51791395-6-Sisteme-de-semnalizare-celulara.pdf

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DBB Masterat Inginerie Medicala si Clinica Biologie Celulara si Histologie 6. Semnalizare celulara

Biologie Celulara si HistologieBiologie Celulara si Histologie

Curs 6 Sisteme de semnalizare celularaCurs 6 Sisteme de semnalizare celulara


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CuprinsCuprins

DefinitieDefinitie

ClasificariClasificari

Notiuni de baza:Notiuni de baza:

SemnaleSemnale

Receptori, liganziReceptori, liganzi

Mesageri primi, mesageri secunziMesageri primi, mesageri secunzi

Cai de semnalizare de bazaCai de semnalizare de baza

Cai de semnalizare complexeCai de semnalizare complexe


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DefinitieDefinitie

Semnalizarea celularaSemnalizarea celulara = transmiterea= transmitereainformatiei in interiorul unei celule si intre celuleinformatiei in interiorul unei celule si intre celulediferitediferite

Comunicarea intercelulara se afla la bazaComunicarea intercelulara se afla la bazafunctionarii organismelorfunctionarii organismelor


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ClasificariClasificari

Semnalizare endocrinaSemnalizare endocrina Semnalele ajung la celula prinSemnalele ajung la celula prin

sange, dupa ce au fost produse sisange, dupa ce au fost produse sisecretate intr-o glanda cu secretiesecretate intr-o glanda cu secretieinternainterna

Semnalizare paracrinaSemnalizare paracrina Semnalele produse de o celulaSemnalele produse de o celula

influenteaza activitatea celulelor dininfluenteaza activitatea celulelor dinjurjur

Semnalizare autocrinaSemnalizare autocrina O celula isi automoduleazaO celula isi automoduleaza

activitatea prin secretia de factoriactivitatea prin secretia de factoriumoraliumorali


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Notiuni de bazaNotiuni de baza

ReceptorReceptor roteina situata in membrana ! citoplasma ! nucleuroteina situata in membrana ! citoplasma ! nucleu "egarea unei molecule #= ligand$ determina modificarea conformationala"egarea unei molecule #= ligand$ determina modificarea conformationala

a acestuia % cascada de alte modificari ale unor componente celulare,a acestuia % cascada de alte modificari ale unor componente celulare,cu rezultat final un raspuns celularcu rezultat final un raspuns celular

"igand"igand Molecula care se leaga cu un grad mai mic sau mai mare de specificitateMolecula care se leaga cu un grad mai mic sau mai mare de specificitate

de un anumit receptorde un anumit receptor

"iganzii pot fi:"iganzii pot fi: AgonistiAgonisti determina acti&area receptorului determina acti&area receptorului

AntagonistiAntagonisti' determina inacti&area ! blocarea receptorului' determina inacti&area ! blocarea receptorului


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Legarea liganzilor la receptoriLegarea liganzilor la receptori


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Notiuni de bazaNotiuni de baza

Mesager primMesager prim

"igandul care, prin legarea de receptor, declanseaza o"igandul care, prin legarea de receptor, declanseaza ocascada de modificari care are ca efect final un raspunscascada de modificari care are ca efect final un raspunscelularcelular

Mesageri secundMesageri secund

Molecule sintetizate in urma acti&arii receptorului deMolecule sintetizate in urma acti&arii receptorului decatre mesagerul primcatre mesagerul prim

(cti&eaza un sistem enzimatic cu rol in raspunsul(cti&eaza un sistem enzimatic cu rol in raspunsulcelularcelular

(u rol de amplificare a semnalelor(u rol de amplificare a semnalelor


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Receptori celulariReceptori celulari

Receptori membranariReceptori membranari )onotropici #canale ionice$)onotropici #canale ionice$

MetabotropiciMetabotropici

Cuplati cu proteine *Cuplati cu proteine *

Cuplati cu enzime #+inaze$Cuplati cu enzime #+inaze$

Receptori intracelulariReceptori intracelulari

Citoplasmatici #de obicei, pentru mesageri secunzi$Citoplasmatici #de obicei, pentru mesageri secunzi$

NucleariNucleari


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Receptori ionotropiciReceptori ionotropici

Receptori nicotinici ptr (CReceptori nicotinici ptr (C

Receptori pentru *(-( #*(-(Receptori pentru *(-( #*(-((,C(,C

$$

Receptori pentru glicinaReceptori pentru glicina

Receptori pentru serotoninaReceptori pentru serotonina

Receptori pentru glutamat #(M(, NMD(, rec. ptr +ainat$Receptori pentru glutamat #(M(, NMD(, rec. ptr +ainat$

Receptori pentru (/ #01$Receptori pentru (/ #01$


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Cai de semnalizare implicand receptori ionotropiciCai de semnalizare implicand receptori ionotropici

Contractia muscularaContractia musculara

http://www.blackwellpublishing.com/matthews/myosin2.swf
http://storage/lucru_5/studenti/curs_biocel/cursuri/curs5/myosin2.swfhttp://storage/lucru_5/studenti/curs_biocel/cursuri/curs5/myosin2.swfhttp://storage/lucru_5/studenti/curs_biocel/cursuri/curs5/myosin2.swfhttp://storage/lucru_5/studenti/curs_biocel/cursuri/curs5/myosin2.swf


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Receptori cuplati cu proteine * #*CR$Receptori cuplati cu proteine * #*CR$

2oarte multe tipuri2oarte multe tipuri

)mplicati in:)mplicati in: erceptia &izuala, olfacti&aerceptia &izuala, olfacti&a

Neurotransmisia &egetati&a si in sistemul ner&os central #roluri modulatoare, frec&ent$Neurotransmisia &egetati&a si in sistemul ner&os central #roluri modulatoare, frec&ent$

Roluri modulatoare in lanturile de semnalizare ale sistemului imunRoluri modulatoare in lanturile de semnalizare ale sistemului imun

3xemple:3xemple:

Receptori muscarinici pentru acetilcolinaReceptori muscarinici pentru acetilcolina

Receptori muscarinici pentru *(-(Receptori muscarinici pentru *(-(


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SIGMA-ADRIC!

Diversity of G Protein-Coupled ReceptorSignal Transduction Pathways


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Diversity of G Protein-Coupled Receptor

Signal Transduction PathwaysReceptors coupled to heterotrimeric GTP-binding proteins (G proteins) areintegral transmembrane proteins that transduce extracellular signals to the cellinterior. G protein-coupled receptors exhibit a common structural motifconsisting of seven membrane spanning regions. Receptor occupation promotesinteraction between the receptor and the G protein on the interior surface of themembrane. This induces an exchange of GDP for GTP on the G protein subunitand dissociation of the subunit from the heterodimer. Depending on itsisoform the GTP-subunit complex mediates intracellular signaling eitherindirectl! b! acting on effector molecules such as aden!l!l c!clase ("#) or

phospholipase # (P$#) or directl! b! regulating ion channel or %inase function.References&choneberg T. et al. &tructural basis of G protein-coupled receptor function.'ol. #ell. ndocrinol. "#" *-+, (+++).$eine . ,rd. &tructural features of heterotrimeric G protein-coupled receptorsand their modulator! proteins. 'ol. /eurobiol. "$ -0+ (+++).'orris ".1. et al. Ph!siological regulation of G protein-lin%ed signaling. Ph!siol.Rev. %$ ,2,-0,3 (+++).


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Cai de semnalizare implicand receptori cuplati cu proteine GCai de semnalizare implicand receptori cuplati cu proteine G
http://storage/lucru_5/studenti/curs_biocel/cursuri/curs5/protG.swf


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http://bcs.whfreeman.com/thelifewire/content/chp15/1501.swf

Calea de semnalizare a adrenalineiCalea de semnalizare a adrenalinei
http://storage/lucru_5/studenti/curs_biocel/cursuri/curs6/1501.swf


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Receptori cuplati cu enzime #R/4$Receptori cuplati cu enzime #R/4$

roteina receptor are acti&itate de tirozin'+inaza #protein'+inaza$,roteina receptor are acti&itate de tirozin'+inaza #protein'+inaza$,

in forma fosforilatain forma fosforilata

Categoria cuprinde receptori pentru:Categoria cuprinde receptori pentru:

2actori de crestere2actori de crestere

5ormoni5ormoni

Cito+ineCito+ine 3xemplu: receptorul pentru insulina3xemplu: receptorul pentru insulina


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Familia protein-kinazelor umaneFamilia protein-kinazelor umane


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Receptori citoplasmaticiReceptori citoplasmatici

Sunt receptori acti&ati de mesageri secunzi in lanturile deSunt receptori acti&ati de mesageri secunzi in lanturile de

semnalizaresemnalizare3xemple:3xemple:

Receptorul pentru ) din reticulul endoplasmicReceptorul pentru ) din reticulul endoplasmic

Receptorul r7anodinic din fibra musculara striata sau miocardicaReceptorul r7anodinic din fibra musculara striata sau miocardica


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Receptori nucleariReceptori nucleari#factori de transcriptie$#factori de transcriptie$

(cti&area lor influenteaza direct transcrierea(cti&area lor influenteaza direct transcriereainformatiei din (DN in (RN #receptorul acti&atinformatiei din (DN in (RN #receptorul acti&atse leaga direct de (DN si influenteazase leaga direct de (DN si influenteazatranscrierea genelor adiacente$transcrierea genelor adiacente$

3xemple:3xemple:

Receptori ormonali:Receptori ormonali:

5ormoni corticoizi5ormoni corticoizi

5ormoni tiroidieni5ormoni tiroidieni

3strogeni3strogeni

Receptori pentru unii factori de crestereReceptori pentru unii factori de crestere

Receptori pentru retinoiziReceptori pentru retinoizi


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Calea de semnalizare a corticoizilorCalea de semnalizare a corticoizilor
http://storage/lucru_5/studenti/curs_biocel/cursuri/curs6/steroid_hormons_bio46.swf


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Glucocorticoid Receptor Signaling SIGMA-ADRIC!


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Glucocorticoid Receptor SignalingThe glucocorticoid hormone cortisol passes through the plasma membrane into thec!toplasm where it binds to the specific high-affinit! glucocorticoid receptor (GR). Theresulting complex is the non-D/"-binding oligomer of the GR in which the receptor iscomplexed with other proteins. 4n this complex the D/"-binding domain of the receptoris bound b! the heat shoc% protein +3 (hsp+3) dimer. 5ther proteins in this complexinclude heat shoc% protein 23 (hsp23) and 678P9:. Dissociation of the oligomericcomplex !ields the free cortisol-receptor subunit in the D/"-binding form. The activatedreceptor forms a homodimer and is translocated to the nucleus through the nucleopore.4nside the nucleus the receptor complex binds to specific D/" responsive elements(GR) to activate gene transcription.References8runer 7.$. et al. The unliganded mineralocorticoid receptor is associated with heatshoc% proteins 23 and +3 and the immunophilin 678P-9:. Recept. &ignal Transduct. %*9-+* (++2).Drouin 1. et al. omodimer formation is rate-limiting for high affinit! D/" binding b!glucocorticoid receptor. 'ol ndocrinol. & :++-,3+ (++:).

C l d li i i iC l d li ti i i


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Calea de semnalizare a tiroineiCalea de semnalizare a tiroinei

C i d li i li d t i l iC i d li i li d t i l i
http://storage/lucru_5/studenti/curs_biocel/cursuri/curs6/tyroxine_bio47.swf


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Cai de semnalizare implicand receptori nucleariCai de semnalizare implicand receptori nucleari

M i iM i i
http://storage/lucru_5/studenti/curs_biocel/cursuri/curs5/rec_nucl.swf


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Mesageri secunziMesageri secunzi

Tipuri:Tipuri:

Molecule hidrofobe:Molecule hidrofobe:D(* #diacil glicerol$, ) #inozitol trifosfat$, )D(* #diacil glicerol$, ) #inozitol trifosfat$, )#fosfatidil inozitoli$8 sunt molecule asociate membranei, pot difuza#fosfatidil inozitoli$8 sunt molecule asociate membranei, pot difuzaprin membrana pana in spatiul din apropiere, unde controleazaprin membrana pana in spatiul din apropiere, unde controleazaacti&itatea proteinelor efectoare asociate membraneiacti&itatea proteinelor efectoare asociate membranei

Molecule hidrofile:Molecule hidrofile:c(M, c*M, Cac(M, c*M, Ca09098 situate in citoplasma,8 situate in citoplasma,

actioneaza asupra unor efectori citoplasmaticiactioneaza asupra unor efectori citoplasmatici

Gaze:Gaze:N #oxid nitric$, C #monoxidul de carbon$8 pot difuza atatN #oxid nitric$, C #monoxidul de carbon$8 pot difuza atatprin membrane, cat si prin citoplasmaprin membrane, cat si prin citoplasma

DAG cAMP

Amplificarea semnalului prin mesageriAmplificarea semnalului prin mesageri


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Amplificarea semnalului prin mesageriAmplificarea semnalului prin mesagerisecunzisecunzi

C li ' l id M ( li AMP
http://storage/lucru_5/studenti/curs_biocel/cursuri/curs5/amplification.swf


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SIGMA-ADRIC!Cyclic 'ucleotide Meta(olis) - cAMP

Second Messenger Syste)s Involved in


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Reward and Addiction SIGMA-ADRIC!


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Second Messenger Syste)s Involved inReward and Addiction

;ith repeated ps!chostimulant administration these are changes in dopaminergic andglutamatergic transmission in the nucleus accumbens. The figure depicts the ma


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Cyclic 'ucleotide Meta(olis) - cAMP#!clic nucleotides have been extensivel! studied as second messengers ofintracellular events initiated b! activation of man! t!pes of hormone and

neurotransmitter receptors. Receptors that stimulate the conversion of "TP toc!clic ,> 9>-adenosine monophosphate (c"'P) are associated with G proteins.8inding of the hormone or neurotransmitter to its membrane-bound receptorinduces a conformational change in the receptor that leads to activation of the-subunit of the G protein. The activated Gssubunit stimulates while the Gi

subunit inhibits aden!l!l c!clase ("#). &timulation of "# catal!?es the conversionof c!toplasmic "TP to c"'P. c"'P activates c"'P-dependent protein %inasesincluding protein %inase " (P7"). 8! catal!?ing the phosphor!lation (activation ordeactivation) of intracellular en?!mes c"'P-dependent %inases elicit a widearra! of metabolic and functional processes. /egative regulation can occur in the

pathwa! when phosphodiesterases (PDs) catal!?e the h!drol!sis of c"'P toadenosine-9>-monophosphate (9>-"'P). &everal families of phosphodiesterases(PD-4-4) act as regulator! switches b! catal!?ing the degradation of c"'P toadenosine-9-monophosphate (9>-"'P). PD 44 is a low affinit! PD that cancleave both c"'P and cG'P. The activit! of PD 44 is stimulated b! cG'P. PD 444is a low affinit! PD that is inhibited b! cG'P and is involved in the regulation ofsmooth muscle and cardiac contraction. PD 4 is highl! selective for c"'P andis the high affinit! PD present in most cell t!pes.References6rancis &.. and #orbin 1.D. #!clic nucleotide-dependent protein %inases@intracellular receptors for c"'P and cG'P action. #rit. Rev. #lin. $ab. &ci. *&:29-,:* (+++).

1uilfs D.'. et al. #!clic G'P as substrate and regulator of c!clic nucleotidephosphodiesterases (PDs). Rev. Ph!siol. 8iochem. Pharmacol. "*# A2-30(+++).&imonds ;.6. G protein regulation of aden!late c!clase. Trends Pharmacol. &ci.+, AA-2, (+++).


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3xemple de cai de semnalizare3xemple de cai de semnalizare

complexecomplexe

Calea de semnalizare a proliferarii celulareCalea de semnalizare a proliferarii celulare


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Calea de semnalizare a proliferarii celulareCalea de semnalizare a proliferarii celulare
http://storage/lucru_5/studenti/curs_biocel/cursuri/curs6/cell_prolif.swf


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Wikimedia Commons
http://upload.wikimedia.org/wikipedia/commons/2/29/Signal_transduction_v1.pnghttp://upload.wikimedia.org/wikipedia/commons/2/29/Signal_transduction_v1.png


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SIGMA-ADRIC!


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Insulin Pathway&ignaling through the insulin pathwa! is critical for the regulation of intracellularand blood glucose levels and the avoidance of diabetes. 4nsulin binds to itsreceptor leading to the autophosphor!lation of the B-subunits and the t!rosinephosphor!lation of insulin receptor substrates (4R&). 4R& phosphor!lates the &:domain of &hp: a t!rosine phosphatase and the &, domain of the adaptormolecule Grb:. "ctivated Grb: recruits &os that in turn activates the Rassignaling pathwa! and gene transcription. 4R& also activates phosphoinositide ,-%inase (P4,7) through its &: domain thus increasing the intracellularconcentration of P4P:and P4P. This in turn activates phosphatid!linositol

phosphate-dependent %inase- (PD7-) that subseCuentl! activates "%t=P78 This

results in the translocation of the glucose transporter (G$T0) from c!toplasmicvesicles to the cell membrane.References8evan P. 4nsulin signaling. 1. #ell &ci. "" 0:+-0,3 (:33).7ido E. et al. #linical review :9@ The insulin receptor and its cellular targets. 1.#lin. ndocrinol. 'etab. .& +2:-+2+ (:33).


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hi et al. !olecular "ain 20051:##

$iabetes 52%12&:2'()*2')#+200#


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Disulfide relays and phosphorylativecascades: partners in redox-mediatedsignaling pathways

, -ilomeni+ , otilio and ! Ciriolo

Cell $eath and $ifferentiation %2005& 12+ 155515(#.


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http://storage/lucru_5/studenti/curs_biocel/cursuri/curs6/filme_memorie/signal_molecules-lg.wmv


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http://storage/lucru_5/studenti/curs_biocel/cursuri/curs6/filme_memorie/early_LTP-lg.wmv


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-ibliografie suplimentara-ibliografie suplimentara
http://storage/lucru_5/studenti/curs_biocel/cursuri/curs6/filme_memorie/late_LTP-lg.wmv


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g pg p

ttp:!!pid.nci.ni.go&!bro;se>?0@?A6!A0>>6>!ra&enanimation.tml

ttp:!!;;;.sigmaaldric.com!life'science!cell'biolog7!learning'center!pat;a7'slides'and.tmlttp:!!;;;.sigmaaldric.com!life'science!cell'biolog7!learning'center!pat;a7'slides'and.tml

ttp:!!;;;.mi.org!biointeracti&e!neuroscience!lectures.tmlttp:!!;;;.mi.org!biointeracti&e!neuroscience!lectures.tml
http://pid.nci.nih.gov/browse_pathways.shtml#NCI-Naturehttp://pid.nci.nih.gov/browse_pathways.shtml#NCI-Naturehttp://highered.mcgraw-hill.com/sites/dl/free/0072437316/120060/ravenanimation.htmlhttp://highered.mcgraw-hill.com/sites/dl/free/0072437316/120060/ravenanimation.htmlhttp://www.sigmaaldrich.com/life-science/cell-biology/learning-center/pathway-slides-and.htmlhttp://www.sigmaaldrich.com/life-science/cell-biology/learning-center/pathway-slides-and.htmlhttp://www.hhmi.org/biointeractive/neuroscience/lectures.htmlhttp://www.hhmi.org/biointeractive/neuroscience/lectures.htmlhttp://www.hhmi.org/biointeractive/neuroscience/lectures.htmlhttp://www.sigmaaldrich.com/life-science/cell-biology/learning-center/pathway-slides-and.htmlhttp://highered.mcgraw-hill.com/sites/dl/free/0072437316/120060/ravenanimation.htmlhttp://pid.nci.nih.gov/browse_pathways.shtml#NCI-Nature

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