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ClassesofReceptorProteinsinEukaryotes,
Copyright©2017W.W.Norton&Company
8.4TumorNecrosisFactorReceptorSignaling• Asinglereceptorstimulatesintracellularpathwayswithopposingcellularresponses.
Copyright©2017W.W.Norton&Company
ActivationofTNFReceptorComplexes
• TNFisahomotrimer.• BindingofTNF-α inducesaconformationalchangeintheTNFreceptoratthedeathdomain(DD).• Thiscausesasilencingofthedeathdomain(SODD).
Copyright©2017W.W.Norton&Company
TNFReceptorAssociatedDeathDomain(TRADD)
• TRADDbindstotheTNFreceptor.
Copyright©2017W.W.Norton&Company
Apoptosis
• Procaspase8iscleavedintocaspase8.• Caspase8cleavesprocaspase3andgeneratescaspase3,the“executioner”caspase.• Keyregulatorymoleculesaredegradedandthecelldies.
Copyright©2017W.W.Norton&Company
8.5NuclearReceptorSignaling,Part1
• Alsoknownasintracellularreceptors• Notboundtomembrane• Servesastranscriptionfactorsthatregulategeneexpression
Copyright©2017W.W.Norton&Company
8.5NuclearReceptorSignaling,Part2
• Examplesinclude:• Steroidreceptors• Metabolitereceptors
• Governedbythreeparameters:• Cell-specific expressionofnuclearreceptors• Localizedbioavailabilityofligands• Differentialaccessibility oftargetgeneDNAsequences inchromatintonuclearreceptorbinding
Copyright©2017W.W.Norton&Company
SteroidandMetaboliteReceptors
Copyright©2017W.W.Norton&Company
NuclearReceptorSignalingSynopsis• Bindingoflipophilic firstmessengerstobindingdomain
• CanoccurwithorwithoutDNApresent
• Ligandactivatednuclearreceptorsrecruitco-regulatoryproteinswhichaltertranscriptionratesthroughacetylationordeacetylation
Copyright©2017W.W.Norton&Company
SteroidReceptors
• Head-to-headhomodimersthatcanbindtoinvertedrepeatDNAsequences• Thatis,5ʹ-AGAACA-3ʹ
• Ligandsarecholesterolderivatives.
Copyright©2017W.W.Norton&Company
MetaboliteReceptors
• Formhead-to-tailheterodimer• BindtodirectDNAsequences
• Thatis,5ʹ-AGGTCA-3ʹ• Ligandsarederivedfrom:
• Vitamins• Unsaturatedfattyacids• Essential aminoacids
Copyright©2017W.W.Norton&Company
GlucocorticoidSignaling• Glucocorticoids areimportantforlungdevelopment,carbohydratemetabolism,andtheinflammatoryresponse.
Copyright©2017W.W.Norton&Company
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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