Classes of Receptor Proteins in Eukaryotes,biochemistry-stanislaus.wdfiles.com/.../4420biosignalling3.pdf · of catecholamines binding to the α1A -Adrenergic receptor is less glycogen

ClassesofReceptorProteinsinEukaryotes,

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8.4TumorNecrosisFactorReceptorSignaling• Asinglereceptorstimulatesintracellularpathwayswithopposingcellularresponses.


ActivationofTNFReceptorComplexes

• TNFisahomotrimer.• BindingofTNF-α inducesaconformationalchangeintheTNFreceptoratthedeathdomain(DD).• Thiscausesasilencingofthedeathdomain(SODD).


TNFReceptorAssociatedDeathDomain(TRADD)

• TRADDbindstotheTNFreceptor.


Apoptosis

• Procaspase8iscleavedintocaspase8.• Caspase8cleavesprocaspase3andgeneratescaspase3,the“executioner”caspase.• Keyregulatorymoleculesaredegradedandthecelldies.


8.5NuclearReceptorSignaling,Part1

• Alsoknownasintracellularreceptors• Notboundtomembrane• Servesastranscriptionfactorsthatregulategeneexpression


8.5NuclearReceptorSignaling,Part2

• Examplesinclude:• Steroidreceptors• Metabolitereceptors

• Governedbythreeparameters:• Cell-specific expressionofnuclearreceptors• Localizedbioavailabilityofligands• Differentialaccessibility oftargetgeneDNAsequences inchromatintonuclearreceptorbinding


SteroidandMetaboliteReceptors


NuclearReceptorSignalingSynopsis• Bindingoflipophilic firstmessengerstobindingdomain

• CanoccurwithorwithoutDNApresent

• Ligandactivatednuclearreceptorsrecruitco-regulatoryproteinswhichaltertranscriptionratesthroughacetylationordeacetylation


SteroidReceptors

• Head-to-headhomodimersthatcanbindtoinvertedrepeatDNAsequences• Thatis,5ʹ-AGAACA-3ʹ

• Ligandsarecholesterolderivatives.


MetaboliteReceptors

• Formhead-to-tailheterodimer• BindtodirectDNAsequences

• Thatis,5ʹ-AGGTCA-3ʹ• Ligandsarederivedfrom:

• Vitamins• Unsaturatedfattyacids• Essential aminoacids


GlucocorticoidSignaling• Glucocorticoids areimportantforlungdevelopment,carbohydratemetabolism,andtheinflammatoryresponse.


Theα1A-Adrenergic receptorcascadeinvolves Gq,PLC, IP3,Ca+2 anddiacyl glycerol.Ca+2anddiacyl glycerolactivatePKC andPKCphosphorylates GSK3β (Glycogen Synthase Kinase -3β).Thephosphorylated formofGSK3β isinactiveandthus cannotphosphorylate GlycogenSynthase (GS).ThismakesGlycogenSynthase more active andpromotes glycogensynthesis; thisistheopposite ofwhatisinyourbook.

Thebook givesageneralstatementthatactivationofPKC inhibits glycogen synthase.Afterreadingthisjournal article,thefullstory becomes clearer.Theα1A-Adrenergic receptorhasanother pathwaythat does inhibit glycogensynthesis.Theα1A-Adrenergic receptorcascadeinactivatesAkt (akaPKB).Akt isactivatedbytheInsulin cascade:which isshowninthepowerpoint slides.WhenAkt isinactivatedbytheα1A-Adrenergic receptorcascade,itdoes notphosphorylateGSK3β. Theunphosphorylated formofGSK3β is active,itphosphorylates GlycogenSynthasetomakeGSless active.

Catecholamines work againstinsulin bybinding totheGq coupled receptorthatresults inthe inactivation ofAkt(mechanism under study). This allowsGSK3β toremainactiveanditphosphorylates andinactivatesGS.Thenetresultofcatecholamines binding totheα1A-Adrenergic receptoris lessglycogensynthesis, asstated(vaguely) inthetext.

LisaM.Ballou, Pei-Yu Tian,Hong-Ying Lin, Ya-PingJiangandRichardZ.Lin“DualRegulationofGlycogen Synthase Kinase-3βbytheα1A-Adrenergic Receptor”(2001) Journal ofBiological Chemistry, 276:40910-40916http://www.jbc.org/content/276/44/40910.full

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Classes of Receptor Proteins in Eukaryotes,biochemistry-stanislaus.wdfiles.com/.../4420biosignalling3.pdf · of catecholamines binding to the α1A -Adrenergic receptor is less glycogen