptor desensitization is mediated through a combina-tion phosphorylation, -arr binding, and endocytosis asdescribed above. Downregulation occurs when endocy-tosed receptor is embedded in an endosome that is traf-ficked to merge with an organelle called a lysosome. Be-cause lysosomal membranes are rich in proton pumps,their interiors have low pH (4.8 vs. the pH7.2 cy-tosol), which acts to denature the GPCRs. In addition,lysosomes contain manydegradative enzymes, includingproteases, which can function only at such low pH, andso the peptide bonds joining the residues of the GPCRtogether may be cleaved. Whether or not a given recep-tor is trafficked to a lysosome, detained in endosomes, or

trafficked back to the plasma membrane depends on a va-riety of factors, including receptor type and magnitude ofthe signal. GPCR regulation is additionally mediated by

gene transcription factors. These factors can increase ordecrease gene transcription and thus increase or decreasethe generation of new receptors (up- or down-regulation)that travel to the cell membrane.

9 Receptor oligomerization

Main article:GPCR oligomer

G-protein-coupled receptor oligomerisation is awidespread phenomenon. One of the best-studiedexamples is the metabotropic GABAB receptor.This so-called constitutive receptor is formed by het-erodimerization ofGABABR1andGABABR2subunits.Expression of the GABABR1 without the GABABR2

in heterologous systems leads to retention of the sub-unit in theendoplasmic reticulum. Expression of theGABABR2 subunit alone, meanwhile, leads to surfaceexpression of the subunit, although with no functionalactivity (i.e., the receptor does not bind agonist andcannot initiate a response following exposure to agonist).Expression of the two subunits together leads to plasmamembrane expression of functional receptor. It hasbeen shown that GABABR2 binding to GABABR1causes masking of a retention signal[53] of functionalreceptors.[54]

10 Origin and diversification of the

superfamily

Signal transduction mediated by the superfamily ofGPCRs dates back to the origin of multicellularity.Mammalian-like GPCRs are found infungi, and havebeen classified according to theGRAFS classificationsystem based on GPCR fingerprints.[55] Identificationof the superfamily members across the eukaryoticdo-main, and comparison of the family-specific motifs, have

shown that the superfamily of GPCRs have a commonorigin.[56] Characteristic motifs indicate that three of thefive GRAFS families,Rhodopsin,Adhesion, andFrizzled,evolved from theDictyosteliumdiscoideumcAMP recep-tors before the split of Opisthokonts. Later, the Secretinfamily evolved from theAdhesionGPCR receptor familybefore the split ofnematodes.

11 Dictyostelium discoideum

A novel GPCR containing a lipid kinase domain has re-cently been identified in Dictyostelium discoideum thatregulates cell density sensing.[57]
https://en.wikipedia.org/wiki/Dictyostelium_discoideumhttps://en.wikipedia.org/wiki/Nematodehttps://en.wikipedia.org/wiki/Secretinhttps://en.wikipedia.org/wiki/Dictyosteliumhttps://en.wikipedia.org/wiki/Frizzledhttps://en.wikipedia.org/wiki/Adhesion-GPCRshttps://en.wikipedia.org/wiki/Rhodopsinhttps://en.wikipedia.org/wiki/Eukaryotichttps://en.wikipedia.org/wiki/GRAFShttps://en.wikipedia.org/wiki/Fungihttps://en.wikipedia.org/wiki/Endoplasmic_reticulumhttps://en.wikipedia.org/wiki/GABBR2https://en.wikipedia.org/wiki/GABBR1https://en.wikipedia.org/wiki/GABAB_receptorhttps://en.wikipedia.org/wiki/GPCR_oligomerhttps://en.wikipedia.org/wiki/Degradative_enzymehttps://en.wikipedia.org/wiki/Polymerizationhttps://en.wikipedia.org/wiki/Mitogen-activated_protein_kinase_kinasehttps://en.wikipedia.org/wiki/Raf-1https://en.wikipedia.org/wiki/MAPK/ERK_pathwayhttps://en.wikipedia.org/wiki/MAPK/ERK_pathwayhttps://en.wikipedia.org/wiki/Ras_subfamilyhttps://en.wikipedia.org/wiki/Small_GTPasehttps://en.wikipedia.org/wiki/Small_GTPasehttps://en.wikipedia.org/wiki/Mitogen-activated_protein_kinasehttps://en.wikipedia.org/wiki/Extracellular_signal-regulated_kinaseshttps://en.wikipedia.org/wiki/Src_(gene)https://en.wikipedia.org/wiki/Non-receptor_tyrosine_kinasehttps://en.wikipedia.org/wiki/Non-receptor_tyrosine_kinasehttps://en.wikipedia.org/wiki/Proteolysishttps://en.wikipedia.org/wiki/Lysosomeshttps://en.wikipedia.org/wiki/Protein_targetinghttps://en.wikipedia.org/wiki/Dissociatedhttps://en.wikipedia.org/wiki/Vesicle_(biology)https://en.wikipedia.org/wiki/Endocytosishttps://en.wikipedia.org/wiki/Dynaminhttps://en.wikipedia.org/wiki/Amphiphysinhttps://en.wikipedia.org/wiki/Plasma_membranehttps://en.wikipedia.org/wiki/Opsonizationhttps://en.wikipedia.org/wiki/Plasma_membranehttps://en.wikipedia.org/wiki/Clathrinhttps://en.wikipedia.org/wiki/AP2_adaptorshttps://en.wikipedia.org/wiki/Kinasehttps://en.wikipedia.org/wiki/Heterologous_desensitization


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11

12 See also

G protein-coupled receptors database

Metabotropic receptor

Orphan receptor Pepducins, a class of drug candidates targeted at

GPCRs

Receptor activated solely by a synthetic ligand, atechnique for control of cell signaling through syn-thetic GPCRs

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14 External links

G-protein-coupled receptors at the US NationalLibrary of Medicine Medical Subject Headings(MeSH)

Wikipedia:MeSH D12.776#MeSHD12.776.543.750.100 --- receptors.2C g-protein-coupled

GPCR Database. IUPHAR Database. Interna-tional Union of Basic and Clinical Pharmacology.Retrieved 2008-08-11.

Vriend G, Horn F (2006-06-29). GPCRDB: In-formation system for G protein-coupled receptors(GPCRs)". Molecular Class-Specific InformationSystem (MCSIS) project. Retrieved 2008-08-11.

G Protein-Coupled Receptors on the NET. Re-

trieved 2010-11-10. a classification of GPCRs PSI GPCR Network Center. Retrieved 2013-07-

11. a Protein Structure Initiative:Biology NetworkCenter aimed at determining the 3D structures ofrepresentative GPCR family proteins

GLASS: A comprehensive database forexperimentally-validated GPCR-ligand associ-ations

15 Further reading

The Nobel Prize in Chemistry 2012. Retrieved2012-10-10.
http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2012/popular-chemistryprize2012.pdfhttp://zhanglab.ccmb.med.umich.edu/GLASS/http://zhanglab.ccmb.med.umich.edu/GLASS/http://zhanglab.ccmb.med.umich.edu/GLASS/http://gpcr.scripps.edu/http://www.gproteincoupledreceptors.net/http://www.gpcr.org/7tm/http://www.gpcr.org/7tm/http://www.gpcr.org/7tm/http://www.iuphar-db.org/GPCR/ReceptorFamiliesForwardhttps://en.wikipedia.org/wiki/Wikipedia:MeSH_D12.776#MeSH_D12.776.543.750.100_---_receptors.2C_g-protein-coupledhttps://en.wikipedia.org/wiki/Wikipedia:MeSH_D12.776#MeSH_D12.776.543.750.100_---_receptors.2C_g-protein-coupledhttps://en.wikipedia.org/wiki/Wikipedia:MeSH_D12.776#MeSH_D12.776.543.750.100_---_receptors.2C_g-protein-coupledhttps://en.wikipedia.org/wiki/Medical_Subject_Headingshttps://www.nlm.nih.gov/cgi/mesh/2011/MB_cgi?mode=&term=G-protein-coupled+receptorshttps://www.ncbi.nlm.nih.gov/pubmed/17481898https://en.wikipedia.org/wiki/PubMed_Identifierhttps://dx.doi.org/10.101

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