Overview: The Cellular Internet. General Biology. 7. Cell Communication & Signalling

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1 Course o: BG00 Credits:.00 Generl Biology Overview: The Cellulr Internet Cell-to-cell communiction is bsolutely essentil for multicellulr orgnisms Biologists hve discovered some universl mechnisms of cellulr regultion 7. Cell Communiction & ling rof. Dr. Klus Heese Externl signls re converted into responses within the cell trnsduction pthwys Evolution of Cell ing Yest cells identify their mtes by cell signling Exchnge of mting fctors.ech c ell ty pe secretes mting fctor tht binds to rec eptors on the other cell type. Mting. Binding of the fc tors to rec eptors induces chnges in the cells tht led to their fusion. ew /cell. The nucleus of the fus ed c ell inc ludes ll the genes from the nd c ells. Yest cell, mting type fctor / fctor Yest cell, mting type convert signls on cell s surfce into cellulr responses re similr in microbes nd mmmls, suggesting n erly origin Locl nd Long-Distnce ing Cells in multicellulr orgnism communicte vi chemicl messengers Animl nd plnt cells hve cell junctions tht directly connect the cytoplsm of djcent cells In locl signling, niml cells my communicte vi direct contct [e.g. Delt- otch (neurodevelopment)] lsm membrnes Gp junctions between niml cells lsmodesmt between plnt cells () Cell junctions. Both nimls nd plnts hve cell junctions tht llow s to pss redily between djcent cells without crossing plsm membrnes. (b) Cell-cell r ecognition. Two cells in n niml my communicte by interction between s protruding from their surfces.

2 In other cses, niml cells communicte using locl regultors Long-distnce signling Endocrine cell Blood vessel Trget cell Sec retory vesicle Locl signling Electricl signl long nerve cell triggers relese of neurotrnsmitter e u ro tr n s mi tter diffuses cross synpse In long distnce signling both plnts nd nimls use hormones Trget cell Hormone trvels in bloodstrem to trget cells Locl regultor diffuses through extrcellulr fluid () rcrine signling. A s ecreting c ell cts on nerby trget cells by dischrging s of locl regultor ( growth fc tor, for ex mple) into the ex trc ellulr fluid. Trget cell is stimulted (b) Synptic signling. A nerv e c ell releses neurotrnsmitter s into synpse, stimulting the trget cell. Hormonl signling. Specilized endocrine cells secrete hormones into body fluids, often the blood. Hormones my rech virtully ll body cells. The Three Stges of Cell ing: A review Erl W. Sutherlnd discovered how the hormone epinephrine cts on cells Sutherlnd suggested tht cells receiving signls went through three processes Reception Overview of cell signling EXTRACELLULAR Three Stges of Cell ing lsm membrne CYTOLASM Reception Trnsduction Response Trnsduction Response Rely s in signl trnsduction pthwy Activtion of cellulr response Reception: A signl binds to receptor, cusing it to chnge shpe The binding between signl (lignd) nd receptor is highly specific A conformtionl chnge in receptor is often the initil trnsduction of the signl Intrcellulr receptors re cytoplsmic or nucler s s tht re smll or hydrophobic nd cn redily cross the plsm membrne use these receptors Steroid hormones bind to intrcellulr receptors ( lignd) Re c e p tor mra Ho rmo n e (tes tos terone) UCL EUS CYTOL ASM DA EXTRACELLULAR ls m me mb r n e Ho rmo n e - rec eptor complex e w p ro tei n The steroid hormone testosterone psses through the plsm membrne. Te s to s te r o n e binds to receptor in the cytoplsm, ctivting it. The hormone- receptor complex enters the nuc leus nd binds to specific genes. 4 The bound stimultes the trns c ription of the gene into mra. 5 The mra is trnslted into specific.

3 i i s in the lsm Membrne There re three min types of membrne receptors G--linked G--linked receptors Segment tht intercts with G p rote i n s -binding site 7 TM Rs osine kinses Ion chnnel G--linked CYTOLASM lsm Membrne α, β nd γ units GD G- (inctive) Enzyme Activted GD GT Inctivte enzyme Ac tiv ted enzyme GT GD i Cellulr response tyrosine kinses Ion chnnel receptors (lignd) Gte closed Ions -binding site Helix in the Membrne mo l e c u l e Lignd-gted ion chnnel receptor lsm Membrne osines Gte open CYTOLASM tyrosine kinse s (inc tiv e monomers ) Dimer Activted rely s Cellulr response 6 AT 6 AD Cellulr response Cellulr response Gte close Activted tyrosinekinse regions (unphosphorylted dimer) Fully ctivted receptor tyrosine-kinse (phosphorylted dimer) rely s Trnsduction: Cscdes of moleculr interctions rely signls from receptors to trget s in the cell Multistep pthwys cn mplify signl provide more opportunities for coordintion nd regultion Trnsduction thwys At ech step in pthwy the signl is trnsduced into different form, commonly conformtionl chnge in rotein hosphoryltion nd Dephosphoryltion Mny signl pthwys include phosphoryltion cscdes In this process series of kinses dd phosphte to the next one in line, ctivting it; phosphtse enzymes then remove the phosphtes A phosphoryltion cscde Re c e p tor kinse kinse kinse kinse 5 Enz y mes c lled phosphtses () ctlyze the removl of the phosphte groups from the s, mking them inctive nd vilble for reuse. Activted rely mo l e c u l e AT AD AT A rely molec ule ctivtes kinse. kinse AD i Active kinse trnsfers phosphte from AT to n inctive of kinse, thus ctivting this second kinse. AT kinse AD Active kinse then ctlyzes the phosphoryltion (nd ctivtion) of kinse. 4 Finlly, ctive kinse phosphoryltes (pink) tht brings bout the cell s response to the signl. Ce l l u l r res pons e

4 Smll Molecules nd Ions s Second Messengers Second messengers re smll, non, wter-soluble s or ions Mny G-s trigger the formtion of cam, which then cts s second messenger in cellulr pthwys Cyclic AM Cyclic AM (cam) is mde from AT Fir st m essenger (signl such s epinephrine) G Adenylyl cyclse G--linke d receptor GT H H H O O O O Adenylyl cyclse hoshodiesterse O O O O Ch HO O CH O - O - O - O O CH O O O - O yrophosphte HO i O - O OH OH OH OH OH AT Cyclic AM AM AT cam Cellulr responses rotein kinse A Clcium ions nd Inositol Triphosphte (I ) Clcium, when relesed into the cytosol of cell Clcium ling A s ignl molec ule binds to receptor, leding to ctivtion of phospholipse C. hos pholipse C c leves plsm membrne phospholipid clled I into DAG nd I. (dicylglycerol) DAG fun c tio n s s second messenger in other pthwys. cts s second messenger in mny different pthwys Clcium is n importnt second messenger becuse cells re ble to regulte its concentrtion in the cytosol Other second messengers such s inositol triphosphte (e.g. I ) nd dicylglycerol (DG) cn trigger n increse in clcium in the cytosol EXTRACELLULAR CYTOSOL AT AT C + pum p C + pum p Mitochondrion ucleus Endoplsmic reticulum (ER) lsm membrne C + pum p Key High [C + ] Low [C + ] EXTRA- CELLULAR Endoplsmic reticulum (ER) G--linked receptor (first messenger) I -gted clcium chnnel C + C + G GT (s ec ond me s s e n g e r) hospholipse C Vrious s ctivted 4 I quickly diffuses through 5 Clc ium ions flow out of 6 The clcium ions the cytosol nd binds to n I the ER (down their concentrtion grdient), rising in one or more ctivte the next gted clcium chnnel in the ER membrne, cusing it to open. the C + level in the cytosol. signling pthwys. I DAG I (s ec ond mes s enger) Cellulr response Fine-Tuning of the Response pthwys with multiple steps cn mplify the signl nd contribute to the specificity of the response Amplifiction Ech in signling pthwy mplifies the signl by ctivting multiple copies of the next component in the pthwy The Specificity of Cell ing The different combintions of s in cell give the cell gret specificity in both the signls it detects nd the responses it crries out Response: Cell signling leds to regultion of cytoplsmic ctivities or trnscription Cytoplsmic nd ucler Responses In the cytoplsm ing pthwys regulte vriety of cellulr ctivities signl mplifiction: Re c e ption Binding of epinephrine to G--linked receptor ( ) Trnsduction G denylyl cyclse Re s ponse G (0 mo l e c ul e s) deny lyl c yc ls e (0 ) kinse A phosphorylse kinse k ins e A (0 4 ) phos phorylse k inse (0 5 ) glycogen phosphorylse gly c ogen phos phory ls e (0 6 ) Gl y c o g e n Gl u c o s e --phosphte Cytoplsmic response to signl Glucose-6-phos ph t e <--- AT Cy c l i c AM ( 0 4 ) (0 8 mo l e c u l e s ) Glucolysis<--- 4

5 thwy brnching nd cross-tlk Other pthwys Growth fctor Re c e ption regulte genes by ctivting trnscription fctors tht turn genes on or off further help the cell to coordinte incoming signls Si g n l mo l e c u l e h o s p h o ry l ti o n Re c e p to r c s c de Tr ns duc tion Re l y mo l e c u l e s CYTOLASM Cell A. thwy leds Re s p o n s e Re s p o n s ere s p o n s e to single response trnscription fctor Active trnscription fctor Cell B. thwy brnches, leding to two responses Re s pons e Ac ti v ti o n o r i n h i b i ti o n DA Gene Cell C. Cross-tlk occurs UCLEUS Re s p o n s e 4 between two pthwys mra Re s p o n s e 5 Cell D. Different receptor leds to different response ing Efficiency: Scffolding roteins nd ing Complexes Scffolding s cn increse the signl trnsduction efficiency Termintion of the response is terminted quickly lsm membrne by the reversl of lignd binding Scffolding Three different kinses Tking home messge homework Estrogen signlling s exmple: Estrogen receptors re group of s found inside cells. They re receptors tht re ctivted by the hormone estrogen (7β-estrdiol). Two clsses of estrogen receptor exist: ER, which is member of the nucler hormone fmily of intrcellulr receptors, nd GER (GR0), which is member of the rhodopsin-like fmily of G -coupled receptors. Once ctivted by estrogen, the ER is ble to trnslocte into the nucleus nd bind to DA to regulte the ctivity of different genes (i.e. it is DA-binding trnscription fctor). However, it lso hs dditionl functions independent of DA binding. 5

6 Intr- vs Extr Cellulr Ion concentrtions for e.g. neuronl cell for e.g.: +, K +, C +, Cl -, 6