TN HIU T BO

Ni dung S trao i thng tin gia cc t bo Cc loi tn hiu ngoi bo Cc bc lin quan n qu trnh trao i thng tin giu cc t bo thng qua cc tn hiu ngoi bo Cc loi truyn tin gia cc t bo (intercellular signalling): Hormones Th th tip nhn tn hiu : Receptor v cc phn t gn Ligand Cc phn t truyn tin th 2 Gii thiu mt s con ng truyn tn hiu.

Cc loi tn hiu ngoi bo Cc kch thch t mi trng: nh sng, mi v, m thanh, dinh dng T t bo pht tn hiu: phn chia, bit ha, cc phn t truyn tn hiu sn sinh bi cc t bo : peptid, protein, hormone..

S truyn tn hiu ngoi bo Cc phn t tn hiu c gii phng bi cc t bo pht tn hiu Cc tn hiu ny gi l cht gn ligand L bm vo th th c hiu tng ng trn t bo ch l S tng tc gia RL to ra s thay i cu hnh ca R Kch thch s sn sinh cc phn ng p tr c hiu ca t bo

A cell targeted by a particular chemical signal has a receptor protein that recognizes the signal molecule.

Cc bc chnh ca qu trnh trao i thng tin gia cc t bo thng qua cc tn hiu ngoi bo1. Tng hp cc phn t tn hiu 2. Gii phng cc phn t tn hiu bi cc t bo pht tn hiu 3. vn chuyn tn hiu n t bo ch 4. Tip nhn tn hiu bi cc th th 5. Phn ng tr li ca t bo thong qua cc con ng truyn tn hiu 6. Nhng thay i nhng thay i c th trong chc nng, ng ho hay pht trin ca t bo v cc iu ho p ng li thng i km theo; 7. Bt hot cc th th receptor 8. Loi b cc phn t tn hiu

Cc loi tn hiu gia cc t bo (intercellular signalling):

Hormones Nhm a lipid: (lipophilic): l cc phn t a lipid c kch thc nh, c kh nng khuych tn qua mng sinh cht v tng tc vi cc th th ni bo Steroid: cortisol, progesterone, estradiol v testosterone) Thyroxine Retinoic acid Tc ng chm tng hp theo nhu cu, c gii phng trc tip t mng sinh cht Rt bn vng do bm vo cc protein vn chuyn mng

Nhm tan trong nc vi th th bm b mt t bo Peptide hormones: insulin, yu t sinh trng v glucagon Cc phn t tch in c kch thc nh: v d epinephrine v histamine, catecholamines l nhng cht cu to t amino acids v c chc nng nh cc hormones v cht dn truyn thn kinh. Tc ng nhanh: giy n vi pht Tch ly v gii phng nhanh thong qua hin tng xut bo Phn r nhanh chng

Nhm a lipid lien kt vi th th b mt t bo Prostaglandins (eicosanoid super family): t nht 16 loi prostaglandins thuc 9 nhm khc nhau, gi l PGA-PGI. H eicosonoid hormone cn bao gm prostacyclins, thromboxanes v leukotrienes. Brassinosteroids

C ch hot ng ca hormone tan trong lipid Hormon khuych tn qua lp phospholipid kp vo trong t bo Bm vo th th, bt /tt cc gen c hiu Phn t mRNA mi c hnh thnh v iu khin s tng hp protein mi Protein mi thay i cc hot ng ca t bo

C ch hot ng ca hormone tan trong nc Khngth khuych tn quan mng Hormone receptors l cc protein t hp vi mng, hot ng nh phn t truyn tn hiu th nht Protein th th hot ha G-protein trong mng G-protein hot ha adenylate cyclase chuyn ha ATP thnh cAMP trong t bo cht Cyclic AMP l phn t truyn tin th hai Hot ha kinases trong t bo cht tng tc /lm gim cc phn ng tr li sinh l Phosphodiesterase bt hot cAMP mt cch nhanh chng Phn ng tr li t bo c tt i tr khi hormone mi xut hin

Phn ng tr li ca t bo

Th th-Receptor Th th ni bo: l cc protein ha tan nh v trong dch nhn v t bo cht, cc ligand ca receptor ni bo bao gm: steroid hormones, thyroid hormone, retinoic acid, v cc dn xut ca vitamin A, D3. bm c vo th th, cc ligand ny phi i xuyn qua c mng t bo. Th th mng t bo: cc th th mng t bo khng th c khuych tn qua mng t bo. Cc tn hiu bm vo cc protein th th trn b mt t bo, chuyn cc tn hiu ngoi bo thnh tn hiu ni bo v sn sinh ra nhng thay i trong t bo ca t bo.

4 loi th th mng t bo

Th th lien kt vi G-protein: s bm ca cht gn Ligand (L) hot ha 1 protein G, dn n s hot hay c ch sau mt enzyme c chc nng sn sinh ra mt phn t truyn tin th 2 c th hoc iu ha mt knh ion, gy ra s thay i trong th mng. V d: cc th th cho epinephrine, serotonin v glucagon.

adenylyl cyclase (AC)

4 loi th th mng t bo

Th th lien kt vi knh ion: s gn ca L lm thay i cu hnh khng gian ca th th do cc ion c hiu c th i qua n; s di chuyn cc ion lm thay i th in t qua mng t bo. V d th th acetylcholine m lien kt c-thn kinh

4 loi th th mng t bo

Cc th th lien kt Tyrosine kinase: cc th th ny b mt hot ng xc tc vn c nhng s bm ca L kch thch s hnh thnh cc th th nh phn t l cu trc sau s tng tc vi v hot ha mt hay nhiu protein-tyrosine kinase trong dch bo. Thuc loi ny l cc th th cho cytokines, interferons v nhn t iu ha sinh trng ngi.

4 loi th th mng t bo

Signal transduction Cascade

-receptor tyrosine kinases OR ligand-triggered protein kinases - Cc th th vi hot tnh enzyme: mt s th th c hot ng xc tc c hot ha bi s bm ca mt L. V d mt s th th sau khi hot ha c th xc tc s chuyn ha GTP thnh cMP. Mt s khc hot ng nh mt protein phosphatases, loi b nhm phosphate t gc phosphotyronsine trong protein xc tc v do vy bin i hot tnh ca chng. Nhm ny cng c gi l th th serine/threonine kinases hoc receptor tyrosine kinase

Th th lin kt vi G-protein Th th lin kt G protein l nhm ph bin nht trong cc th th, c tm thy trong mi loi sinh vt t nm men n ngi. S hot ho th th bi vic bm vi vt gn gy ra s hot ho ca protein G (coupled trimeric), G protein sau s tng tc vi cc protein truyn tn hiu downstream. Tt c cc cn ng truyn tn hiu GPCR u c chung cc thnh phn/yu t sau: mt th th c cha 7 vng xuyn mng mt cp protein G gm 3 phn t (coupled trimeric G protein) c chc nng nh mt nt cng tc bng cch quay vng gia trng thi hot ng v khng hot ng mt protein phn ng li kch thch bao quanh mng

Cc protein gn vi guanine ny c bt ln on khi chng gn vi GTP v Off khi GTP b thu phn thnh GDP (fig. 3.32). S chuyn ho cm ng bi cc tn hiu t trng thi khng hot ng sang trng thi hot ng c iu khin bi nhn t trao i Guanine nucleotid (GEF), l nhn t gy ra s gii phng GDP t switch protein. S gn GTP tip theo c la chn bi nng ni bo cao ca n lin quan n i lc bm gn, cm ng s thay i v cu trc khng gian trong t nht 2 on protin c tnh bo th cao , wocj gi l switch I v S-II, cho php protein gn vo v hot ho cc protein tn hiu downstream (Fig. 15-8). Hot ng bn cht ca GTPase ca protein sau s thu phn lin GTP thanhg GDP v Pi, v vy thay i cu hnh khng gian cu SI v SII t dng hot ng thnh khng hot ng.

GTPase switch protein

C ch hot ng ca GPCRs

RTKs:

Receptor tyrosine kinase

l nhm th th b mt t bo ln th hai sau th th G. Cht gn cho RTKs l cc hormone ha tan hoc cc protein/peptid bm mng nh: nerve growth factor (NGF), platelet-derived growth factor (PDGF), fibroblast growth factor (FGF), epidermal growth factor (EGF), v insulin. Vic bm ca cc L vo th th loi ny kch thch hot tnh protein tyrosine kinase ca th th dn n vic kch thch tip theo cc bc truyn tn hiu dn n s thay i trong sinh l t bo hoc biu hin gen.

Cc bc truyn tn hiu v s khuych i tn hiu c im quan trng ca cc cht truyn tin th cp v con ng truyn tn hiu l kh nng khuch i tn hiu. Vic bm vo cc th th b mt t bo thng khng hot ha mt phn t enzyme m khi ng nhiu phn t enzyme trn mng sinh cht. S hat ha adenylate cyclase dn n s sn xut nhiu cAMP dn n s khuch i thgn tin sau . Cc cAMP ny li hot ha rt nhiu kinases c tc dng phosphoryl ha nhiu phn t protein v dn n s khuch i tip theo.

Nh vy s bm ca 1 phn t tn hiu vi R ca n c th dn n s hot ha hng trm, hng nghn cc phn t enzyme trong t bo .

S khuych i tn hiu bn ngoi t mt th th b mt t bo

or

switch proteinkiu phosphoryl haS hat ho hu ht tt c cc th th b mt dn n s thay i trc tip hay gin tip trong s phosphoryl ho protein thng qua s hat ho protein kinase, c chc nng thm nhm phosphat vo cc gc c hiu hay protein phosphatase c kh nng ct nhm phosphate. Cc t bo ng vt c cha 2 loi protein kinase: nhm cc enzyme gn thm phosphate vo nhm hydrroxyl trn cht nhn tyrosine v nhm m thm phosphate vo nhm hydroxyl ca serine hoc threonine (hoc c hai).

Phosphatase c th cng hot ng vi kinase bt tt chc nng ca cc protein khc nhau.

serine (Ser)H H3N+ C CH2 OH COO

threonine (Thr)H H3N+ C COO

CH OH CH3

Nhiu enzyme c iu ha bi lin kt ng ha tr ca phosphate, trong lin kt ester , vi nhm hydroxyl ca mt gc amino acid c bit (serine, threonine, or tyrosine).

Protein KinaseProtein Pi OH + ATP Protein H2O O

O P O O + ADP

Protein Phosphatase

Mt protein kinase chuyn gc phosphate u kt thc ca ANT thnh mt nhm hydroxyl trn 1 phn t protein . Mt protein phosphatase hot ha s loi b ca Pi bng s thy phn (hydrolysis).

S phosphoryl ha Phosphorylation c th thay i trc tip hot ng ca 1 enzyme, v d thc y s thay i cu hnh. Hoc, s thay i hot tnh c th l kt qu ca vic bm vo mt phn t protein khc m nhn dng mt cch c hiu mt vng c phosphoryl ha

Protein KinaseProtein Pi OH + ATP Protein H2O O

O P O O + ADP

Protein Phosphatase

Protein kinases v phosphatases c iu ha bi mt lot cc tn hiu phc tp , v d: Mt s protein kinases c hot ha bi Ca++-calmodulin. Protein Kinase A c hot ha bi cyclicAMP (cAMP).

Cc cht truyn tin th 2 S bm ca cc ligand (truyn tin th nht) ti nhiu th th mng t bo dn n s tng tn ti trong thi gian ngn (hoc gim) trong nng ca mt s phn t tn hiu ni bo c khi lng phn t thp c gi l cc second mesenger cht thng tin th cp. Cc cht ny sau s bm vo cc protein khc bin i hot ng ca chng. Cc loi cht truyn tin th 2: 3,5-cyclic AMP (cAMP); 3,5-cyclic GMP (cGMP); 1,2-diacylglycerol (DAG); inositol 1,4,5-trisphosphate (IP3); Ca++

Cc loi cht truyn tin th 2 ph bin

cAMP Cyclic adenosine monophosphate (cAMP, cyclic AMP or 3'-5'-cyclic adenosine monophosphate) l cht truyn tin th hai ng vai tr quan trong trong nhiu qu trnh ca t bo c s dng truyn cc tn hiu ni bo nh l chuyn cc tc ng ca hormone ( glucagon, adrenaline) vn khng i xuyn qua c thnh t bo.

Lin quan n s hot ha protein kinase v iu ha cc tc dng ca adrenaline v glucagon cng nh iu ha s i qua ca Ca== qua cc knh ion

Protein Kinase A (cAMP-Dependent Protein Kinase) chuyn Pi t ATP thnh OH ca mt Ser or Thr Protein Kinase A trng thi ngh l phc h gm : 2 catalytic subunits (C) v 2 regulatory subunits (R). R2C2

Adenylate cyclase l mt trong nhng phn t tr li kch thch chnh ca nhm GPCR

Mt s GPCR c gn lin vi cc cng trao i ion

cGMP Cyclic guanosine monophosphate (cGMP) l mt nucleotid mch vng bt ngun t guanosine triphosphate (GTP). cGMP hot ng nh mt cht truyn tin th hai ging nh cAMP, c vai tr hot ha protein kinase trong phn ng tr li s bm vo b mt t bo bi cc peptid hormone khng c kh nng thm thu qua mng. S tng hp cGMP c xc tc bi guanylate cyclase (GC), chuyn GTP thnh cGMP. GC bm mng c hot ha bi peptide hormones v d e atrial natriuretic factor, trong khi GC dng ho tan c hot ha bi nitric oxide NO kch thhc s tng hp cGMP. cGMP ng vai tr iu ha cc knh ion, ng ha ng, s t cht ca t bo, co gin c.

DAG, IP3, Ca++ inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 v DAG l cc sn phm ca qu trnh b gy phn t phosphotidylinositol (PI), c sn sinh thng qua s hot ha cc loi th th ca nhiu hormone ((GPCRs and RTKs)

Ca++ Nhiu tn hiu ngoi bo cm ng s tng nng Ca++ iu ha nhiu chc nng ca t bo: pht trin phi, s bi tit, co rt c. Ca++ c th c dng nh mt tn hiu bi chng c nng thp trong t bo cht v cao trong dch ngoi bo cng nh ER. Khi mt tn hiu gip m knh Ca++ mng sinh cht hoc mang ER, Ca++ b vo dch bo thc hin cc tc ng ca chng.

Gii thiu mt s con ng truyn tn hiuMAP kinase pathway SAP/JNK pathway p38 pathway ERK pathway NFkB pathway Cell survival pathway Wnt signaling pathway Jak/Stat pathway Smad pathway

Con ng tn hiu MAP kinase Hot ha bi RTK thng quan yu t sinh trng, hormone Dn n s hot ha apdaptor protein gi l Ras-GTPase Ras cm ng cc bc tn hiu kinase khi u vi 1 kinase gi l rac v s hot ha ca MAP kinase t cc i Mt lot kinase tham gia vo cc bc trung gian S hot ha MAPK dn n s thay i v tr trong nhn v phosphoryl ha nhiu protein khc nhau, bao gm c cc yu t phin m tham gia iu ha s biu hin gen.

MAPK kinase paths

Stress, cytokines, hormones & mitogens signal through cdc42/raccdc42/rac

then activates one of three MAPK paths:

Stress Cytokines

Stress Hormones Cytokines

Mitogens Hormones

p38MAPK: stress

response & apoptosis (MAPKAP(MAPKAPcdc42/rac

2, HSP27)JNK:

stress response & proliferation (jun) (jun)

Activation of ras/MEK/ERK path: proliferation & differentiationMEKKsMEKKs

grb2

ras

sos

MEK 3/6

JNKK 1/2

raf-1

MAPK kinase

p38MAPK

JNK 1/2

MEK 1/2

transcription factors (nucleus)

MAPKAP-2 HSP27

ATF elk

ATFjun elk

ERK 1/2elk RSK

fos